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  • 151. Bousquet, Jean
    et al.
    Hellings, Peter W
    Agache, Ioana
    Amat, Flore
    Annesi-Maesano, Isabella
    Ansotegui, Ignacio J
    Anto, Josep M
    Bachert, Claus
    Bateman, Eric D
    Bedbrook, Anna
    Bennoor, Kazi
    Bewick, Mickael
    Bindslev-Jensen, Carsten
    Bosnic-Anticevich, Sinthia
    Bosse, Isabelle
    Brozek, Jan
    Brussino, Luisa
    Canonica, Giorgio W
    Cardona, Victoria
    Casale, Thomas
    Cepeda Sarabia, Alfonso M
    Chavannes, Niels H
    Cecchi, Lorenzo
    Correia de Sousa, Jaime
    Costa, Elisio
    Cruz, Alvaro A
    Czarlewski, Wienczyslawa
    De Carlo, Giuseppe
    De Feo, Giulia
    Demoly, Pascal
    Devillier, Philippe
    Dykewicz, Mark S
    El-Gamal, Yehia
    Eller, Esben E
    Fonseca, Joao A
    Fontaine, Jean-François
    Fokkens, Wytske J
    Guzmán, Maria-Antonieta
    Haahtela, Tari
    Illario, Maddalena
    Ivancevich, Juan-Carlos
    Just, Jocelyne
    Kaidashev, Igor
    Khaitov, Musa
    Kalayci, Omer
    Keil, Thomas
    Klimek, Ludger
    Kowalski, Marek L
    Kuna, Piotr
    Kvedariene, Violeta
    Larenas-Linnemann, Desiree
    Laune, Daniel
    Le, Lan T T
    Carlsen, Karin Lodrup
    Lourenço, Olga
    Mahboub, Bassam
    Mair, Alpana
    Menditto, Enrica
    Milenkovic, Branislava
    Morais-Almeida, Mario
    Mösges, Ralph
    Mullol, Joaquim
    Murray, Ruth
    Naclerio, Robert
    Namazova-Baranova, Leyla
    Novellino, Ettore
    O'Hehir, Robyn E
    Ohta, Ken
    Okamoto, Yoshitaka
    Okubo, Kimi
    Onorato, Gabrielle L
    Palkonen, Susanna
    Panzner, Petr
    Papadopoulos, Nikos G
    Park, Hae-Sim
    Paulino, Ema
    Pawankar, Ruby
    Pfaar, Oliver
    Plavec, Davor
    Popov, Ted A
    Potter, Paul
    Prokopakis, Emmanuel P
    Rottem, Menachem
    Ryan, Dermot
    Salimäki, Johanna
    Samolinski, Boleslaw
    Sanchez-Borges, Mario
    Schunemann, Holger J
    Sheikh, Aziz
    Sisul, Juan-Carlos
    Rajabian-Söderlund, Rojin
    Sooronbaev, Talant
    Stellato, Cristiana
    To, Teresa
    Todo-Bom, Ana-Maria
    Tomazic, Peter-Valentin
    Toppila-Salmi, Sanna
    Valero, Antonio
    Valiulis, Arunas
    Valovirta, Erkka
    Ventura, Maria-Teresa
    Wagenmann, Martin
    Wang, De Yun
    Wallace, Dana
    Waserman, Susan
    Wickman, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Yorgancioglu, Arzu
    Zhang, Luo
    Zhong, Nanshan
    Zidarn, Mihaela
    Zuberbier, Torsten
    Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology.2019In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 3, p. 864-879Article in journal (Refereed)
    Abstract [en]

    Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.

  • 152.
    Bradding, Peter
    et al.
    Univ Leicester, Inst Lung Hlth, Dept Infect Immun & Inflammat, Leicester, Leics, England..
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    The controversial role of mast cells in fibrosis2018In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 282, no 1, p. 198-231Article, review/survey (Refereed)
    Abstract [en]

    Fibrosis is a medical condition characterized by an excessive deposition of extracellular matrix compounds such as collagen in tissues. Fibrotic lesions are present in many diseases and can affect all organs. The excessive extracellular matrix accumulation in these conditions can often have serious consequences and in many cases be life-threatening. A typical event seen in many fibrotic conditions is a profound accumulation of mast cells (MCs), suggesting that these cells can contribute to the pathology. Indeed, there is now substantialv evidence pointing to an important role of MCs in fibrotic disease. However, investigations from various clinical settings and different animal models have arrived at partly contradictory conclusions as to how MCs affect fibrosis, with many studies suggesting a detrimental role of MCs whereas others suggest that MCs can be protective. Here, we review the current knowledge of how MCs can affect fibrosis.

  • 153.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Andersson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Moench, Johanna
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Friedrich, Olaf
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Raemsch-Guenther, Nicole
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Raemsch, Christian
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Steffens, Melanie
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Lambrecht, Joerg
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Schraeder, Thomas
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Kurfuerst, Manfred
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Andersson, Helene H.
    Univ Hosp, Dept Nephrol & Transplantat, Malmo, Sweden..
    Felldin, Marie
    Univ Hosp, Dept Transplantat, Gothenburg, Sweden..
    Foss, Aksel
    Univ Oslo, Rikshosp, Oslo Univ Hosp, Div Surg,Sect Transplantat, N-0027 Oslo, Norway..
    Salmela, Kaija
    Univ Helsinki, Surg Hosp, Div Transplantat, Helsinki, Finland..
    Tibell, Annika
    Karolinska Inst, Div Transplantat Surg, CLINTEC, Stockholm, Sweden..
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The Effect of Truncated Collagenase Class I Isomers on Human Islet Isolation Outcome2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, no 3, p. 334-335Article in journal (Refereed)
  • 154.
    Brandsma, Arianne M.
    et al.
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Ridgeview Instruments AB, Vänge, Sweden.
    Evers, Mitchell
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    Koutstaal, Rosanne
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    Nederend, Maaike
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    Jansen, J. H. Marco
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    Rosner, Thies
    Univ Kiel, Div Stem Cell Transplantat & Immunotherapy, Dept Internal Med 2, Kiel, Germany.
    Valerius, Thomas
    Univ Kiel, Div Stem Cell Transplantat & Immunotherapy, Dept Internal Med 2, Kiel, Germany.
    Leusen, Jeanette H. W.
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    ten Broeke, Toine
    Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands.
    Potent Fc Receptor Signaling by IgA Leads to Superior Killing of Cancer Cells by Neutrophils Compared to IgG2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 704Article in journal (Refereed)
    Abstract [en]

    Antibody therapy of cancer is increasingly used in the clinic and has improved patient's life expectancy. Except for immune checkpoint inhibition, the mode of action of many antibodies is to recognize overexpressed or specific tumor antigens and initiate either direct F(ab')(2)-mediated tumor cell killing, or Fc-mediated effects such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/P) after binding to activating Fc receptors. All antibodies used in the clinic are of the IgG isotype. The IgA isotype can, however, also elicit powerful anti-tumor responses through engagement of the activating Fc receptor for monomeric IgA (Fc alpha RI). In addition to monocytes, macrophages and eosinophils as Fc alpha RI expressing immune cells, neutrophils are especially vigorous in eliminating IgA opsonized tumor cells. However, with IgG as single agent it appears almost impossible to activate neutrophils efficiently, as we have visualized by live cell imaging of tumor cell killing. In this study, we investigated Fc receptor expression, binding and signaling to clarify why triggering of neutrophils by IgA is more efficient than by IgG. Fc alpha RI expression on neutrophils is similar to 2 times and similar to 20 times lower than that of Fc gamma receptors Fc gamma RIIa and Fc gamma RIIIb, but still, binding of neutrophils to IgA- or IgG-coated surfaces was similar. In addition, our data suggest that IgA- mediated binding of neutrophils is more stable compared to IgG. IgA engagement of neutrophils elicited stronger Fc receptor signaling than IgG as indicated by measuring the p-ERK signaling molecule. We propose that the higher stoichiometry of IgA to the Fc alpha R/FcR gamma-chain complex, activating four ITAMs (Immunoreceptor Tyrosine-based Activating Motifs) compared to a single ITAM for Fc gamma RIIa, combined with a possible decoy role of the highly expressed Fc gamma RIIIb, explains why IgA is much better than IgG at triggering tumor cell killing by neutrophils. We anticipate that harnessing the vast population of neutrophils by the use of IgA monoclonal antibodies can be a valuable addition to the growing arsenal of antibody-based therapeutics for cancer treatment.

