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  • 1.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

  • 2.
    Al-Amin, Rasel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for Life Laboratory, SciLifeLab, Science for Life Laboratory, SciLifeLab.
    Johansson, Lars
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Blokzijl, Andries
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Dept. Of Immunology, Genetics and Pathology,.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Target Engagement-Mediated Amplification for Monitoring Drug-Target Interactions in SituManuscript (preprint) (Other academic)
    Abstract [en]

    It is important to determine the localization of drugs or drug candidates at cellular and subcellular resolution in relevant clinical specimens. This is necessary to evaluate drug candidates from early stages of drug development to clinical evaluation of mutations potentially causing resistance to targeted therapy. We describe a technology where oligonucleotide-conjugated drug molecules are used to visualize and measure target engagement in situ via rolling-circle amplification (RCA) of circularized oligonucleotide probes (padlock probes). We established this target engagement-mediated amplification (TEMA) technique using kinase inhibitor precursor compounds, and we applied the assay to investigate target interactions by microscopy in pathology tissue sections and using flow cytometry for blood samples from patients, as well as in commercial arrays including almost half of all human proteins.  In the variant proxTEMAtechnique, in situ proximity ligation assays were performed by combining drug-DNA conjugates with antibody-DNA conjugates to specifically reveal drug binding to particular on- or off-targets in pathological tissues sections. In conclusion, the TEMA methods successfully visualize drug-target interaction by experimental and clinically approved kinase inhibitors in situ and with kinases among a large collection of arrayed proteins. 

  • 3.
    Albrecht, Inka
    et al.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wick, Cecilia
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Tjarnlund, Anna
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Nagaraju, Kanneboyina
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Andrade, Felipe
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA..
    Thompson, Kathryn
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Coley, William
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Phadke, Aditi
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Diaz-Gallo, Lina-Marcela
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Bottai, Matteo
    Karolinska Inst, Inst Environm Med, Unit Biostat, SE-17176 Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Inst, Dept Lab Med, SE-17176 Stockholm, Sweden..
    Chemin, Karine
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Johansson, Karin
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wikberg, Anders
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Ytterberg, A. Jimmy
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Danielsson, Olof
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Neurol, Linkoping, Sweden..
    Krystufkova, Olga
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Vencovsky, Jiri
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med Solna, Expt Rheumatol Unit, SE-17176 Stockholm, Sweden..
    Padyukov, Leonid
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Lundberg, Ingrid E.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 12, p. 4612-4624Article in journal (Refereed)
    Abstract [en]

    Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

  • 4.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Punga, Anna Rostedt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Correlation of Botulinum Toxin Dose with Neurophysiological Parameters of Efficacy and Safety in the Glabellar Muscles: A Double-blind, Placebo-controlled, Randomized Study2014In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 94, no 1, p. 32-37Article in journal (Refereed)
    Abstract [en]

    Despite the extensive use of botulinum toxin type A (BoNT-A) in treatments for glabellar frown lines, the dose-response effect in the glabellar muscles remains unknown. The aim of this randomized, double-blind, placebo-controlled prospective study was to characterize the neurophysiological parameters that correlate with the effect of BoNT-A in the glabellar muscles and its diffusion to surrounding ocular muscles. Sixteen healthy women were recruited and randomized to 3 different dose-groups of onabotulinumtoxin A (Vistabel (R)) or placebo and followed 24 weeks by neurophysiological examinations. Efficacy of treatment on corrugator supercilii muscles was measured by compound motor action potential (CMAP) and electromyography (EMG). Photographs were used to score glabellar frown lines. Diffusion of the drug to surrounding muscles was assessed by CMAP of the nasalis muscle, EMG and concentric needle electrode jitter analysis (CNE) of the orbicularis oculi muscle. CMAP reduction correlated well with intramuscular BoNT-A dose. Muscle paralysis, measured by EMG, began from 2 weeks and was not entirely reversed at 24 weeks in individuals who received high dose of onabotulinumtoxin. Limited diffusion of orbicularis oculi was detected with CNE. In conclusion, we developed a novel neurophysiological strategy for effect evaluation of BoNT-A in glabellar muscles. CMAP and EMG correlated with given BoNT-A dose and are more defined effect measures than clinical glabellar photo scales.

  • 5. Bjornsdottir, Sigridur
    et al.
    Oksnes, Marianne
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Methlie, Paal
    Nilsen, Roy M.
    Hustad, Steinar
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Hulting, Anna-Lena
    Husebye, Eystein S.
    Lovas, Kristian
    Nystrom, Thomas
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Circadian hormone profiles and insulin sensitivity in patients with Addison's disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 1, p. 28-35Article in journal (Refereed)
    Abstract [en]

    ContextConventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). ObjectiveThe aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. Design and settingAn open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. PatientsTen Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. InterventionThrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. Main outcome measureWe measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. ResultsContinuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. ConclusionContinuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD.

  • 6. Bjornsdottir, Sigridur
    et al.
    Sundstrom, Anders
    Ludvigsson, Jonas F.
    Blomqvist, Paul
    Kampe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Drug Prescription Patterns in Patients With Addison's Disease: A Swedish Population-Based Cohort Study2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 5, p. 2009-2018Article in journal (Refereed)
    Abstract [en]

    Context: There are no published data on drug prescription in patients with Addison's disease ( AD). Objective: Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls. Design and Setting: We conducted a population-based cohort study in Sweden. Patients: Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population. Main Outcome Measure: We determined the ratio of observed to expected number of patients treated with prescribed drugs. Results: Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD. Conclusion: Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.

  • 7.
    Blokzijl, Andries
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chen, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafsdottir, Sigrun M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vuu, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Hedstrand, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0154214Article in journal (Refereed)
    Abstract [en]

    Background

    The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder.

    Objectives

    To investigate SOX10 as a potential biomarker for melanoma and vitiligo.

    Methods

    In this study we have applied proximity ligation assay (PLA) to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes.

    Results

    The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically.

    Conclusions

    We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically.

  • 8. Bratland, Eirik
    et al.
    Magitta, Ng'weina Francis
    Wolff, Anette Susanne Boe
    Ekern, Trude
    Knappskog, Per Morten
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Haavik, Jan
    Husebye, Eystein Sverre
    Autoantibodies against aromatic amino acid hydroxylases in patients with autoimmune polyendocrine syndrome type 1 target multiple antigenic determinants and reveal regulatory regions crucial for enzymatic activity2013In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 218, no 6, p. 899-909Article in journal (Refereed)
    Abstract [en]

    Patients with autoimmune polyendocrine syndrome type 1 (APS-1) frequently have autoantibodies directed against the aromatic amino acid hydroxylases tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH). We aimed to characterize these autoantibodies with regard to their antigenic determinants, their influence on enzymatic activity and their clinical associations. In particular, we wanted to compare autoantibodies against the two different isoforms of TPH, which display different tissue distribution. Using sera from 48 Scandinavian APS-1 patients we identified 36 patients (75%) with antibodies against one or more of these three enzymes. Antibodies against TPH1, but not TPH2, were associated with malabsorption in the whole Scandinavian cohort, while TH antibodies were associated with dental enamel hypoplasia in Norwegian patients. Subsequent experiments with selected patient sera indicated that while the C-terminal domain was the immunodominant part of TPH1, the epitopes of TPH2 and TH were mainly located in the N-terminal regulatory domains. We also identified a TPH1 specific epitope involved in antibody mediated inhibition of enzyme activity, a finding that provides new insight into the enzymatic mechanisms of the aromatic amino acid hydroxylases and knowledge about structural determinants of enzyme autoantigens. In conclusion, TPH1,TPH2 and TH all have unique antigenic properties in spite of their structural similarity. 

