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  • 51. Apcher, Sebastien
    et al.
    Martins, Rodrigo Prado
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Equipe Labellisée la Ligue Contre le Cancer, Inserm UMR1162, Université Paris, France ; RECAMO, Masaryk Memorial Cancer Institute, Czech Republic.
    The source of MHC class I presented peptides and its implications2016In: Current Opinion in Immunology, ISSN 0952-7915, E-ISSN 1879-0372, Vol. 40, p. 117-122Article, review/survey (Refereed)
    Abstract [en]

    The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-todate account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.

  • 52.
    Apostolou, Eirini
    et al.
    Univ Athens, Greece; Univ Athens, Greece.
    Moustardas, Petros
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Acad Athens, Greece.
    Iwawaki, Takao
    Kanazawa Med Univ, Japan.
    Tzioufas, Athanasios G.
    Univ Athens, Greece; Univ Athens, Greece.
    Spyrou, Ioannis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ablation of the Chaperone Protein ERdj5 Results in a Sjogrens Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 506Article in journal (Refereed)
    Abstract [en]

    Objective: Sjogrens syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity. Methods: In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate). Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice. Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.

  • 53.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Giusti, Pablo
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Boström, Stephanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Varani, Stefania
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Interethnic Differences in Antigen-Presenting Cell Activation and TLR Responses in Malian Children during Plasmodium falciparum Malaria2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18319-Article in journal (Refereed)
    Abstract [en]

    The Fulani ethnic group from West Africa is relatively better protected against Plasmodium falciparum malaria as compared to other sympatric ethnic groups, such as the Dogon. However, the mechanisms behind this lower susceptibility to malaria are largely unknown, particularly those concerning innate immunity. Antigen-presenting cells (APCs), and in particular dendritic cells (DCs) are important components of the innate and adaptive immune systems. Therefore, in this study we investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. Lower frequency and increased activation was observed in circulating plasmacytoid DCs and BDCA-3+ myeloid DCs of infected Fulani as compared to their uninfected counterparts. Conversely, a higher frequency and reduced activation was observed in the same DC subsets obtained from peripheral blood of P. falciparum-infected Dogon children as compared to their uninfected peers. Moreover, infected individuals of both ethnic groups exhibited higher percentages of both classical and inflammatory monocytes that were less activated as compared to their non-infected counterparts. In line with APC impairment during malaria infection, TLR4, TLR7 and TLR9 responses were strongly inhibited by P. falciparum infection in Dogon children, while no such TLR inhibition was observed in the Fulani children. Strikingly, the TLR-induced IFN-γ release was completely abolished in the Dogon undergoing infection while no difference was seen within infected and non-infected Fulani. Thus, P. falciparum infection is associated with altered activation status of important APC subsets and strongly inhibited TLR responses in peripheral blood of Dogon children. In contrast, P. falciparum induces DC activation and does not affect the innate response to specific TLR ligands in Fulani children. These findings suggest that DCs and TLR signalling may be of importance for the protective immunity against malaria observed in the Fulani.

  • 54.
    Ardesjö Lundgren, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of complement C3 as an autoantigen in inflammatory bowel disease2010In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 22, no 4, p. 429-436Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Autoantibodies against goblet cells in the gastrointestinal mucosa have been described in patients with inflammatory bowel disease (IBD) but a corresponding autoantigen has not yet been identified. The aim of this study was to identify such an antigen. METHODS: First, 10 candidate autoantigens were discarded based on double stainings of appendiceal sections and a mucin-producing cell line (HT29-mtx). Second, an appendiceal cDNA library was immunoscreened with IBD sera. RESULTS: Three out of 48 positive clones were identified as complement C3. Using immunoprecipitation of in vitro transcribed and translated C3, seven of 17 primary sclerosing cholangitis patient sera, 15 of 65 IBD sera, and none out of 54 sera from healthy blood donors showed C3 immunoreactivity. The results were confirmed using western blot and an enzyme-linked immunosorbent assay with alternative sources of C3 protein. CONCLUSION: In conclusion, we have identified complement C3 as a potential autoantigen in IBD and primary sclerosing cholangitis.

  • 55. Arkema, Elizabeth V
    et al.
    Jonsson, Jerker
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bruchfeld, Judith
    Feltelius, Nils
    Askling, Johan
    Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 6, p. 1212-1217Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies.

    METHODS: Data from the Swedish National Population Registers, Tuberculosis Register and the Swedish Biologics Register were used to conduct a prospective population-based national cohort study (2002-2011). We estimated the rate of incident TB in the general population and in a cohort of biological-naïve and biological-exposed patients diagnosed with RA. Cox models were used to estimate HRs with particular attention to risks by calendar and follow-up time and individual biologics.

    RESULTS: Compared to the general population, RA patients not exposed to biologicals had a fourfold increased risk of TB (HR 4.2; 95% CI 2.7 to 6.7), which did not decline over calendar time. In contrast, the risk of TB in the biological-exposed RA population decreased since 2002 compared with biological-naïve; from HR=7.9 (95% CI 3.3 to 18.9) in 2002-2006 to HR=2.4 (95% CI 0.9 to 6.1) in 2007-2011. The HRs for most recent exposure to adalimumab and infliximab compared with etanercept were 3.1 (95% CI 0.8 to 12.5) and 2.7 (95% CI 0.7 to 10.9), respectively, and the HR for etanercept compared with biological-naïve RA was 1.7 (95% CI 0.6 to 4.6).