  • 155.
    Brandstrom, Josef
    et al.
    Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden..
    Lilja, Gunnar
    Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden..
    Nilsson, Caroline
    Soder Sjukhuset, Sachs Children & Youth Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden..
    Ingemarsson, Niklas
    Thermo Fisher Sci, ImmunoDiagnost, R&D, Uppsala, Sweden..
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Thermo Fisher Sci, ImmunoDiagnost, R&D, Uppsala, Sweden..
    Brostedt, Peter
    Thermo Fisher Sci, ImmunoDiagnost, R&D, Uppsala, Sweden..
    Englund, Hillevi
    Thermo Fisher Sci, ImmunoDiagnost, R&D, Uppsala, Sweden..
    IgE to novel citrus seed allergens among cashew-allergic children2016In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 27, no 5, p. 550-553Article in journal (Refereed)
  • 156.
    Brehony, Carina
    et al.
    Dept Zool, Univ Oxford, Oxford, England..
    Trotter, Caroline L.
    Dept Vet Med, Univ Cambridge, Cambridge, England.
    Ramsay, Mary E.
    Publ Hlth England, London, England.
    Chandra, Manosree
    Publ Hlth England, London, England.
    Jolley, Keith A.
    Dept Zool, Univ Oxford, Oxford, England.
    van der Ende, Arie
    Dept Med Microbiol, Netherlands Reference Lab Bacterial Meningitis, Acad Med Ctr, Univ Amsterdam, Amsterdam, Netherlands.
    Carion, Francoise
    Meningococcal Reference Lab, Sci Inst Publ Hlth, Brussels, Belgium.
    Berthelsen, Lene
    Neisseria & Streptococcus Reference Lab, Statens Serum Inst, Copenhagen, Denmark.
    Hoffmann, Steen
    Neisseria & Streptococcus Reference Lab, Statens Serum Inst, Copenhagen, Denmark.
    Hardardottir, Hjordis
    Dept Microbiol, Landspitali Univ Hosp, Reykjavik, Iceland.
    Vazquez, Julio A.
    Meningococcal Reference Lab, Madrid, Spain.
    Murphy, Karen
    Irish Meningococcal & Meningitis Reference Lab, Dublin, Ireland.
    Toropainen, Maija
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Canica, Manuela
    Dept Infect Dis, Lab Antimicrobial Resistance, Natl Inst Hlth Dr Ricardo Jorge, Lisbon, Portugal.
    Ferreira, Eugenia
    Dept Infect Dis, Lab Antimicrobial Resistance, Natl Inst Hlth Dr Ricardo Jorge, Lisbon, Portugal.
    Diggle, Mathew
    Scottish Haemophilus Legionella Meningococcus & P, Glasgow, UK.
    Edwards, Giles F.
    Scottish Haemophilus Legionella Meningococcus & P, Glasgow, UK.
    Taha, Muhamed-Kheir
    Inst Pasteur, Natl Reference Ctr Meningococci, Institut Pasteur, Paris, France.
    Stefanelli, Paola
    Dept Infect Parasit & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Kriz, Paula
    Natl Reference Lab Meningococcal Infect, Natl Inst Publ Hlth, Prague, Czech Republic.
    Gray, Steve J.
    Meningococcal Reference Unit, Manchester Royal Infirm, Manchester, England.
    Fox, Andrew J.
    Meningococcal Reference Unit, Manchester Royal Infirm, Manchester, England.
    Jacobsson, Susanne
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Claus, Heike
    Inst Hyg & Mikrobiol, Wurzburg, Germany.
    Vogel, Ulrich
    Inst Hyg & Mikrobiol, Wurzburg, Germany.
    Tzanakaki, Georgina
    Natl Meningococcal Reference Lab, Natl Sch Publ Hlth, Athens, Greece.
    Heuberger, Sigrid
    Natl Reference Ctr Meningococci, Inst Med Microbiol & Hyg, Graz, Austria.
    Caugant, Dominique A.
    Dept Bacteriol & Immunol, Norwegian Inst Publ Hlth, Oslo, Norway.
    Frosch, Matthias
    Inst Hyg & Mikrobiol, Wurzburg, Germany.
    Maiden, Martin C. J.
    Dept Zool, Univ Oxford, Oxford, England.
    Implications of Differential Age Distribution of Disease-Associated Meningococcal Lineages for Vaccine Development2014In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, no 6, p. 847-853Article in journal (Refereed)
    Abstract [en]

    New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects <1 year of age experienced lower risk of sequence type 11 (ST-11) cc, ST-32 cc, and ST-269 cc disease and higher risk of disease due to unassigned STs, 1- to 4-year-olds experienced lower risk of ST-11 cc and ST-32 cc disease, 5- to 14-year-olds were less likely to experience ST-11 cc and ST-269 cc disease, and >= 25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines, as different variants, or perhaps targets, may be required for different age groups.

  • 157.
    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.

  • 158. Brenner, David
    et al.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Univ Ulm, Dept Neurol, Ulm, Germany.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice"2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 2, p. 530-Article in journal (Refereed)
  • 159.
    Brew, Bronwyn K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundholm, Cecilia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gong, Tong
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet; Sweden Pediatric Allergy and Pulmonology Unit,t Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    The familial aggregation of atopic diseases and depression or anxiety in children2018In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 48, no 6, p. 703-711Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases have strong genetic and environmental components, therefore it seems likely that there is a shared liability rather than causative risk.

    OBJECTIVE: To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety.

    METHODS: Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n= 14197. Current and ever asthma, eczema, hayfever and food-allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic MZ twins and same-sex dizygotic DZ twins for atopic disease in one twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth.

    RESULTS: Familial co-aggregation analysis found that if one twin had at least one current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (Adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates.

    CONCLUSIONS AND CLINICAL RELEVANCE: Atopic diseases and depression or anxiety tend to occur together in families, therefore when treating for one disease the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation.

  • 160.
    Broeker, Michael
    et al.
    Novartis Vaccines & Diagnost GmbH, Marburg, Germany.
    Bukovski, Suzana
    Univ Hosp Infect Dis Dr Fran Mihaljevic, Zagreb, Croatia.
    Culic, Davor
    Haemophilus & Meningococcus Reference Lab, Ctr Microbiol, Inst Publ Hlth, Srbija, Serbia.
    Jacobsson, Susanne
    Örebro University Hospital.
    Koliou, Maria
    Unit Surveillance & Control Communicable Dis, Minist Hlth, Nikosia, Cyprus.
    Kuusi, Markku
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Simoes, Maria Joao
    Inst Nacl Saude Dr Ricardo Jorge, Lisbon, Portugal.
    Skoczynska, Anna
    Natl Reference Ctr Bacterial Meningitis, Natl Med Inst, Warsaw, Poland.
    Toropainen, Maija
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Taha, Muhamed-Keir
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France.
    Tzanakaki, Georgina
    Natl Meningitis Reference Lab, Natl Sch Publ Hlth, Athens, Greece.
    Meningococcal serogroup Y emergence in Europe High importance in some European regions in 20122014In: Human Vaccines & Immunotherapeutics, ISSN 2164-5515, E-ISSN 2164-554X, Vol. 10, no 6, p. 1725-1728Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis is differentiated into 12 distinct serogroups, of which A, B, C, W, X, and Y are medically most important and represent an important health problem in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Recent epidemiological surveillance has indicated an increase of serogroup Y invasive meningococcal disease in some parts of Europe as shown in the epidemiological data for 2010 and 2011 from various European countries previously published in this journal. 1,2 Here, data from 33 European countries is reported indicating that the emergence of serogroup Y continued in 2012 in various regions of Europe, especially in Scandinavia, while in Eastern and South-Eastern Europe the importance of serogroup Y remained low.