  • 9.
    Bremer, Hanna D.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden..
    Sjöberg, Ronald
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Hallgren, Åsa
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden..
    Renneker, Stefanie
    Euroimmun AG, D-23560 Lubeck, Germany..
    Lattwein, Erik
    Euroimmun AG, D-23560 Lubeck, Germany..
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Lilliehöök, Inger
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst Harvard & MIT, Cambridge, USA..
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway.;Univ Bergen, KG Jebsen Ctr Autoimmune Disorders, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Hansson-Hamlin, Helene
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4852Article in journal (Refereed)
    Abstract [en]

    Dogs can spontaneously develop complex systemic autoimmune disorders, with similarities to human autoimmune disease. Autoantibodies directed at self-antigens are a key feature of these autoimmune diseases. Here we report the identification of interleukin enhancer-binding factors 2 and 3 (ILF2 and ILF3) as autoantigens in canine immune-mediated rheumatic disease. The ILF2 autoantibodies were discovered in a small, selected canine cohort through the use of human protein arrays; a method not previously described in dogs. Subsequently, ILF3 autoantibodies were also identified in the same cohort. The results were validated with an independent method in a larger cohort of dogs. ILF2 and ILF3 autoantibodies were found exclusively, and at a high frequency, in dogs that showed a speckled pattern of antinuclear antibodies on immunofluorescence. ILF2 and ILF3 autoantibodies were also found at low frequency in human patients with SLE and Sjogren's syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.

  • 10.
    Brozzetti, Annalisa
    et al.
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morelli, Silvia
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Minarelli, Viviana
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Giordano, Roberta
    Univ Turin, Dept Med Sci, Div Endocrinol Diabetol & Metab, I-10126 Turin, Italy..
    De Bellis, Annamaria
    Univ Naples 2, Endocrinol Unit, Dept Cardiothorac & Resp Sci, I-80132 Naples, Italy..
    Perniola, Roberto
    V Fazzi Reg Hosp, Dept Pediat Neonatal Intens Care, I-73100 Lecce, Italy..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falorni, Alberto
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy.
    Autoantibody Response Against NALP5/MATER in Primary Ovarian Insufficiency and in Autoimmune Addison's Disease2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 5, p. 1941-1948Article in journal (Refereed)
    Abstract [en]

    Context: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. Objectives: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. Methods: Autoantibodies against NALP5/MATER and inhibin chains-alpha and -beta A were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. Results: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-alpha/beta A autoantibodies. Conclusions: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.

  • 11.
    Bruserud, Oyvind
    et al.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Oftedal, Bergithe E.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden..
    Erichsen, Martina M.
    Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Bratland, Eirik
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Lima, Kari
    Akershus Univ Hosp, Dept Med, N-1747 Nordbyhagen, Norway.;Oslo Univ Hosp, Dept Endocrinol, N-0372 Oslo, Norway..
    Jorgensen, Anders P.
    Oslo Univ Hosp, Dept Endocrinol, N-0372 Oslo, Norway..
    Myhre, Anne G.
    Oslo Univ Hosp, Dept Pediat, N-0424 Oslo, Norway..
    Svartberg, Johan
    Univ Hosp North Norway, Div Internal Med, N-9019 Tromso, Norway.;Artic Univ Norway, Univ Tromso, Inst Clin Med, N-9019 Tromso, Norway..
    Fougner, Kristian J.
    St Olavs Hosp, Dept Endocrinol, N-7006 Trondheim, Norway..
    Bakke, Asne
    Stavanger Univ Hosp, Dept Med, N-4011 Stavanger, Norway..
    Nedrebo, Bjorn G.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haugesund Hosp, Dept Med, N-5504 Haugesund, Norway..
    Mella, Bjarne
    Ostfold Hosp, Dept Med, N-1603 Fredrikstad, Norway..
    Breivik, Lars
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Viken, Marte K.
    Oslo Univ Hosp, Dept Immunol, N-0372 Oslo, Norway.;Univ Oslo, N-0372 Oslo, Norway..
    Knappskog, Per M.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway..
    Marthinussen, Mihaela C.
    Univ Bergen, Fac Med & Dent, Dept Clin Dent, N-5021 Bergen, Norway.;Oral Hlth Ctr Expertise Western Norway, N-5021 Bergen, Norway..
    Lovas, Kristian
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Kampe, Olle
    Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden..
    Wolff, Anette B.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Husebye, Eystein S.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 12016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 8, p. 2975-2983Article in journal (Refereed)
    Abstract [en]

    Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016). Patients: All known Norwegian patients with APS1. Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceasedsiblingswithahighprobability of undisclosed APS1. All except three had interferon-omega) autoantibodies, and allhadorgan-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-omega) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

  • 12.
    Cui, Tao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Hurtig, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Elgue, Graciela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Veronesi, Giulia
    Essaghir, Ahmed
    Demoulin, Jean-Baptiste
    Pelosi, Giuseppe
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Öberg, Kjell
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Giandomenico, Valeria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 12, p. e16010-Article in journal (Refereed)
    Abstract [en]

    Background: Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. Methodology/Principal Findings: A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC), to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. Conclusion: Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors.

     

  • 13.
    Dahlqvist, Per
    et al.
    Umea University.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Bensing, Sophie
    Karolinska Institute.
    Is Adrenal Insufficiency a Rare Disease?2016In: Cortisol Excess And Insufficiency / [ed] Arvat, E; Falorni, A, KARGER , 2016, p. 106-114Chapter in book (Refereed)
    Abstract [en]

    Adrenal insufficiency (AI) is a potentially life-threatening condition and it is of utmost importance to identify and adequately manage affected individuals. Diagnosis is often delayed, probably partly because diseases of the adrenal or pituitary region that cause primary AI (PAI) or central AI are relatively rare conditions. However, iatrogenic AI, i.e. the physiological downregulation of the hypothalamic-pituitary-adrenal axis and adrenal atrophy caused by glucocorticoid treatment for different inflammatory conditions is likely to be considerably more common. The type of glucocorticoid, dose and duration of treatment are factors to consider when trying to predict the risk of developing symptoms of AI. However, the considerable individual variation in the sensitivity for developing iatrogenic AI impedes prediction. In industrialized countries, autoimmune adrenalitis accounts for the majority of cases of PAI. Among children, genetic conditions - in particular congenital adrenal hyperplasia - need to be considered. Important risk groups for central AI are patients with tumours in the hypothalamic-pituitary region, moderate-to-severe traumatic head injury and patients who receive cranial radiotherapy or cytotoxic T-lymphocyte antigen 4 blockade treatment. Structured endocrine follow-up is essential in these groups. Health workers need to be attentive to these potentially fatal conditions and at-risk populations should be carefully informed about symptoms and signs of AI.