  • 161.
    Brorsson, Caroline
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Lund University.
    Bergholdt, Regine
    Danmark.
    Eising, Stefanie
    Danmark.
    Nilsson, Anita
    Lund University.
    Svensson, Jannet
    Danmark.
    Lernmark, Ake
    Lund University.
    Pociot, Flemming
    Danmark.
    Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes2011In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, no 2, p. 107-114Article in journal (Refereed)
    Abstract [en]

    We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.

  • 162. Browall, Sarah
    et al.
    Norman, Martin
    Tångrot, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Bioinformatics Infrastructure for Life Sciences, Computational Life Science Cluster.
    Galanis, Ilias
    Sjöstrom, Karin
    Dagerhamn, Jessica
    Hellberg, Christel
    Pathak, Anuj
    Spadafina, Tiziana
    Sandgren, Andreas
    Bättig, Patrick
    Franzén, Oscar
    Andersson, Björn
    Örtqvist, Åke
    Normark, Staffan
    Henriques-Normark, Birgitta
    Intraclonal Variations Among Streptococcus pneumoniae Isolates Influence the Likelihood of Invasive Disease in Children2014In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 209, no 3, p. 377-388Article in journal (Refereed)
    Abstract [en]

    Background. Pneumococcal serotypes are represented by a varying number of clonal lineages with different genetic contents, potentially affecting invasiveness. However, genetic variation within the same genetic lineage may be larger than anticipated. Methods. A total of 715 invasive and carriage isolates from children in the same region and during the same period were compared using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Bacterial genome sequencing, functional assays, and in vivo virulence mice studies were performed. Results. Clonal types of the same serotype but also intraclonal variants within clonal complexes (CCs) showed differences in invasive-disease potential. CC138, a common CC, was divided into several PFGE patterns, partly explained by number, location, and type of temperate bacteriophages. Whole-genome sequencing of 4 CC138 isolates representing PFGE clones with different invasive-disease potentials revealed intraclonal sequence variations of the virulence-associated proteins pneumococcal surface protein A (PspA) and pneumococcal choline-binding protein C (PspC). A carrier isolate lacking PcpA exhibited decreased virulence in mice, and there was a differential binding of human factor H, depending on invasiveness. Conclusions. Pneumococcal clonal types but also intraclonal variants exhibited different invasive-disease potentials in children. Intraclonal variants, reflecting different prophage contents, showed differences in major surface antigens. This suggests ongoing immune selection, such as that due to PspC-mediated complement resistance through varied human factor H binding, that may affect invasiveness in children.

  • 163. Bruening, Janina
    et al.
    Weigel, Bettina
    Gerold, Gisa
    Institute for Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Hannover, Germany.
    The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy2017In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 7232361Article in journal (Refereed)
    Abstract [en]

    The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.

  • 164. Brändstedt, Jenny
    et al.
    Wangefjord, Sakarias
    Nodin, Bjorn
    Eberhard, Jakob
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Manjer, Jonas
    Jirstrom, Karin
    Associations of Anthropometric Factors with KRAS and BRAF Mutation Status of Primary Colorectal Cancer in Men and Women: A Cohort Study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e98964-Article in journal (Refereed)
    Abstract [en]

    Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist-and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmo Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRA-Smutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.

  • 165. Brändström, J.
    et al.
    Vetander, M.
    Lilja, G.
    Sundqvist, A.
    Kalm, Frida
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Johansson, S.
    Nilsson, C.
    Nopp, A.
    Peanut oral immunotherapy during omalizumab protection; a clinical trial on severely peanut allergic adolescents2017In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 72, p. 65-66Article in journal (Other academic)
  • 166.
    Bränn, Emma
    et al.
    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), Obstetrics and Reproductive Health Research.
    Fransson, Emma
    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), Obstetrics and Reproductive Health Research. Karolinska Institutet, Stockholm, Sweden..
    White, Richard A
    Norwegian Institute of Public Health, Oslo, Norway.
    Papadopoulos, Fotios C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Edvinsson, Åsa
    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), Reproductive Health.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cunningham, Janet L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Sundström Poromaa, Inger
    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), Reproductive Health.
    Skalkidou, Alkistis
    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), Obstetrics and Reproductive Health Research.
    Inflammatory markers in women with postpartum depressive symptoms2018In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547Article in journal (Refereed)
    Abstract [en]

    Postpartum depression (PPD) is a devastating disorder affecting not only more than 10% of all women giving birth, but also the baby, the family, and the society. Compiling evidence suggests the involvement of the immune system in the pathophysiology of major depression; yet, the immune response in perinatal depression is not as well studied. The aim of this study was to investigate the alterations in peripheral levels of inflammatory biomarkers in 169 Swedish women with and without depressive symptoms according to the Edinburgh postnatal depression scale or the M.I.N.I neuropsychiatric interview at eight weeks postpartum. Among the 70 markers analyzed with multiplex proximity extension assay, five were significantly elevated in women with postpartum depressive symptoms in the adjusted LASSO logistic regression analysis: Tumor necrosis factor ligand superfamily member (TRANCE) (OR-per 1 SD increase = 1.20), Hepatocyte growth factor (HGF) (OR = 1.17) Interleukin (IL)-18 (OR = 1.06), Fibroblast growth factor 23 (FGF-23) (OR = 1.25), and C-X-C motif chemokine 1 (CXCL1) (OR 1.11). These results indicate that women with PPD have elevated levels of some inflammatory biomarkers. It is, therefore, plausible that PPD is associated with a compromised adaptability of the immune system.

  • 167.
    Bråbäck, Lennart
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Department of Research and Development, Västernorrland County Council and Sundsvalls sjukhus, Sundsvall.
    Ekéus, Cecilia
    Lowe, Adrian J
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Murdoch Childrens Research Institute and Centre for MEGA Epidemiology , School of Population Health, The University of Melbourne, Melbourne, Australia.
    Hjern, Anders
    Confounding with familial determinants affects the association between mode of delivery and childhood asthma medication: a national cohort study2013In: Allergy, Asthma & Clinical Immunology, ISSN 1710-1484, E-ISSN 1710-1492, Vol. 9, no 1, p. 14-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mode of delivery may affect the risk of asthma but the findings have not been consistent and factors shared by siblings may confound the associations in previous studies. METHODS: The association between mode of delivery and dispensed inhaled corticosteroid (ICS) (a marker of asthma) was examined in a register based national cohort (n=199 837). A cohort analysis of all first born children aged 2-5 and 6-9 years was performed. An age-matched sibling-pair analysis was also performed to account for shared genetic and environmental risk factors. RESULTS: Analyses of first-borns demonstrated that elective caesarean section was associated with an increased risk of dispensed ICS in both 2-5 (adjusted odds ratio (aOR)=1.19, 95% confidence interval (CI) 1.09-1.29) and 6-9 (aOR=1.21, 1.09-1.34) age groups. In the sibling-pair analysis, the increased risk associated with elective caesarean section was confirmed in 2-5 year olds (aOR=1.22, 1.05-1.43) but not in 6-9 year olds (aOR=1.06, 0.78-1.44). Emergency caesarean section and vacuum extraction had some association with dispensed ICS in the analyses of first-borns but these associations were not confirmed in the sibling-pair analyses. CONCLUSIONS: Confounding by familial factors affects the association between mode of delivery and dispensed ICS. Despite this confounding, there was some evidence that elective caesarean section contributed to a modestly increased risk of dispensed ICS but only up to five years of age.

  • 168.
    Bröms, Jeanette E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    IglG and IglI of the Francisella pathogenicity island are important virulence determinants of Francisella tularensis LVS2011In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 9, p. 3683-3696Article in journal (Refereed)
    Abstract [en]

    The Gram-negative bacterium Francisella tularensis is the causative agent of tularemia, a disease intimately associated with the multiplication of the bacterium within host macrophages. This in turn requires the expression of Francisella pathogenicity island (FPI) genes, believed to encode a type VI secretion system. While the exact functions of many of the components have yet to be revealed, some have been found to contribute to the ability of Francisella to cause systemic infection in mice as well as to prevent phagolysosomal fusion and facilitate escape into the host cytosol. Upon reaching this compartment, the bacterium rapidly multiplies, inhibits activation of the inflammasome, and ultimately causes apoptosis of the host cell. In this study, we analyzed the contribution of the FPI-encoded proteins IglG, IglI, and PdpE to the aforementioned processes in F. tularensis LVS. The ΔpdpE mutant behaved similarly to the parental strain in all investigated assays. In contrast, ΔiglG and ΔiglI mutants, although they were efficiently replicating in J774A.1 cells, both exhibited delayed phagosomal escape, conferred a delayed activation of the inflammasome, and exhibited reduced cytopathogenicity as well as marked attenuation in the mouse model. Thus, IglG and IglI play key roles for modulation of the intracellular host response and also for the virulence of F. tularensis.

  • 169.
    Bulfone-Paus, Silvia
    et al.
    Univ Manchester, Div Musculoskeletal & Dermatol Sci, Fac Biol Med & Hlth, Manchester, Lancs, England..
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med, Immunol & Allergy Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
    Draber, Petr
    Acad Sci Czech Republ, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic..
    Blank, Ulrich
    INSERM, U1149, Ctr Rech Inflammat, Paris, France.;CNRS, ERL8252, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, Fac Med, Site Xavier Bichat,Inflamex Lab Excellence, Paris, France..
    Levi-Schaffer, Francesca
    Hebrew Univ Jerusalem, Inst Drug Res, Sch Pharm, Fac Med,Pharmacol & Expt Therapeut Unit, Jerusalem, Israel..
    Positive and Negative Signals in Mast Cell Activation2017In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 38, no 9, p. 657-667Article, review/survey (Refereed)
    Abstract [en]

    Mast cells are powerful immune modulators of the tissue microenvironment. Within seconds of activation, these cells release a variety of preformed biologically active products, followed by a wave of mediator synthesis and secretion. Increasing evidence suggests that an intricate network of inhibitory and activating receptors, specific signaling pathways, and adaptor proteins governs mast cell responsiveness to stimuli. Here, we discuss the biological and clinical relevance of negative and positive signaling modalities that control mast cell activation, with an emphasis on novel Fc epsilon RI regulators, immunoglobulin E (IgE)-independent pathways [e.g., Mas-related G protein-coupled receptor X2 (MRGPRX2)], tetraspanins, and the CD300 family of inhibitory and activating receptors.

  • 170.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Curing Multiple Sclerosis: How to do it and how to prove it2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for multiple sclerosis (MS) with now more than 600 documented cases in the medical literature. Long-term remission can be achieved with this therapy, but when is it justified to claim that a patient is cured from MS? In attempt to answer this question, the outcome of the Swedish patients is described, mechanisms behind the therapeutic effect are discussed and new tools for demonstration of absence of disease have been developed.

    In Swedish patients treated with HSCT for aggressive MS, disease free survival was 68 % at five years, and no patient progressed after three years of stable disease. Presence of gadolinium enhancing lesions prior to HSCT was associated with a favorable outcome (disease free survival 79 % vs 46 %, p=0.028). There was no mortality and no patient required intensive care.

    The immune system of twelve of these patients was investigated further. In most respects HSCT-treated patients were similar to healthy controls, demonstrating normalization. In the presence of a potential antigen, leukocytes from HSCT-treated patients ceased producing pro-inflammatory IL-17 and increased production of the inhibitory cytokine TGF-β1 suggesting restoration of tolerance.

    Cytokine levels and biomarkers of tissue damage were investigated in cerebrospinal fluid from a cohort of MS patients. The levels were related to clinical and imaging findings. A cytokine signature of patients with relapsing-remitting MS could be identified, characterized by increased levels of CCL22, CXCL10, sCD40L, CXCL1 and CCL5 as well as down-regulation of CCL2. Further, we could demonstrate that active inflammation in relapsing-remitting MS is a tissue damaging process, with increased levels of myelin basic protein and neurofilament light. Importantly, relapsing-remitting MS patients in remission displayed no tissue damage. In secondary progressive MS, moderate tissue damage was present without signs of active inflammation.

    From a clinical vantage point, it seems that we confidently can claim cure of relapsing-remitting MS patients after five years absence of disease activity. The new tools for evaluation of disease can strengthen this assertion and may enable earlier prediction of outcome.

  • 171.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tim-3 and PD-1: Regulators of adaptive immunity in multiple sclerosis2014In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 275, no 1-2, p. 141-141Article in journal (Other academic)
  • 172.
    Burns, R. E.
    et al.
    University of Calif San Diego, CA 92103 USA.
    Gaffney, P. M.
    University of Calif San Diego, CA 92103 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Armien, A. G.
    University of Minnesota, MN 55108 USA.
    Pessier, A. P.
    University of Calif San Diego, CA 92103 USA.
    Systemic Amyloidosis in an African Tiger Snake (Telescopus semiannulatus)2017In: Journal of Comparative Pathology, ISSN 0021-9975, E-ISSN 1532-3129, Vol. 157, no 2-3, p. 136-140Article in journal (Refereed)
    Abstract [en]

    An adult male African tiger snake (Telescopts semiannulatus) was diagnosed with disseminated mycobacteriosis and a hepatic biliary cystadenocarcinoma. Histologically, the spleen was largely replaced by extracellular deposits of eosinophilic, fibrillar to hyaline material. Similar material was also present in the testicular interstitium and occasional blood vessel walls. This material was congophilic with strong green birefringence under polarized light and emitted fluorescence when bound to the luminescent-conjugated oligothiophene, h-FTAA, an amyloid binding probe. Ultrastructurally, deposits were composed of aggregates of haphazardly arranged, non-branching fibrils up to 8 nm in diameter and of indeterminate length. These findings all supported a diagnosis of amyloidosis, most likely amyloid A (AA) type based on concurrent inflammatory disease in this snake. However, immunohistochemistry for serum amyloid A was negative. There are only rare previous reports of amyloidosis in reptiles and many have been incompletely characterized. This case presents a thorough investigation into an occurrence of systemic amyloidosis in a snake, including a novel use of luminescent-conjugated oligothiophene binding in a reptile to confirm the diagnosis. (C) 2017 Elsevier Ltd. All rights reserved.

  • 173.
    Butwicka, Agnieszka
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden;.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden .
    Frisén, Louise
    Child and Adolescent Psychiatry Research Center, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Child and Adolescent Psychiatry Research Center, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Celiac disease is associated with childhood psychiatric disorders: A Population-Based Study2017In: Journal of Pediatrics, ISSN 0022-3476, E-ISSN 1097-6833, Vol. 184, p. 87-93.e1, article id S0022-3476(17)30153-1Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine the risk of future childhood psychiatric disorders in celiac disease, assess the association between previous psychiatric disorders and celiac disease in children, and investigate the risk of childhood psychiatric disorders in siblings of celiac disease probands.

    STUDY DESIGN: This was a nationwide registry-based matched cohort study in Sweden with 10 903 children (aged <18 years) with celiac disease and 12 710 of their siblings. We assessed the risk of childhood psychiatric disorders (any psychiatric disorder, psychotic disorder, mood disorder, anxiety disorder, eating disorder, psychoactive substance misuse, behavioral disorder, attention-deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and intellectual disability). HRs of future psychiatric disorders in children with celiac disease and their siblings was estimated by Cox regression. The association between previous diagnosis of a psychiatric disorder and current celiac disease was assessed using logistic regression.

    RESULTS: Compared with the general population, children with celiac disease had a 1.4-fold greater risk of future psychiatric disorders. Childhood celiac disease was identified as a risk factor for mood disorders, anxiety disorders, eating disorders, behavioral disorders, ADHD, ASD, and intellectual disability. In addition, a previous diagnosis of a mood, eating, or behavioral disorder was more common before the diagnosis of celiac disease. In contrast, siblings of celiac disease probands were at no increased risk of any of the investigated psychiatric disorders.