  • 14.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Adamus, Grazyna
    Oregon Hlth & Sci Univ, Casey Eye Inst, Ocular Immunol Lab, Portland, OR 97201 USA..
    Yang, Sufang
    Oregon Hlth & Sci Univ, Casey Eye Inst, Ocular Immunol Lab, Portland, OR 97201 USA..
    Landgren, Eva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hallgren, Åsa
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hugosson, Therese
    Lund Univ, Dept Clin Sci, Ophthalmol, Lund, Sweden..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Eriksson, Daniel
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Andreasson, Sten
    Lund Univ, Dept Clin Sci, Ophthalmol, Lund, Sweden..
    Tabbara, Khalid F.
    Ctr Eye, Riyadh, Saudi Arabia..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy2016In: Ophthalmology (Rochester, Minn.), ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Other academic)
  • 15.
    Dalin, Frida
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Adamus, Grazyna
    Yang, Sufang
    Landgren, Eva
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hallgren, Åsa
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hugosson, Therése
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Daniel
    Andreasson, Sten
    Tabbara, Khalid F.
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Alimohammadi, Mohammad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy2016In: Ophthalmology (Rochester, Minn.), ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Refereed)
  • 16.
    Dalin, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Nordling Eriksson, Gabriel
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Hallgren, Åsa
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Wahlberg, Jeanette
    Linkoping Univ, Div Endocrinol, Dept Med & Hlth Sci, Fac Hlth Sci, SE-58183 Linkoping, Sweden.
    Ekwall, Olov
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Söderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olcén, Per
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Winqvist, Ola
    Karolinska Inst, Karolinska Univ Hosp, Translat Immunol, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Catrina, Sergiu-Bogdan
    Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Kriström, Berit
    Umea Univ, Inst Clin Sci, Pediat, SE-90736 Umea, Sweden.
    Laudius, Maria
    Umea Univ, Dept Publ Hlth & Clin Med, SE-90736 Umea, Sweden.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Halldin Stenlid, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Gebre-Medhin, Gennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Björnsdottir, Sigridur
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Janson, Annika
    Karolinska Inst, Dept Womens & Childrens Hlth, SE-17176 Stockholm, Sweden.
    Åkerman, Anna-Karin
    Univ Orebro, Dept Lab Med, SE-70281 Orebro, Sweden.
    Åman, Jan
    Univ Orebro, Dept Pediat, Fac Med & Hlth, SE-70281 Orebro, Sweden.
    Duchen, Karel
    Linkoping Univ, Div Pediat, Dept Clin & Expt Med, SE-58183 Linkoping, Sweden.
    Bergthorsdottir, Ragnhildur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Inst Med, SE-40530 Gothenburg, Sweden; Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Sahlgrenska Acad, SE-40530 Gothenburg, Sweden.
    Lindskog, Emma
    Univ Gothenburg, Dept Pediat, Inst Clin Sci, SE-40530 Gothenburg, Sweden.
    Landin-Olsson, Mona
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Elfving, Maria
    Lund Univ, Dept Pediat, Pediat Endocrinol, Clin Sci, SE-22362 Lund, Sweden.
    Waldenström, Erik
    Skane Univ Hosp, Dept Endocrinol, SE-22362 Lund, Sweden.
    Hulting, Anna-Lena
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden; Karolinska Inst, Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, SE-17176 Stockholm, Sweden.
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 379-389Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 17. Dawoodji, Amina
    et al.
    Chen, Ji-Li
    Shepherd, Dawn
    Dalin, Frida
    Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Tarlton, Andrea
    Alimohammadi, Mohammad
    Penna-Martinez, Marissa
    Meyer, Gesine
    Mitchell, Anna L.
    Gan, Earn H.
    Bratland, Eirik
    Bensing, Sophie
    Husebye, Eystein S.
    Pearce, Simon H.
    Badenhoop, Klaus
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cerundolo, Vincenzo
    High Frequency of Cytolytic 21-Hydroxylase-Specific CD8(+) T Cells in Autoimmune Addison's Disease Patients2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 5, p. 2118-2126Article in journal (Refereed)
    Abstract [en]

    The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs <= 20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.

  • 18. Ek, Weronica
    et al.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Crooks, Lucy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Sgonc, Roswitha
    Dietrich, Hermann
    Wick, Georg
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mapping QTL affecting a systemic sclerosis-like disorder in a cross between UCD-200 and red jungle fowl chickens2012In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 38, no 2, p. 352-359Article in journal (Refereed)
    Abstract [en]

    Systemic sclerosis (SSc) or scleroderma is a rare, autoimmune, multi-factorial disease characterized by early microvascular alterations, inflammation, and fibrosis. Chickens from the UCD-200 line develop a hereditary SSc-like disease, showing all the hallmarks of the human disorder, which makes this line a promising model to study genetic factors underlying the disease. A backcross was generated between UCD-200 chickens and its wild ancestor - the red jungle fowl and a genome-scan was performed to identify loci affecting early (21days of age) and late (175days of age) ischemic lesions of the comb. A significant difference in frequency of disease was observed between sexes in the BC population, where the homogametic males were more affected than females, and there was evidence for a protective W chromosome effect. Three suggestive disease predisposing loci were mapped to chromosomes 2, 12 and 14. Three orthologues of genes implicated in human SSc are located in the QTL region on chromosome 2, TGFRB1, EXOC2-IRF4 and COL1A2, as well as CCR8, which is more generally related to immune function. IGFBP3 is also located within the QTL on chromosome 2 and earlier studies have showed increased IGFBP3 serum levels in SSc patients. To our knowledge, this study is the first to reveal a potential genetic association between IGFBP3 and SSc. Another gene with an immunological function, SOCS1, is located in the QTL region on chromosome 14. These results illustrate the usefulness of the UCD-200 chicken as a model of human SSc and motivate further in-depth functional studies of the implicated candidate genes.

  • 19.
    Eriksson, D.
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, G. N.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zetterqvist, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Farias, F. H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, S. R.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Soderkvist, P.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hulting, A. -L
    Wahlberg, J.
    Linkoping Univ, Dept Endocrinol, Dept Med & Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden..
    Ekwall, O.
    Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden.;Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Dahlqvist, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bensing, S.
    Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Pielberg, Gerli R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed)
    Abstract [en]

    BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

  • 20.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Bacchetta, Rosa
    Stanford Univ, Dept Pediat, Sch Med, Div Stem Cell Transplantat & Regenerat Med, Stanford, CA 94305 USA.
    Gunnarsson, Hörður Ingi
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Chan, Alice
    Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA.
    Barzaghi, Federica
    IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy, Pediat Immunohematol & Bone Marrow Transplantat U, Milan, Italy.
    Ehl, Stephan
    Univ Freiburg, Freiburg Univ Hosp, Ctr Chron Immunodeficiency, Fac Med, Freiburg, Germany.
    Hallgren, Åsa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    van Gool, Frederic
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Sardh, Fabian
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Lundqvist, Christina
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden.
    Laakso, Saila M.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Ekwall, Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.
    Mäkitie, Outi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden;Folkhalsan Inst Genet, Helsinki, Finland;Univ Helsinki, Helsinki, Finland.
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Husebye, Eystein S.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Med, Bergen, Norway;KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Anderson, Mark
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Kämpe, Olle
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    The autoimmune targets in IPEX are dominated by gut epithelial proteins2019In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 144, no 1, p. 327-330Article in journal (Other academic)
  • 21.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Skov, Jakob
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Soderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hulting, Anna-Lena
    Wahlberg, Jeanette
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Endocrinol, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kampe, Olle
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 22.
    Falorni, Alberto
    et al.
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Bini, Vittorio
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Betterle, Corrado
    Univ Padua, Dept Med, Endocrine Unit, Padua, Italy..
    Brozzetti, Annalisa
    Univ Perugia, Dept Med, I-06126 Perugia, Italy..
    Castano, Luis
    Univ Basque Country, Cruces Univ Hosp, Ciberdem, BioCruces, Bilbao, Spain..
    Fichna, Marta
    Poznan Univ Med Sci, Dept Endocrinol & Metab, Poznan, Poland.;Polish Acad Sci, Inst Human Genet, PL-60479 Poznan, Poland..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mellgren, Gunnar
    Haukeland Hosp, Hormone Lab, N-5021 Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Peterson, Pärt
    Univ Tartu, Inst Biomed & Translat Med, Mol Pathol, EE-50090 Tartu, Estonia..
    Chen, Shu
    RSR Ltd, FIRS Labs, Cardiff, S Glam, Wales..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seissler, Jochen
    Klinikum Univ Munchen, Med Klin & Poliklin 4, Diabet Zentrum, Munich, Germany..
    Tiberti, Claudio
    Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy..
    Uibo, Raivo
    Univ Tartu, Inst Biomed & Translat Med, Dept Immunol, EE-50090 Tartu, Estonia..
    Yu, Liping
    Univ Colorado Denver, Barbara Davis Ctr Diabet, Aurora, CO USA..
    Lernmark, Åke
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Malmo, Sweden..
    Husebye, Eystein
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Determination of 21-hydroxylase autoantibodies: inter-laboratory concordance in the Euradrenal International Serum Exchange Program2015In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 53, no 11, p. 1761-1770Article in journal (Refereed)
    Abstract [en]