    CONCLUSIONS: Children with celiac disease are at increased risk for most psychiatric disorders, apparently owing to the biological and/or psychological effects of celiac disease.

  • 174. Bäck, Jennie
    et al.
    Sanchez, Javier
    Elgue, Graciela
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Activated platelets induce FXII-mediated contact activation2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 391, no 1, p. 11-17Article in journal (Refereed)
    Abstract [en]

    Earlier studies have shown that isolated platelets in buffer systems can promote activation of FXII or amplify contact activation. in the presence of it negatively charge Substance or material Still proof is lacking that FXII is activated by platelets in a more physiological environment In this study we investigate if activated platelets can induce FXII-mediated contact activation and whether this activation affects clot formation in human blood.

    Human platelets were activated with a thrombin receptor-activating peptide, SFLLRN-amide, in platelet-rich plasma or in whole blood. FXIIa and FXIa in complex with preferentially antithrombin (AT) and to some extent C1-inhibitor (C1INH) were generated in response to TRAP stimulation. This contact activation was independent of surface-mediated contact activation, tissue factor pathway or thiombin. In clotting whole blood FXIIa-AT and FXIa-AT complexes were specifically formed. demonstrating that AT is a potent inhibitor of FXIIa and FXIa generated by platelet activation Contact activation proteins were analyzed by flow cytometry and FXII, FXI, high-molecular weight kininogen, and prekallikrein were detected oil activated platelets Using chromogenic assays, enzymatic activity of platelet-associated FXIIa, FXIa, and kallikrein were demonstrated Inhibition of FXIIa in non-anticoagulated blood also prolonged the clotting time.

    We conclude that platelet activation triggers FXII-mediated contact activation oil the Surface and in the vicinity of activated platelets This leads specifically to generation of FXIIa-AT and FXIa-AT complexes, and contributes to clot formation Activated platelets may thereby constitute an intravascular locus for contact activation, which may explain the recently reported importance of FXII in thrombus formation (C) 2009 Published by Elsevier Inc.

  • 175.
    Calla-Magariños, Jacqueline
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Bioactive leishmanicidal alkaloid molecules from Galipea longiflora Krause with immunomodulatory activity2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    According to WHO, leishmaniasis is endemic in 98 countries, and has been placed ninth in a global analysis of infectious diseases. Treatment of leishmaniasis is based on pentavalent antimonials but toxicity and developing resistance have been reported. Traditional medicine and scientific studies have shown that the extract of Galipea longiflora Krause (Evanta) exhibits antileishmanial activity. We hypothesized that the healing observed when using this plant might not only be due to the direct action on the parasite, but possibly to a parallel effect on the host immune response. We found that an alkaloid extract of Evanta (AEE) inhibited the growth of Leishmania braziliensis promastigotes while viability of eukaryotic cells was practically not affected. We also found that AEE interfered with polyclonal activation or Leishmania-specific re-stimulation of lymphocytes, as revealed by a reduction of in vitro cellular proliferation and IFN-g production. More important, AEE treatment of mice hosting L. braziliensis showed that AEE is able to control both inflammation and parasite load. Additionally, the healing process was improved when AEE and meglumine antimoniate were administered simultaneously. Dendritic cells (DCs) play a pivotal role in T-cell stimulation and polarization of naïve T cells. Therefore, we investigated if AEE could alter the activation of DCs and if allostimulatory DCs properties were altered if activated in the presence of AEE. DCs activated in the presence of AEE reduced the production of IL-12p40 and IL-23. When we analyzed the allostimulatory capacity of AEE-treated DCs, we found that allogeneic CD4+ T-cells secreted lower levels of IFN-γ.

    In conclusion, this thesis provides valuable insight into the effects of Evanta derived extract. The dual effect found for AEE, on Leishmania parasite and on the immune response, suggests that AEE may be useful in controlling the parasite burden and preventing over-production of inflammatory mediators and subsequently avoiding tissue damage.

  • 176. Camussone, C. M.
    et al.
    Pujato, N.
    Renna, M. S.
    Veaute, C. M.
    Morein, Bror
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Marcipar, I. S.
    Calvinho, L. F.
    Immune response and functional role of antibodies raised in heifers against a Staphylococcus aureus CP5 lysate and recombinant antigens vaccine formulated with Iscom Matrix adjuvant2014In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 162, no 3-4, p. 96-107Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus is the most frequently isolated pathogen from bovine intramammary infections worldwide. Commercially available vaccines for mastitis control are composed either of S. aureus lysates or inactivated whole-cells formulated with traditional adjuvants. We recently showed the ability of a S. aureus CP5 lysate vaccine adjuvanted with Iscom Matrix to generate a longer lasting specific antibody response in blood and milk with improved opsonic capacity compared with a S. aureus CP5 whole-cell formulation. The aim of the present study was to obtain an experimental immunogen composed of lysed cells of a CP5 S. aureus strain supplemented with recombinant clumping factor A fibronectin binding protein A and beta-toxin formulated with Iscom Matrix characterize the immune response generated when immunizing pregnant heifers and assess the functional role of antibodies raised against this immunogen in experimental models. Both a lysate vaccine and a lysate + recombinant antigens vaccine elicited antibodies that promoted neutrophil phagocytosis and inhibited internalization into mammary epithelial cells in vitro. Incorporation of defined antigenic molecules to the lysate formulation elicited a strong specific humoral immune response against both lysate and recombinant antigens and was associated with higher expression of regulatory and pro-inflammatory cytokines. In addition antibodies were efficient for blocking S. aureus binding to bovine fibrinogen and fibronectin and neutralizing beta-toxin effect in vitro placing these antigens as candidates to be included in a formulation directed to prevent staphylococcal bovine mastitis. (C) 2014 Elsevier B.V. All rights reserved.

  • 177.
    Carlsson, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Adoptive T Cell Therapy of Viral Infection and Cancer: Ex vivo Expansion of Cytomegalovirus- and Prostate Antigen-specific T Cells2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main focus of my thesis has been to develop protocols for generating antigen-specific cytotoxic T lymphocytes (CTLs) and T helper cells (TH) for adoptive transfer to treat cytomegalovirus (CMV) disease and prostate cancer. CMV viremia is a severe complication in immunocompromised stem cell transplanted patients. Prostate cancer is a leading cause of death for men in Western countries. Although different in nature, CMV-infected cells and prostate cancer cells can both be eliminated through specific activation of the adaptive immune system.

    To generate CMV pp65-specific T cells, I utilized dendritic cells (DCs) modified with an HLA-A*0201/pp65495-503 peptide, a recombinant adenovirus coding for pp65, in vitro transcribed pp65 mRNA and a recombinant pp65 protein. Peptide stimulation yielded large numbers of peptide-specific CD8+ T cells with high lytic activity while adenovirus or mRNA stimulation resulted in the expansion of CTLs against multiple pp65 epitopes. The recombinant protein activated primarily CD4+ TH cells. Stimulation with DCs co-modified with pp65 mRNA and pp65 protein simultaneously generated both pp65-specific CTLs and TH cells. Such T cells would cover all pp65 epitopes while avoiding potential virus related biohazards. The mRNA/protein combinatory approach can be used to stimulate T cells ex vivo from virtually all stem cell donors for adoptive T cell transfer.

    I have identified two immunogenic HLA-A*0201-restricted peptide epitopes from the prostate tissue antigen TARP. Repeated stimulations with TARP peptide-pulsed DCs yielded up to 20% TARP-directed CD8+ T cells even when starting from undetectable frequencies (<0.01%). The T cells could be sorted to 99% purity and expanded 1000-fold with retained specificity and activity. We also detected TARP-directed CD8+ T cells in the blood of prostate cancer patients. Therefore, TARP seems to have potential as antigen in DC vaccination or adoptive T cell therapy of prostate cancer.

  • 178.
    Carlsson, Fredrik
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Antibody Feedback Regulation and T Cells2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antibodies, passively administered or actively produced, regulate immune responses to the antigen they recognize. This phenomenon is called antibody-mediated feedback regulation. Feedback regulation can be positive or negative, resulting in >1000-fold enhancement or >99% suppression of the specific antibody response. The outcome depends on size, structure, dose, and route of administration of the antigen as well as on class and subclass of the regulating antibody. This thesis investigates the role of T cells in antibody-mediated feedback enhancement, using both in vivo and in vitro approaches. IgE-antibodies enhance antibody responses to small soluble proteins. This effect is entirely dependent on the low-affinity receptor for IgE, CD23, and most likely depends on increased antigen presentation by CD23+ B cells. Strengthening this hypothesis, we show that IgE-mediated CD4+ T cell proliferation in vitro required the presence of CD19+ CD43- CD23+ B cells. CD23 has also been shown to negatively regulate immune responses. Transgenic mice overexpressing CD23 are known to have impaired responses to antigens in alum. We here demonstrate that they are normal regarding IgE-mediated enhancement. IgG3 enhances antibody responses, and previous data suggested involvement of complement. We found that IgG3-mediated enhancement works well in mice lacking the only Fc-receptor known to bind IgG3, CD64. Although IgG3 could enhance antibody responses it had no major effect on T cell responses. Complement-receptors 1/2 (CR1/2) are required for the initiation of normal antibody responses. Although mice lacking CR1/2 had impaired antibody responses after immunization with sheep erythrocytes, their specific T cell responses were unaffected. The presented data do not support the idea that increased complement-mediated antigen presentation is a major mechanism behind the involvement of complement in antibody responses. They support the hypothesis that antigens forming complement-containing immune complexes may activate specific B cells by co-crosslinking BCR and CR1/2.

  • 179. Carlsson, Hanna
    et al.
    Sandholm, Kerstin
    Tjernberg, Ivar
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Complement activation in asymptomatic Lyme borreliosis and neuroborreliosis2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 128-128Article in journal (Other academic)
  • 180.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Rotem, Avi
    Zimermann, Baruch
    Grinberg, Helena
    Goldman, Tali
    Barkai, Uriel
    Avni, Yuval
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlbom, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical AB, Mölndal, Sweden.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 7, p. 1735-1744Article in journal (Refereed)
    Abstract [en]

    Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

  • 181.
    Carré, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lindström, Richard
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lundqvist, Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Asking about condom use: a key to individualized care when screening for chlamydia2011In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 22, no 8, p. 436-441Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis (CT) infection has been a target for both selective and national screening programmes, and Sweden has an opportunistic approach. A national plan of action states that risk groups should be identified and offered risk reduction counselling. Patients attending a drop-in sexually transmitted infection (STI) clinic reception at the University Hospital, Umeå, Sweden, were invited to complete a questionnaire regarding sociodemographic characteristics, symptoms and sexual risk behaviour; all had a CT test taken. A total of 1305 patients were included, 58% men, mean age 27.8 years. CT prevalence was 11%; 51% of those with CT were ≥ 25 years old. Only 5% used a condom during the entire sexual intercourse with their last new/temporary partner. Sexually active inconsistent condom users comprised 62% of the study population and contributed to 81% of the chlamydia infections. Asking whether a condom was used could quickly triage patients into groups with a 'higher risk' (none or inconsistent use of condoms and at least one new/temporary partners), and 'lower risk' (with more consistent condom use, although not always accurate) allowing for individualized care and counselling when screening for chlamydia. Evaluating whether a condom was used throughout the sexual intercourse did not add any useful information.

  • 182.
    Cauvi, D.M.
    et al.
    University of California, San Diego, CA, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Pollard, K. Michael
    The Scripps Research Institute, La Jolla, CA, USA.
    Autoimmune models2015In: Reference module in biomedical sciences, Elsevier, 2015, p. 413-438Chapter in book (Refereed)
    Abstract [en]

    Models of autoimmunity fall into four categories: (a) those induced by immunization with self-antigen, (b) those induced by exogenous agents, (c) those which arise spontaneously, and (d) those which are produced by genetic manipulation. The autoimmunity exhibited by these models covers a spectrum of diseases which fall into the two broad categories, organ-specific and systemic autoimmunity. Animal models of autoimmune diseases have played an essential role in the discovery of many of mechanisms that result in the breaking of self-tolerance. This chapter describes a number of experimental animal models of autoimmunity and the underlying mechanisms that lead to disease.

  • 183.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction2016In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 3, article id e1098803Article in journal (Other academic)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are part of the innate immune defense against microbes, but their contribution to several non-infectious inflammatory conditions has recently been unraveled. We demonstrate that NETs accumulate in the peripheral circulation in tumor-bearing mice, causing systemic inflammation and vascular dysfuntion in organs not affected by tumor cells.

  • 184.
    Cerenius, Lage
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Kenneth
    Arthropoda:: Pattern recognition proteins in crustacean immunity2018In: Advances in Comparative Immunology, Springer, 2018Chapter in book (Other academic)
  • 185. Cerveny, Lukas
    et al.
    Straskova, Adela
    Dankova, Vera
    Hartlova, Anetta
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ceckova, Martina
    Staud, Frantisek
    Stulik, Jiri
    Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms2013In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 3, p. 629-635Article, review/survey (Refereed)
    Abstract [en]

    The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while high-lighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of Yersinia, Pseudomonas, and Shigella.

  • 186. Chatzouli, Maria
    et al.
    Ntoufa, Stavroula
    Papakonstantinou, Nikos
    Chartomatsidou, Elisavet
    Anagnostopoulos, Achilles
    Kollia, Panagoula
    Ghia, Paolo
    Muzio, Marta
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Belessi, Chrysoula
    Heterogeneous Functional Effects of Concomitant B Cell Receptor and TLR Stimulation in Chronic Lymphocytic Leukemia with Mutated versus Unmutated Ig Genes2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 192, no 10, p. 4518-4524Article in journal (Refereed)
    Abstract [en]

    We recently reported that chronic lymphocytic leukemia (CLL) subgroups with distinct clonotypic BCRs present discrete patterns of TLR expression, function, and/ or tolerance. In this study, to explore whether specific types of BCR/TLR collaboration exist in CLL, we studied the effect of single versus concomitant BCR and/or TLR stimulation on CLL cells from mutated (M-CLL) and unmutated CLL (U-CLL) cases. We stimulated negatively isolated CLL cells by using anti-IgM, imiquimod, and CpG oligodeoxynucleotide for BCR, TLR7, and TLR9, respectively, alone or in combination for different time points. After in vitro culture in the absence of stimulation, differences in p-ERK were identified at any time point, with higher p-ERK levels in U-CLL versus M-CLL. Pronounced p-ERK induction was seen by single stimulation in U-CLL, whereas BCR/TLR synergism was required in M-CLL, in which the effect was overall limited in scale. An opposite pattern was observed regarding induction of apoptosis, as studied by Western blotting for the cleaved fragment of poly(ADP-ribose) polymerase, and the active isoform of caspase-8, with M-CLL responding even to single stimulation, contrasting with U-CLL that showed minimal response. Our findings suggest that concomitant engagement of BCR and TLR leads to differential responses in CLL depending on the mutational status of the BCR. Differential intensity and duration of responses in M-CLL versus U-CLL indicates that the differences in signal transduction between the two subgroups may be primarily quantitative rather than qualitative.

  • 187. Chen, Dan
    et al.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    MICA polymorphism: biology and importance in cancer2014In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, no 12, p. 2633-2642Article, review/survey (Refereed)
    Abstract [en]

    The major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), γδ T and CD8(+) αβ T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses of NK and γδ T cells against infected and tumor cells expressing MICA. Therefore, membrane-bound MICA acts as a signal during the early immune response against infection or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, causing the downregulation of NKG2D and in turn severe impairment of the antitumor immune response of NK and CD8(+) T cells. This is considered to promote tumor immune evasion and also to compromise host resistance to infections. MICA is the most polymorphic non-classical class I gene. A possible association of MICA polymorphism with genetic predisposition to different cancer types has been investigated in candidate gene-based studies. Two genome-wide association studies have identified loci in MICA that influence susceptibility to cervical neoplasia and hepatitis C virus-induced hepatocellular carcinoma, respectively. Given the current level of interest in the field of MICA gene, we discuss the genetics and biology of the MICA gene and the role of its polymorphism in cancer. Gaps in our understanding and future research needs are also discussed.