    Background: 21-Hydroxylase autoantibodies (21OHAb) are markers of an adrenal autoimmune process that identifies individuals with autoimmune Addison's disease (AAD). Quality and inter-laboratory agreement of various 21OHAb tests are incompletely known. The objective of the study was to determine inter-laboratory concordance for 21OHAb determinations. Methods: Sixty-nine sera from 51 patients with AAD and 51 sera from 51 healthy subjects were blindly coded by a randomization center and distributed to 14 laboratories that determined 21OHAb, either by an "in-house" assay (n=9) using in vitro-translated S-35-21OH or luciferase-labeled 21OH or a commercial kit with I-125-21OH (n=5). Main outcome measures were diagnostic accuracy of each participating laboratory and inter-laboratory agreement of 21OHAb assays. Results: Intra-assay coefficient of variation ranged from 2.6% to 5.3% for laboratories using the commercial kit and from 5.1% to 23% for laboratories using "in-house" assays. Diagnostic accuracy, expressed as area under ROC curve (AUC), varied from 0.625 to 0.947 with the commercial kit and from 0.562 to 0.978 with "in-house" methods. Cohen's. of inter-rater agreement was 0.603 among all 14 laboratories, 0.691 among "in-house" laboratories, and 0.502 among commercial kit users. Optimized cutoff levels, calculated on the basis of AUCs, increased the diagnostic accuracy of every laboratory (AUC >0.9 for 11/14 laboratories) and increased the Cohen's. of inter-rater agreement. Discrepancies in quantitation of 21OHAb levels among different laboratories increased with increasing autoantibody levels. Conclusions: The quality of 21OHAb analytical procedures is mainly influenced by selection of cutoff value and correct handling of assay materials. A standardization program is needed to identify common standard sera and common measuring units.

  • 23. Husebye, E. S.
    et al.
    Allolio, B.
    Arlt, W.
    Badenhoop, K.
    Bensing, S.
    Betterle, C.
    Falorni, A.
    Gan, E. H.
    Hulting, A. -L
    Kasperlik-Zaluska, A.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Lovas, K.
    Meyer, G.
    Pearce, S. H.
    Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 2, p. 104-115Article, review/survey (Refereed)
    Abstract [en]

    Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.

  • 24.
    Isaksson, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Ardesjö Lundgren, Brita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Ahlgren, Kerstin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE2012In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 42, no 10, p. 2555-2563Article in journal (Refereed)
    Abstract [en]

    EAE, an animal model for multiple sclerosis, is a Th17- and Th1-cell-mediated auto-immune disease, but the mechanisms leading to priming of encephalitogenicTcells in autoimmune neuroinflammation are poorly understood. To investigate the role of dendritic cells (DCs) in the initiation of autoimmuneTh17- andTh1-cell responses andEAE, we used mice transgenic for a simian diphtheria toxin receptor (DTR) expressed under the control of the murineCD11c promoter (CD11c-DTRmice onC57BL/6 background).EAEwas induced by immunization with myelin oligodendrocyte glycoprotein (MOG) protein in CFA. DCs were depleted on the day before and 8 days afterMOG immunization. The mean clinicalEAEscore was only mildly reduced inDC-depleted mice when DCs were ablated beforeEAEinduction. The frequency of activatedTh cells was not altered, andMOG-inducedTh17 orTh1-cell responses were not altered, in the spleens ofDC-depleted mice. Similar results were obtained ifDCswere ablated the first 10 days afterMOGimmunization with repeatedDCdepletions. Unexpectedly, transient depletion of DCs did not affect priming or differentiation of MOG-inducedTh17 andTh1-cell responses or the incidence ofEAE. Thus, the mechansim of priming ofTh cells inEAEremains to be elucidated.

  • 25. Johnsson, M.
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hoglund, A.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Jensen, P.
    Wright, D.
    The role of pleiotropy and linkage in genes affecting a sexual ornament and bone allocation in the chicken2014In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 23, no 9, p. 2275-2286Article in journal (Refereed)
    Abstract [en]

    Sexual selection and the ornaments that inform such choices have been extensively studied, particularly from a phenotypic perspective. Although more is being revealed about the genetic architecture of sexual ornaments, much still remains to be discovered. The comb of the chicken is one of the most widely recognized sexual ornaments, which has been shown to be correlated with both fecundity and bone allocation. In this study, we use a combination of multiple intercrosses between White Leghorn populations and wild-derived Red Junglefowl to, first, map quantitative trait loci (QTL) for bone allocation and, second, to identify expression QTL that correlate and colocalize with comb mass. These candidate quantitative genes were then assessed for potential pleiotropic effects on bone tissue and fecundity traits. We identify genes that correlate with both relative comb mass and bone traits suggesting a combination of both pleiotropy and linkage mediates gene regulatory variation in these traits.

  • 26. Johnsson, Martin
    et al.
    Gustafson, Ida
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Wright, Dominic
    A Sexual Ornament in Chickens Is Affected by Pleiotropic Alleles at HAO1 and BMP2, Selected during Domestication2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 8, p. e1002914-Article in journal (Refereed)
    Abstract [en]

    Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.

  • 27.
    Karlsson, Calr-Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Jansson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Inhalationssteroider kan ge sekundär binjurebarkssvikt2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 15, p. 674-675Article in journal (Other academic)
    Abstract [sv]

    Inhalationssteroider har under de senaste decennierna revolutionerat astmabehandlingen, men de har också i sporadiska fall (i första hand bland barn) medfört sekundär binjurebarkssvikt som oönskad bieffekt.

    Tre fallbeskrivningar av sekundär binjurebarkssvikt hos vuxna svenska astmatiker presenteras.

    Bakomliggande orsak bedömdes i samtliga fall vara användande av inhalationssteroider i höga doser.