  • 188. Chen, G.
    et al.
    Sidhu, S. S.
    Nilvebrant, Johan
    KTH, School of Biotechnology (BIO), Protein Technology. University of Toronto, Canada.
    Synthetic antibodies in infectious disease2017In: Recombinant Antibodies for Infectious Diseases, Springer-Verlag New York, 2017, p. 79-98Chapter in book (Refereed)
    Abstract [en]

    Rapid spread of microbial resistance and recent outbreaks of viral disease have led to renewed interest in antibody-based therapies for infectious diseases. Synthetic antibody libraries displayed on phage offer unique advantages over traditional immunization-based antibody generation, including full control over library design and selection conditions. The technology has matured beyond natural antibodies and is capable of providing novel insights into infectious disease and can generate novel antibodies that cannot be produced by the natural immune system. This chapter gives an overview of recombinant antibody library technology with an emphasis on our work using a highly successful synthetic single framework Fab library. We demonstrate its utility in targeting viruses and bacterial toxins in five case studies.

  • 189.
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.

    Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.

    Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

  • 190.
    Chenna Narendra, Sudeep
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Chalise, Jaya Prakash
    Osaka Univ, Japan.
    Biggs, Sophie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kalinke, Ulrich
    Zentrum Expt and Klin Infekt Forsch, Germany.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Regulatory T-Cells Mediate IFN-alpha-Induced Resistance against Antigen-Induced Arthritis2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 285Article in journal (Refereed)
    Abstract [en]

    Objective: CD4(+)FoxP3(+)CD25(+) regulatory T-cells (T-regs) are important for preventing tissue destruction. Here, we investigate the role of T-regs for protection against experimental arthritis by IFN-alpha. Methods: Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP(+/-) mice [allowing selective depletion of T-regs by diphtheria toxin (DT)] and CD4-Cre(+/-) IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-alpha or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine. T-regs were depleted in DT-treated Foxp3DTReGFP(+/-) mice and enumerated by FoxP3 staining. Suppressive capacity of FACS-sorted CD25(+high)CD4(+) T-regs was tested in vivo by adoptive transfer and ex vivo in cocultures with antigen-stimulated CFSE-stained T-responder (CD25-CD4(+)) cells. IDO was inhibited by 1-methyl tryptophan. Results: Both control mice and mice devoid of IFNAR-signaling in T helper cells were protected from arthritis by IFN-alpha. Depletion of T-regs in the arthritis phase, but not at immunization, abolished the protective effect of IFN-alpha and kynurenine against arthritis. IFN-alpha increased the number of T-regs in ex vivo cultures upon antigen recall stimulation but not in naive cells. IFN-alpha also increased the suppressive capacity of T-regs against mBSA-induced T-responder cell proliferation ex vivo and against arthritis when adoptively transferred. The increased suppressive activity against proliferation conferred by IFN-alpha was clearly reduced by in vivo inhibition of IDO at immunization, which also abolished the protective effect of IFN-alpha against arthritis. Conclusion: By activating IDO during antigen sensitization, IFN-alpha activates T-regs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-alpha suppresses inflammation.

  • 191.
    Chenxiao, Liu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Characteristics of Vg9Vd2 T cell in colon cancer progressionManuscript (preprint) (Other academic)
  • 192. Cherif, Mariama K.
    et al.
    Sanou, Guillaume S.
    Bougouma, Edith C.
    Diarra, Amidou
    Ouedraogo, Alphonse
    Dolo, Amagana
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cavanagh, David R.
    Theisen, Michael
    Modiano, David
    Sirima, Sodiomon B.
    Nebie, Issa
    Is Fc gamma receptor IIA (Fc gamma RIIA) polymorphism associated with clinical malaria and Plasmodium falciparum specific antibody levels in children from Burkina Faso?2015In: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 142, p. 41-46Article in journal (Refereed)
    Abstract [en]

    In the present study, the influences of Fc gamma RIIA polymorphism on susceptibility to malaria and antibody responses to Plasmodium falciparum antigens were analyzed in children. We recruited 96 healthy children between 3 and 10 years at the beginning of the high transmission season and we followed up for 5 months through the high transmission season to assess the parasitological, immunological and genetic endpoints in relation to clinical malaria status. There was a similar distribution of homozygous and heterozygous individuals carrying the Fc gamma RIIA-131R/R and Fc gamma RIIA-131R/H allele, whereas the number of Fc gamma RIIA-131H/H homozygous individuals was lower. P. falciparum infection frequency was not associated with the Fc gamma RIIa-131R/H polymorphism. Only IgG antibody responses to GLURP R0 showed a significant association between antibody levels and Fc gamma RIIA polymorphism (p = 0.02). IgG levels to MSP2a were significantly higher in children who did not experience any clinical malaria episode compared to those who experienced at least one malaria episode (p = 0.019). Cytophilic and non-cytophylic IgG subclass levels were higher in children without malaria than those who experienced at least one malaria episode. This difference was statistically significant for IgG1 to MSP3 (p = 0.003) and to MSP2a (p = 0.006); IgG3 to MSP2a (p = 0.007) and to GLURP R0 (p = 0.044); IgG2 to MSP2b (p = 0.007) and IgG4 to MSP3 (p = 0.051) and to MSP2a (p = 0.049). In this study, homozygous carriers of the Fc gamma RIIA-131R/R allele had higher malaria-specific antibody levels compare to the heterozygous carriers Fc gamma RIIA-131R/H alleles and to homozygous carriers of Fc gamma RIIA-131H/H alleles. The pre-existing antibodies responses were related to a reduced subsequent risk of clinical malaria.

  • 193. Chinh, Bkrong
    et al.
    Alsøe, Lene
    Lindvall, Jessica M.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sulheim, Dag
    Fagermoen, Even
    Winger, Anette
    Kaarbø, Mari
    Nilsen, Hilde
    Bruun Wyller, Vegard
    Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival2017In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, article id 102Article in journal (Refereed)
    Abstract [en]

    Background

    Chronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group.

    Methods

    CFS patients (12-18 years old) were recruited nation-wide to a single referral center as part of the Nor-CAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/ relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings.

    Results

    A total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated.

    Conclusion

    Adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise.

  • 194. Chiu Götlind, Y. Y.
    et al.
    Raghavan, S.
    Bland, P. W.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    CD4+FoxP3+ regulatory T cellsare functionally active in the Gαi2−/− mouse, but do not prevent thedevelopment of colitis2010Conference paper (Other academic)
  • 195.
    Chlibek, Roman
    et al.
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic..
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    van Rijckevorsel, Gini
    Publ Hlth Serv Amsterdam, Dept Infect Dis, Amsterdam, Netherlands..
    Richardus, Jan H.
    Municipal Publ Hlth Serv Rotterdam Rijnmond, Rotterdam, Netherlands..
    Plassmann, Georg
    Unterfrintroper Hausarztzentrum, Essen, Germany..
    Schwarz, Tino F.
    Stiftung juliusspital, Cent Lab, Wurzburg, Germany.;Stiftung juliusspital, Vaccinat Ctr, Wurzburg, Germany..
    Catteau, Gregory
    GSK Vaccines, Wavre, Belgium..
    Lal, Himal
    GSK Vaccines, King Of Prussia, PA USA..
    Heineman, Thomas C.
    GSK Vaccines, King Of Prussia, PA USA..
    Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults2016In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 34, no 6, p. 863-868Article in journal (Refereed)
    Abstract [en]

    Background: An investigational subunit vaccine containing the varicella-zoster virus (VZV) glycoprotein E (gE) and the AS01(B) adjuvant system is being evaluated for the prevention of herpes zoster (HZ) in older adults. A phase II trial evaluating different formulations of this vaccine (containing 25 mu g, 50 mu g, or 100 mu g gE) was conducted in adults >= 60 years of age and showed that all formulations elicited robust cellular and humoral immune responses for up to 3 years after vaccination. In this follow-up study in subjects who received two doses of the 50 mu g gE/AS01(B) formulation (HZ/su), we assessed the persistence of the immune responses for up to 6 years after vaccination. Methods: This phase II, open-label, multicenter, single-group trial conducted in the Czech Republic, Germany, Sweden, and the Netherlands followed 129 subjects who had received two doses (2 months apart) of HZ/su during the initial trial. Vaccine-induced immune responses (frequencies of gE-specific CD4(+) T cells expressing >= 2 activation markers and serum anti-gE antibody concentrations) were evaluated at 48, 60, and 72 months after the first HZ/su dose. Results: Six years after vaccination with HZ/su, gE-specific cell-mediated immune responses and anti-gE antibody concentrations had decreased by 20-25% from month 36, but remained higher than the prevaccination values. At month 72, the gE-specific cell-mediated immune response was 3.8 times higher than the prevaccination value (477.3 vs. 119.4 activated gE-specific CD4(+) T cells per 10(6) cells), and the anti-gE antibody concentration was 7.3 times higher than the prevaccination value (8159.0 vs. 1121.3 mIU/mL). No vaccine-related serious adverse events were reported between months 36 and 72. Conclusions: gE-specific cellular and humoral immune responses persisted for 6 years after two-dose vaccination with HZ/su in healthy older adults. No safety concerns were identified.

  • 196. Ch'ng, Jun-Hong
    et al.
    Sirel, Madle
    Zandian, Arash
    del Pilar Quintana, Maria
    Chan, Sherwin Chun Leung
    Moll, Kirsten
    Tellgren-Roth, Åsa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nilsson, Peter
    Qundos, Ulrika
    Wahlgren, Mats
    Epitopes of anti-RIFIN antibodies and characterization of rif-expressing Plasmodium falciparum parasites by RNA sequencing2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43190Article in journal (Refereed)
    Abstract [en]

    Variable surface antigens of Plasmodium falciparum have been a major research focus since they facilitate parasite sequestration and give rise to deadly malaria complications. Coupled with its potential use as a vaccine candidate, the recent suggestion that the repetitive interspersed families of polypeptides (RIFINs) mediate blood group A rosetting and influence blood group distribution has raised the research profile of these adhesins. Nevertheless, detailed investigations into the functions of this highly diverse multigene family remain hampered by the limited number of validated reagents. In this study, we assess the specificities of three promising polyclonal anti-RIFIN antibodies that were IgG-purified from sera of immunized animals. Their epitope regions were mapped using a 175,000-peptide microarray holding overlapping peptides of the P. falciparum variable surface antigens. Through immunoblotting and immunofluorescence imaging, we show that different antibodies give varying results in different applications/assays. Finally, we authenticate the antibody-based detection of RIFINs in two previously uncharacterized non-rosetting parasite lines by identifying the dominant rif transcripts using RNA sequencing.

  • 197.
    Cholujová, Dana
    et al.
    Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Jakubíková, Jana
    Laboratory of Tumor Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Kubeš, Miroslav
    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Arendacká, Barbora
    Institute of Measurement Science, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Sapák, Michal
    Institute of Immunology, Medical Faculty of Comenius University, Sasinkova 4, Bratislava, Slovakia.
    Ihnatko, Robert
    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Sedlák, Ján
    Laboratory of Tumor Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Comparative study of four fluorescent probes for evaluation of natural killer cell cytotoxicity assays2008In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 213, no 8, p. 629-640Article in journal (Refereed)
    Abstract [en]

    Cytotoxicity is one of the major defence mechanisms against both virus-infected and tumor cells. Radioactive 51chromium (51Cr) release assay is a “gold standard” for assessment of natural killer (NK) cytolytic activity in vitro. Several disadvantages of this assay led us to design alternative tools based on flow cytometry analysis. Four different fluorescent dyes, calcein acetoxymethyl ester (CAM), carboxyfluorescein succinimidyl ester (CFSE), Vybrant DiO (DiO) and MitoTracker Green (MTG) were tested for labeling of NK target K-562 cells. Target staining stability, spontaneous release of fluorochromes and subsequent accumulation in bystander unstained cells were measured using fluorimetry and flow cytometry. Healthy donor peripheral blood mononuclear cells and affinity column purified NK cells were used as effectors coincubated with target K-562 cells at different E:T ratios for 3h and 90min, respectively. Fluorescent probe 7-amino-actinomycin D was used for live and dead cell discrimination. Bland–Altman statistical method was applied to measure true agreement for all CAM–51Cr, CFSE–51Cr, DiO–51Cr and MTG–51Cr pairs analyzed. Based on the data, none of the four proposed methods can be stated equivalent to the standard 51Cr release assay. Considering linear relationships between data obtained with four fluorochromes and 51Cr release assay as well as linear regression analysis with R2=0.9393 value for CAM–51Cr pair, we found the CAM assay to be the most closely related to the 51Cr assay.

  • 198.
    Christensen, Kjeld
    et al.
    Örebro University Hospital.
    Kozarcanin, Huda
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Evidence of contact activation in patients suffering from ST-elevation myocardial infarction2016In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 141, p. 158-162Article in journal (Refereed)
    Abstract [en]

    Introduction: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. Methods and patients: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3 days post-percutaneous intervention (PCI) and, in one-third of the patients, 3 months after PCI. In order to investigate the degree of Factor XII (FXII) activation, changes in FXIIa/AT and FXIIa/C1INH complex levels were quantified by ELISA. Results: FXIIa/AT levels at admission (0.89 +/- 0.50; p < 0.01) were significantly higher than those in normal individuals (0.39 +/- 0.28), but the levels after 1-3 days (0.33 +/- 0.33; p < 0.05) were essentially normalized. In contrast, the FXII/C1INH levels at admission (1.40 +/- 0.72; p < 0.001) and after 1-3 days (0.83 +/- 0.59; p < 0.001) were both significantly higher than those in normal individuals (0.40 +/- 0.30). FXIIa/AT and FXIIa/C1INH complexes at admission (p < 0.001; p < 0.001) and after 1-3 days (p < 0.02; p < 0.001) were significantly different from those at 3 months. No significant differences were observed when the data were stratified for patency (open/closed culprit lesions). Conclusion: Both FXIIa/AT and FXIIa/C1INH complexes were significantly increased and reflected the activation of FXII in STEMI patients at admission. In particular, FXIIa/AT complex elevations support the hypothesis that clot propagation-mediated FXII activation had occurred, and this activation may be a target for anticoagulation in patients with cardiac infarction. Based on previous studies, the FXIIa/C1INH complex levels were primarily interpreted to reflex endothelial cell activation. (C) 2016 Published by Elsevier Ltd.

  • 199.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.

  • 200.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    von Herrath, Matthias
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA;Novo Nordisk Res Ctr, Seattle, WA 98109 USA.
    Regulatory Immune Mechanisms beyond Regulatory T Cells2019In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 40, no 6, p. 482-491Article, review/survey (Refereed)
    Abstract [en]

    In autoimmunity, aggressive immune responses are counteracted by suppressive rejoinders. For instance, FOXP3-expressing regulatory T cells (Tregs), have shown remarkable effects in limiting autoimmunity in preclinical models. However, early results from human Treg trials have not been as positive. Here, we highlight questions surrounding Treg transfers as putative treatments for autoimmunity. We discuss whether lack of antigenic recognition might be key to shifting cells from contributing to an aggressive autoresponse, to being part of a regulatory network. Moreover, we argue that identifying the physiological range of immunosuppression of Tregs might help potentiate their efficacy. We propose widening the view on immunoregulation by considering the participation of CD8(+) Tregs in this process, which could have major implications in autoimmunity.

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