  • 28.
    Kerje, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellman, Urban
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Do, Lan
    Umea Univ, Dept Med Chem & Biophys, Unit Res Educ & Dev Ostersund, Umea, Sweden..
    Larsson, Göran
    Umea Univ, Dept Med Chem & Biophys, Unit Res Educ & Dev Ostersund, Umea, Sweden..
    Kampe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Engstrom-Laurent, Anna
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Lindqvist, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Is low molecular weight hyaluronan an early indicator of disease in avian systemic sclerosis?2016In: Connective Tissue Research, ISSN 0300-8207, E-ISSN 1607-8438, Vol. 57, no 5, p. 337-346Article in journal (Refereed)
    Abstract [en]

    Aim of the study: To further elucidate the pathogenesis of systemic sclerosis (SSc) an experimental avian model was used. The University of California at Davis line 200 (UCD-200) chickens spontaneously develop a SSc-like disease that has most features of human SSc with vascular effects, inflammation, autoimmunity, and fibrosis. The first signs of disease in UCD-200 chickens are swelling and ischemic lesions of the comb and the presence of a tissue containing high amounts of glycosaminoglycan hyaluronan (HA). The aim of this study was to evaluate inflammatory and fibrotic processes of the disease with regard to the molecular weight of HA.Material and methods: Comb biopsies from UCD-200 and healthy White Leghorn (WL) chickens, as controls, at different ages were studied with the histochemical localization of HA, hyaluronidase-1 (Hyal-1), cluster of differentiation 3, immunoglobulin Y, and collagen I and III. The molecular weight distribution of HA was estimated with gas-phase electrophoretic analysis.Results: At 2 days of age, HA was visualized in UCD-200 chickens at the dermal part of the comb with no simultaneous staining of Hyal-1. In adult UCD-200 chickens, the comb skin was almost totally devoid of HA compared to WL chickens of the same age. An increase of low molecular weight (LMW) HA was detected in comb tissue from UCD-200 at the age of 1 day, 1 week, 2 weeks, and 4 weeks, in contrast to adult animals.Conclusions: An early inflammatory process involving LMW HA was confirmed as a possible profibrotic process. This indicates that HA might be an important participant in the early inflammatory events of SSc in UCD-200 chickens and that the disappearance of HA in skin predisposes to fibrosis.

  • 29.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Biomarker Discovery in Tissue-specific Autoimmune Disease2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autoimmune diseases encompass a diverse group of disorders that collectively affect 5% of the population. Despite large clinical variability, autoimmune disorders share a common etiology in that they all develop from immune responses against self. T-cell receptors and antibodies recognize distinct self-molecules and direct destructive effector mechanisms to the target organs. Characterization of autoimmune targets can help in the understanding autoimmune disease features and is of additional importance for subsequent use in clinical diagnosis.

    Rare monogenic disorder can provide an access to the study and understanding of mechanisms underlying common and more complex diseases. Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the AIRE gene, and is a valuable model of tissue-specific autoimmune disease. APS1 patients develop multiple autoimmune disease manifestations and display autoantibodies against the affected tissues.

    Recent development in protein array technology has opened a novel avenue for explorative biomarker studies in autoimmune disorders. Present-day protein arrays contain many thousands of full-length human proteins and enable autoantibody screens at the proteome-scale.

    In the current work I have utilized proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Survey of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of 9000 proteins we further identified three novel, major autoantigens. Our findings revealed a marked enrichment for tissue-specific immune targets and further suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1. This work identifies prostatic transglutaminase 4 as novel male-specific autoantigen. In the mouse model of APS1 we could link TGM4 immunity with a tissue-destructive prostatitis, a compromised prostatic secretion of TGM4 and with defect in the establishment of central immune tolerance for TGM4. Our findings suggest prostate autoimmunity is a major manifestation in male APS1 patients with potential role in development of subfertility. In this doctoral work we also report on collecting duct autoantibodies in APS1 patients with interstitial nephritis and on the identification of aquaporin 2 as a collecting duct autoantigen. Collectively, the present investigations provide an overview-perspective on the autoimmune target repertoire in APS1 and identify novel autoimmune manifestations of the syndrome.

  • 30.
    Landegren, Nils
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Pourmousa Lindberg, Mina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skov, Jakob
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Eriksson, Daniel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Lisberg Toft-Bertelsen, Trine
    Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
    MacAulay, Nanna
    Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Räisänen-Sokolowski, Anne
    Helsinki Univ Hosp, Dept Pathol, Helsinki, Finland.; Univ Helsinki, Helsinki, Finland.
    Saha, Heikki
    Tampere Univ Hosp, Sch Med, Dept Med, Tampere, Finland.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Ohlsson, Sophie
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Husebye, Eystein S
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, Bergen, Norway.; Haukeland Hosp, Dept Med, Bergen, Norway.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Anderson, Mark S
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Perheentupa, Jaakko
    Univ Helsinki, Hosp Children & Adolescents, Helsinki, Finland.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Fenton, Robert A
    Aarhus Univ, Dept Biomed, Interact Prot Epithelial Transport Ctr, Aarhus, Denmark.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.2016In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, no 10, p. 3220-3228Article in journal (Refereed)
    Abstract [en]

    Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

  • 31.
    Landegren, Nils
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.
    Rosen, Lindsey B.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Bioinformat Infrastruct, Dept Med Sci, Uppsala, Sweden.
    Eriksson, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Smith, Gustav
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;MIT, Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02139 USA;Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden.
    Ferre, Elise M. N.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Brodin, Petter
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, Stockholm, Sweden;Karolinska Univ Hosp, Dept Newborn Med, Stockholm, Sweden.
    Sharon, Donald
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Snyder, Michael
    Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden;Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Lionakis, Michail
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Anderson, Mark
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Kampe, Olle
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Univ Bergen, KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e43578Article in journal (Other academic)
    Abstract [en]

    The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.

  • 32.
    Landegren, Nils
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sharon, Donald
    Freyhult, Eva
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hallgren, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Daniel
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bensing, Sophie
    Wahlberg, Jeanette
    Nelson, Lawrence M
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Husebye, Eystein S
    Anderson, Mark S
    Snyder, Michael
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 12016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20104Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance.

  • 33.
    Landegren, Nils
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Sharon, Donald
    Shum, Anthony K.
    Khan, Imran S.
    Fasano, Kayla J.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ardesjo-Lundgren, Brita
    Alimohammadi, Mohammad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Rathsman, Sandra
    Ludvigsson, Jonas F.
    Lundh, Dan
    Motrich, Ruben
    Rivero, Virginia
    Fong, Lawrence
    Giwercman, Aleksander
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Perheentupa, Jaakko
    Husebye, Eystein S.
    Anderson, Mark S.
    Snyder, Michael
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Transglutaminase 4 as a prostate autoantigen in male subfertility2015In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 292, article id 292ra101Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.

  • 34. Ludvigsson, Jonas F.
    et al.
    Lebwohl, Benjamin
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Murray, Joseph A.
    Green, Peter H.
    Ekbom, Anders
    Risk of Thyroid Cancer in a Nationwide Cohort of Patients with Biopsy-Verified Celiac Disease2013In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 23, no 8, p. 971-976Article in journal (Refereed)
    Abstract [en]

    Background: In earlier studies based on selected populations, the relative risk for thyroid cancer in celiac disease has varied between 0.6 and 22.5. We aimed to test this relationship in a population-based setting. Methods: We collected small intestinal biopsy report data performed in 1969-2008 from all 28 Swedish pathology departments. 29,074 individuals with celiac disease (villous atrophy; Marsh histopathology stage III) were matched for sex, age, calendar year, and county to 144,440 reference individuals from the Swedish general population. Through Cox regression, we then estimated hazard ratios (HRs) and confidence intervals (CIs) for any thyroid cancer and papillary thyroid cancer (defined according to relevant pathology codes in the Swedish Cancer Register) in patients with celiac disease. Results: During follow-up, any thyroid cancer developed in seven patients with celiac disease (expected = 12) and papillary thyroid cancer developed in five patients (expected = 7). Celiac disease was not associated with an increased risk of any thyroid cancer (HR 0.6 [CI 0.3-1.3]) or of papillary thyroid cancer (HR 0.7 [CI 0.3-1.8]). All cases of thyroid cancer in celiac disease occurred in female patients. Risk estimates were similar before and after the year 2000 and independent of age at celiac diagnosis (<= 24 years vs. >= 25 years). Conclusions: We conclude that, in the Swedish population, there is no increased risk of thyroid cancer in patients with celiac disease. This differs from what has been reported in smaller studies in Italy and the United States.

  • 35.
    Marchesi, Silvia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Lattuada, M.
    Policlin Milano, Milan, Italy..
    Ortiz-Nieto, Francisco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Enhanced Abdominal Inflammation In Acute Respiratory Failure - Is The Culprit Ventilator Associated Abdominal Edema Or Inadequate Perfusion?: A Magnetic Resonance Imaging Pilot Study2015In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191Article in journal (Other academic)
  • 36. Mitchell, Anna L.
    et al.
    Macarthur, Katie D. R.
    Gan, Earn H.
    Baggott, Lucy E.
    Wolff, Anette S. B.
    Skinningsrud, Beate
    Platt, Hazel
    Short, Andrea
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Betterle, Corrado
    Kasperlik-Zaluska, Anna
    Zurawek, Magdalena
    Fichna, Marta
    Kockum, Ingrid
    Eriksson, Gabriel Nordling
    Ekwall, Olov
    Wahlberg, Jeanette
    Dahlqvist, Per
    Hulting, Anna-Lena
    Penna-Martinez, Marissa
    Meyer, Gesine
    Kahles, Heinrich
    Badenhoop, Klaus
    Hahner, Stephanie
    Quinkler, Marcus
    Falorni, Alberto
    Phipps-Green, Amanda
    Merriman, Tony R.
    Ollier, William
    Cordell, Heather J.
    Undlien, Dag
    Czarnocka, Barbara
    Husebye, Eystein
    Pearce, Simon H. S.
    Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e88991-Article in journal (Refereed)
    Abstract [en]

    Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.

  • 37. Oftedal, Bergithe E.
    et al.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Meager, Anthony
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Husebye, Eystein S
    Wolff, Anette S B
    Measuring autoantibodies against IL17F and IL-22 in  autoimmune polyendocrine syndromme type I by radioligand binding assay using fusion proteins2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, no 3, p. 327-333Article in journal (Refereed)
    Abstract [en]

    Autoantibodies against interleukin (IL)-17A, IL-17F and IL-22 have recently been described in patients with autoimmune polyendocrine syndrome type I (APS I), and their presence is reported to be highly correlated with chronic mucocutaneous candidiasis (CMC). The aim of this study was to develop a robust high-throughput radioligand binding assays (RLBA) measuring IL-17F and IL-22 antibodies, to compare them with current enzyme-linked immunosorbent assays (ELISA) of IL-17F and IL-22 and, moreover, to correlate the presence of these antibodies with the presence of CMC. Interleukins are small molecules, which makes them difficult to express in vitro. To overcome this problem, they were fused as dimers, which proved to increase the efficiency of expression. A total of five RLBAs were developed based on IL-17F and IL-22 monomers and homo- or heterodimers. Analysing the presence of these autoantibodies in 25 Norwegian APS I patients revealed that the different RLBAs detected anti-IL-17F and anti-IL-22 with high specificity, using both homo- and heterodimers. The RLBAs based on dimer proteins are highly reproducible with low inter- and intravariation and have the advantages of high throughput and easy standardization compared to ELISA, thus proving excellent choices for the screening of IL-17F and IL-22 autoantibodies.

  • 38. Oksnes, Marianne
    et al.
    Björnsdottir, Sigridur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Methlie, Paal
    Carlsen, Siri
    Nilsen, Roy M
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Triebner, Kai
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Hulting, Anna-Lena
    Bensing, Sophie
    Husebye, Eystein S
    Løvås, Kristian
    Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of addison's disease: a randomized clinical trial2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 5, p. 1665-1674Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm, which may have implications for morbidity and mortality in patients with Addison's disease.

    OBJECTIVE: The objective of the study was to compare the effects of continuous sc hydrocortisone infusion (CSHI) with conventional oral hydrocortisone (OHC) replacement therapy.

    DESIGN, PATIENTS, AND INTERVENTIONS: This was a prospective crossover, randomized, multicenter clinical trial comparing 3 months of treatment with thrice-daily OHC vs CSHI. From Norway and Sweden, 33 patients were enrolled from registries and clinics. All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm.

    MAIN OUTCOME MEASURES: The morning ACTH level was the primary outcome measure. Secondary outcome measures were effects on metabolism, health-related quality of life (HRQoL), sleep, and safety.

    RESULTS: CSHI yielded normalization of morning ACTH and cortisol levels, and 24-hour salivary cortisol curves resembled the normal circadian variation. Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI but were clearly altered with OHC. Several HRQoL indices in the vitality domain improved over time with CSHI. No benefit was found for either treatments for any subjective (Pittsburgh Sleep Quality Index questionnaire) or objective (actigraphy) sleep parameters.

    CONCLUSION: CSHI safely brought ACTH and cortisol toward normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did. Positive effects on HRQoL were noted with CSHI, indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy.

  • 39.
    Roy, Abhik
    et al.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA..
    Laszkowska, Monika
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lebwohl, Benjamin
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA..
    Green, Peter H. R.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, S-17177 Stockholm, Sweden..
    Ludvigsson, Jonas F.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY USA.;Karolinska Inst, Karolinska Univ Hosp, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.;Orebro Univ Hosp, Dept Paediat, Orebro, Sweden.;Univ Nottingham, Sch Med, Div Epidemiol & Publ Hlth, Nottingham, England..
    Prevalence of Celiac Disease in Patients with Autoimmune Thyroid Disease: A Meta-Analysis2016In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 26, no 7, p. 880-890Article in journal (Refereed)
    Abstract [en]

    Background: Several screening studies have indicated an increased prevalence of celiac disease (CD) among individuals with autoimmune thyroid disease (ATD), but estimates have varied substantially. Objective: The aim of this study was to examine the prevalence of CD in patients with ATD. Method: A systematic review was conducted of articles published in PubMed Medline or EMBASE until September 2015. Non-English papers with English-language abstracts were also included, as were research abstracts without full text available when relevant data were included in the abstract. Search terms included "celiac disease'' combined with "hypothyroidism'' or "hyperthyroidism'' or "thyroid disease.'' Fixed-effects inverse variance-weighted models were used. Meta-regression was used to examine heterogeneity in subgroups. Results: A pooled analysis, based on 6024 ATD patients, found a prevalence of biopsy-confirmed CD of 1.6% [ confidence interval (CI) 1.3-1.9%]. Heterogeneity was large (I-2 = 70.7%). The prevalence was higher in children with ATD (6.2% [ CI 4.0-8.4%]) than it was in adults (2.7%) or in studies examining both adults and children (1.0%). CD was also more prevalent in hyperthyroidism (2.6% [ CI 0.7-4.4%]) than it was in hypothyroidism (1.4% [ CI 1.0-1.9%]). Conclusions: About 1/62 patients with ATD have biopsy-verified CD. It is argued that patients with ATD should be screened for CD, given this increased prevalence.

  • 40.
    Saevik, Å. B.
    et al.
    Univ Bergen, Dept Clin Med, Bergen, Norway..
    Åkerman, A. -K
    Grönning, K.
    Akershus Univ Hosp, Div Med, Lorenskog, Norway..
    Nermoen, I.
    Akershus Univ Hosp, Div Med, Lorenskog, Norway.;Univ Oslo, Akershus Univ Hosp, Inst Clin Med, Lorenskog, Norway..
    Valland, S. F.
    Innlandet Hosp Trust, Div Endocrinol, Hamar, Norway..
    Finnes, T. E.
    Innlandet Hosp Trust, Div Endocrinol, Hamar, Norway..
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Dahlqvist, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Bergthorsdottir, R.
    Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.;Sahlgrens Acad, Inst Med, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Ekwall, O.
    Inst Clin Sci, Dept Pediat, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Skov, J.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karlstad City Hosp, Dept Med, Endocrine Div, Karlstad, Sweden..
    Nedrebö, B. G.
    Haugesund Hosp, Dept Med, Haugesund, Norway..
    Hulting, A. -L
    Wahlberg, J.
    Linkoping Univ, Fac Hlth Sci, Dept Med & Hlth Sci, Div Endocrinol, Linkoping, Sweden..
    Svartberg, J.
    Univ Hosp North Norway, Div Internal Med, Tromso, Norway.;Arctic Univ Norway, UiT, Tromso Endocrine Res Grp, Dept Clin Med, Tromso, Norway..
    Höybye, C.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Bleskestad, I. H.
    Stavanger Univ Hosp, Dept Internal Med, Stavanger, Norway..
    Jörgensen, A. P.
    Oslo Univ Hosp, Dept Endocrinol, Oslo, Norway..
    Kämpe, O.
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.;Solna Karolinska Inst, Dept Med, Stockholm, Sweden.;Univ Bergen, KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway..
    Öksnes, M.
    Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.;Solna Karolinska Inst, Dept Med, Stockholm, Sweden.;Haukeland Hosp, Dept Med, Bergen, Norway..
    Bensing, S.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Husebye, E. S.
    Univ Bergen, Dept Clin Med, Bergen, Norway.;Solna Karolinska Inst, Dept Med, Stockholm, Sweden.;Univ Bergen, KG Jebsen Ctr Autoimmune Disorders, Bergen, Norway.;Haukeland Hosp, Dept Med, Bergen, Norway..
    Clues for early detection of autoimmune Addison's disease - myths and realities2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 2, p. 190-199Article in journal (Refereed)
    Abstract [en]

    Background: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce.

    Objective: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD.

    Material and Methods: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values.

    Results: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L-1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L-1 [2-442]) than in those without (81 nmol L-1 [1-668], P < 0.001).

    Conclusion: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

  • 41.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Genetic Characterization of Chicken Models for Autoimmune Disease2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autoimmune diseases are endemic, but the disease mechanisms are poorly understood. A way to better understand these are to find disease-regulating genes. However, this is difficult as the diseases are complex, with several genes as well as environmental factors influencing the development of disease. A way to facilitate the search for genes responsible for the diseases is to use comparative genomic studies. Animal models are relatively easy to analyze since control of environment and breeding are obtained.

    The University of California at Davies – line 200 (UCD-200) chickens have a hereditary disease that is similar to systemic sclerosis. Using a backcross between UCD-200 chickens and red junglefowl (RJF) chickens we identified three loci linked to the disease. The loci contained immune-regulatory genes suggested to be involved in systemic sclerosis in humans, as well as a previously unidentified linkage between systemic sclerosis in UCD-200 chickens and IGFBP3.

    The Dark brown (Db) gene enhances red pheomelanin and restricts expression of eumelanin in chickens. The Db phenotype is regulated by an 8 kb deletion upstream of SOX10. Pigmentation studies are potentially useful when trying to identify pathogenic mechanisms and candidate genes in vitiligo

    The Obese strain (OS) of chickens spontaneously develops an autoimmune thyroiditis which closely resembles human Hashimoto’s thyroiditis. By using an intercross between OS chickens and RJF chickens, we found several disease phenotypes that can be used in an ongoing linkage analysis with the goal to find candidate genes for autoimmune disease. An important phenotype to record and add to the linkage analysis is autoantibodies against thyroid peroxidase, since this phenotype is a key feature in Hashimoto’s thyroiditis. Previous attempts to measure these titres in OS chickens have failed, hence an assay was developed for this purpose.

  • 42.
    Sahoo, Saroj K.
    et al.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Zaidi, Ghazala
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Srivastava, Rajni
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Clin Immunol, Lucknow, Uttar Pradesh, India..
    Sarangi, Aditya N.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bharti, Niharika
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Eriksson, Daniel
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Bensing, Sophie
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aggarwal, Amita
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Clin Immunol, Lucknow, Uttar Pradesh, India..
    Aggarwal, Rakesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bhatia, Eesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow 226014, Uttar Pradesh, India..
    Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism2016In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 4, p. 544-550Article in journal (Refereed)
    Abstract [en]

    Objective The prevalence of autoimmune polyendocrine syndrome type 1 (APS1) among isolated hypoparathyroidism (HP) or primary adrenal insufficiency (PAI) is not well established. We studied the frequency of APS1 in patients with HP or PAI by measuring interferon-alpha (IFN-alpha) antibody levels, a highly sensitive and specific marker for APS1. Design, patients and measurements In a single-centre cross-sectional study, 37 Indian patients with isolated HP and 40 patients with PAI were tested for IFN-alpha antibody using an indirect ELISA. In patients with elevated IFN-alpha antibody, the autoimmune regulator (AIRE) gene was bidirectionally sequenced. Results Three (8.1%) patients with isolated HP had elevated IFN-alpha antibody levels (range: 367-17382 units; positive titre >56 units). Homozygous or compound heterozygous AIRE mutations were detected in all three patients, including a novel mutation (p.T68P). All three APS1 patients had atypical features. The first patient, diagnosed at 7 years of age, died suddenly 5 months later. The second patient had late-onset HP (at the age of 34 years) and a solitary episode of transient mucocutaneous candidiasis 5 years later. The final patient developed HP at the age of 14 years and premature ovarian insufficiency 14 years later. Interleukin-22 antibodies, as well as most other organ-specific antibodies, were absent in the 3 APS1 patients. All patients with PAI were negative for IFN-alpha antibody. Conclusion Eight percentage of patients with isolated HP had elevated IFN-alpha antibody levels and AIRE mutation-positive APS1. All APS1 patients had atypical clinical features. Testing for IFN-alpha antibody should be considered in patients with idiopathic HP.

  • 43. Shum, Anthony K.
    et al.
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Tan, Catherine L.
    Cheng, Mickie H.
    Metzger, Todd C.
    Law, Christopher S.
    Lwin, Wint
    Perheentupa, Jaakko
    Bour-Jordan, Helene
    Carel, Jean Claude
    Husebye, Eystein S.
    De Luca, Filippo
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Sargur, Ravishankar
    Dubois, Noemie
    Kajosaari, Merja
    Wolters, Paul J.
    Chapman, Harold A.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Anderson, Mark S.
    BPIFB1 Is a Lung-Specific Autoantigen Associated with Interstitial Lung Disease2013In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 5, no 206, p. 206ra139-Article in journal (Refereed)
    Abstract [en]

    Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire(-/-) mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.

  • 44. Skogberg, Gabriel
    et al.
    Lundberg, Vanja
    Lindgren, Susanne
    Gudmundsdottir, Judith
    Sandstrom, Kerstin
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Sunnegardh, Jan
    van der Post, Sjoerd
    Telemo, Esbjorn
    Berglund, Martin
    Ekwall, Olov
    Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 5, p. 2187-2195Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.

  • 45.
    Smith, Casey Jo Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Maltby, Vicki E.
    Zhang, Mingdong
    Scott, Rodney J.
    Smith, Roger
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Hokfelt, Tomas
    Crock, Patricia A.
    Intermediate lobe immunoreactivity in a patient with suspected lymphocytic hypophysitis2014In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 17, no 1, p. 22-29Article in journal (Refereed)
    Abstract [en]

    Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. The spectrum of pituitary autoantibodies characterised by indirect immunofluorescence (IF) in these patients has not been substantially defined. The purpose of this study was to determine the spectrum of pituitary autoantibodies in 16 lymphocytic hypophysitis patients. Pituitary sections were prepared from guinea pigs and sera from 16 lymphocytic hypophysitis patients (13 biopsy proven and 3 suspected cases) and 13 healthy controls were evaluated for immunoreactivity to the pituitary tissue by immunofluorescence. A single patient was found to have high titre pituitary autoantibodies against guinea pig pituitary tissue. Immunoreactivity was directed against cells of the intermediate lobe. We present the case report of the patient who is a 24 year old woman that presented with headaches, polyuria and polydipsia. A uniformly enlarged pituitary mass was visible on MRI and a diagnosis of suspected lymphocytic hypophysitis was made. Based on our IF study, we postulate this patient has an autoimmune process directed towards the major cell type in the intermediate lobe, the melanotroph. Pre-adsorption with peptides representing adrenocorticotropic hormone, alpha-melanocyte stimulating hormone or beta-endorphin did not affect the IF signal suggesting our patient's pituitary autoantibodies may target some other product of Proopiomelanocortin (POMC) processing, such as corticotrophin-like intermediate peptide or gamma-lipoprotein. Alternatively, the autoantibodies may target a peptide completely unrelated to POMC processing.

  • 46.
    Smith-Anttila, Casey J. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Univ Newcastle, John Hunter Childrens Hosp, Dept Paediat Endocrinol & Diabet, Newcastle, NSW, Australia.;Univ Newcastle, Fac Hlth & Med, Newcastle, NSW, Australia.;Univ Melbourne, Dept Anat & Neurosci, Melbourne, Vic, Australia..
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden..
    Oscarson, Mikael
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Zhang, Ming-Dong
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Mol Neurobiol, Stockholm, Sweden..
    Perheentupa, Jaakko
    Helsinki Univ Hosp, Hosp Children & Adolescents, Helsinki, Finland..
    Husebye, Eystein S.
    Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Med, Bergen, Norway..
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Endocrinology. U.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Fransson, Anette
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Meloni, Antonella
    Univ Cagliari, Dept Biomed Biotechnol Sci, Cagliari, Italy..
    Scott, Rodney J.
    Univ Newcastle, Informat Based Med, Hunter Med Res Inst, Newcastle, NSW, Australia.;Univ Newcastle, Sch Biomed Sci, Fac Hlth & Med, Newcastle, NSW, Australia.;Hunter Area Pathol Serv, Div Mol Med, Newcastle, NSW, Australia..
    Hokfelt, Tomas
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Crock, Patricia A.
    Univ Newcastle, John Hunter Childrens Hosp, Dept Paediat Endocrinol & Diabet, Newcastle, NSW, Australia.;Univ Newcastle, Fac Hlth & Med, Newcastle, NSW, Australia..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Hunter Area Pathol Serv, Div Mol Med, Newcastle, NSW, Australia..
    Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 12017In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 4, p. 223-231Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

  • 47.
    Winge, Ingeborg
    et al.
    Univ Bergen, Dept Biomed, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5009 Bergen, Norway..
    Teigen, Knut
    Univ Bergen, Dept Biomed, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5009 Bergen, Norway..
    Fossbakk, Agnete
    Univ Bergen, Dept Biomed, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5009 Bergen, Norway..
    Mahootchi, Elaheh
    Univ Bergen, Dept Biomed, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5009 Bergen, Norway..
    Kleppe, Rune
    Univ Bergen, Dept Biomed, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5009 Bergen, Norway..
    Sköldberg, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, CMM L8 01, Stockholm, Sweden..
    Haavik, Jan
    Univ Bergen, Dept Biomed, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5009 Bergen, Norway.;Haukeland Hosp, Div Psychiat, N-5021 Bergen, Norway..
    Mammalian CSAD and GADL1 have distinct biochemical properties and patterns of brain expression2015In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 90, p. 173-184Article in journal (Refereed)
    Abstract [en]

    Variants in the gene encoding the enzyme glutamic acid decarboxylase like 1 (GADL1) have been associated with response to lithium therapy. Both GADL1 and the related enzyme cysteine sulfinic acid decarboxylase (CSAD) have been proposed to be involved in the pyridoxa1-5'-phosphate (PLP)-dependent biosynthesis of taurine. In the present study, we compared the catalytic properties, inhibitor sensitivity and expression profiles of GADL1 and CSAD in brain tissue. In mouse and human brain we observed distinct patterns of expression of the PLP-dependent decarboxylases CSAD, GADL1 and glutamic acid decarboxylase 67 (GAD67). CSAD levels were highest during prenatal and early postnatal development; GADL1 peaked early in prenatal development, while GAD67 increased rapidly after birth. Both CSAD and GADL1 are being expressed in neurons, whereas only CSAD mRNA was detected in astrocytes. Cysteine sulfinic acid was the preferred substrate for both mouse CSAD and GADL1, although both enzymes also decarboxylated cysteic acid and aspartate. In silica screening and molecular docking using the crystal structure of CSAD and in vitro assays led to the discovery of eight new enzyme inhibitors with partial selectivity for either CSAD or GADL1. Lithium had minimal effect on their enzyme activities. In conclusion, taurine biosynthesis in vertebrates involves two structurally related PLP-dependent decarboxylases (CSAD and GADL1) that have partially overlapping catalytic properties but different tissue distribution, indicating divergent physiological roles. Development of selective enzyme inhibitors targeting these enzymes is important to further dissect their (patho)physiological roles.

  • 48.
    Zaidi, Ghazala
    et al.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Bhatia, Vijayalakshmi
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Sahoo, Saroj K.
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Sarangi, Aditya Narayan
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bharti, Niharika
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Zhang, Li
    Barbara Davis Ctr Childhood Diabet, Dept Immunol, Denver, CO USA..
    Yu, Liping
    Barbara Davis Ctr Childhood Diabet, Dept Immunol, Denver, CO USA..
    Eriksson, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden..
    Bensing, Sophie
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.
    Bharani, Nisha
    Amrita Inst Med Sci, Dept Endocrinol, Kochi, Kerala, India..
    Yachha, Surendra Kumar
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Paediat Gastroenterol, Lucknow, Uttar Pradesh, India..
    Bhansali, Anil
    Postgrad Inst Med Educ & Res, Dept Endocrinol, Chandigarh, India..
    Sachan, Alok
    Sri Venkateshwara Inst Med Sci, Dept Endocrinol, Tirupati, India..
    Jain, Vandana
    All India Inst Med Sci, Dept Paediat, New Delhi, India..
    Shah, Nalini
    King Edward Mem Hosp, Seth GS Med Coll, Dept Endocrinol, Bombay, Maharashtra, India..
    Aggarwal, Rakesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India..
    Aggarwal, Amita
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Clin Immunol, Lucknow, Uttar Pradesh, India..
    Srinivasan, Muthuswamy
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Med Sci, Lucknow, Uttar Pradesh, India..
    Agarwal, Sarita
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Med Sci, Lucknow, Uttar Pradesh, India..
    Bhatia, Eesh
    Sanjay Gandhi Postgrad Inst Med Sci, Dept Endocrinol, Lucknow, Uttar Pradesh, India..
    Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study2017In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 5, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Objective: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design: Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2-19) years. Methods: Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results: Patients varied widely in their age of presentation [3.5 (0.1-17) years] and number of clinical manifestations [5 (2-11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3-23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-a and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions: Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

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