    CONCLUSIONS: In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

  • 56. Arkestal, Kurt
    et al.
    Mints, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Enocson, Anders
    Linton, Ludvig
    Marits, Per
    Glise, Hans
    Andersson, John
    Winqvist, Ola
    CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow2018In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 88, no 6, article id UNSP e12722Article in journal (Refereed)
    Abstract [en]

    Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies.

  • 57.
    Arko-Mensah, John
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Immune evasion and identification of biomarkers associated with mycobacterial infection2007Licentiate thesis, comprehensive summary (Other academic)
  • 58.
    Arko-Mensah, John
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Mycobacterial infection: Immune evasion, host susceptibility and immunological markers of diagnostic importance2008Doctoral thesis, monograph (Other academic)
    Abstract [en]

    IIn the first study, we investigated the functional implications of prolonged TLR signalling on IFN-γ mediated killing of mycobacteria by murine macrophages in vitro. TLR2, but not TLR4 ligation interfered with IFN-γ mediated killing of mycobacteria in macrophages. In terms of mechanisms, neither TNF nor nitric oxide (NO) production was significantly affected, and the refractoriness induced could be reversed with increasing amounts of IFN-γ In the second study, we aimed to identify immunological markers of diagnostic importance in both the respiratory tract and serum during pulmonary mycobacterial infection in mice. We found that increased levels of immunological markers in the respiratory tract, but not serum, correlated better with active mycobacterial infection in the lungs, suggesting that the immune response in the respiratory tract is more reflective of the infection status and pathology than the systemic response. Finally, we investigated the level and nature of immune responses to pulmonary mycobacterial infection in BALB/c and C57BL/6 mice, two mouse strains known to exhibit different susceptibilities to infection with several intracellular pathogens, including mycobacteria. We showed that increased susceptibility of BALB/c mice to early mycobacterial infection was associated with reduced Th1 immune responses, and increased sTNFR secretion in the lung. Moreover, BALB/c mice recruited fewer monocytes/macrophages to the lung, and although IFN-γ stimulation of infected bone marrow derived macrophages in both mouse strains resulted in induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The work presented in this thesis provide further insight into the mechanisms involved in the host-pathogen interaction; from persistence, to the immunological processes induced by the pathogen, to susceptibility of the host to infection.

  • 59. Arko-Mensah, John
    et al.
    Rahman, Muhammad Jubayer
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Julián, Eshter
    Horner, Gudron
    Singh, Mahavir
    Fernández, Carmen
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice2009In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15, no 8, p. 777-786Article in journal (Refereed)
    Abstract [en]

    Immunological tests for the diagnosis of tuberculosis (TB) have relied mostly on detection of immune markers in serum or release of cytokines by mononuclear cells in vitro. These tests, although useful, sometimes fail to discriminate between active infection and contact with mycobacteria or vaccination. TB is primarily a disease of the lung, and therefore identification of immunological markers in the respiratory tract will be more likely to reflect the infection status or disease activity. In this study, it is demonstrated that active infection of mice with Mycobacterium bovis bacille Calmette-Guérin (BCG), but not exposure to heat-killed BCG, induced production of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) or soluble tumour necrosis factor receptors (sTNFRs) locally in the lungs, as detected in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between bacterial growth in the lung and levels of sTNFRs, and to some extent IL-12 and IFN-gamma, in BAL fluid. Furthermore, sTNFR levels increased significantly in BAL fluid after reactivation of controlled infection with dexamethasone, and this correlated with increased bacterial growth in the lungs. Finally, infection, but not exposure to non-replicating mycobacteria, induced specific IgG and IgA in BAL fluid. Elevated levels of all biomarkers measured were also detected in the serum, but correlation with infection was not as clear as in the case of BAL fluid. Taken together, the detection of sTNFRs and mycobacterium-specific antibodies, especially IgA, locally in the lungs could be used as immunological markers for the diagnosis of TB.

  • 60.
    Arnberg, Filip K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry. Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden..
    Lekander, Mats
    Stockholm Univ, Stress Res Inst, S-10691 Stockholm, Sweden.;Karolinska Inst, Osher Ctr Integrat Med, Stockholm, Sweden..
    Morey, Jennifer N.
    Univ Kentucky, Dept Psychol, 125 Kastle Hall, Lexington, KY 40506 USA..
    Segerstrom, Suzanne C.
    Univ Kentucky, Dept Psychol, 125 Kastle Hall, Lexington, KY 40506 USA..
    Self-rated health and interleukin-6: Longitudinal relationships in older adults2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, p. 226-232Article in journal (Refereed)
    Abstract [en]

    Background: Both self-rated health (SRH) and inflammation are implicated in chronic diseases and premature mortality. Better SRH is associated with lower proinflammatory cytokines, but there is little evidence about whether this relationship is more stable or dynamic. Objective: To study the between- and within-person associations between SRH and IL-6. Methods: Older adults (N = 131; M-age = 75 years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6 months over a period up to 5 years. Age, sex, BMI, neuroticism, and statin use were examined as covariates in multilevel models. Results: In bivariate models, better SRH, lower BMI, younger age, and female sex correlated with lower IL-6. In multilevel models, stable SRH (between-person differences; p < .001) but not dynamic SRH (within-person changes; p = .93) correlated with IL-6. The stable relationship persisted with demographic and health covariates in the model. Conclusions: Better stable SRH but not dynamic SRH was robustly associated with lower IL-6 among older adults, lending support to previous cross-sectional findings on the relation between inflammatory markers and SRH. The findings suggest that trait-like mechanisms, rather than changes over a time scale of 6-month waves, govern this association. To further investigate the mechanisms behind the SRH-IL-6 association, studies with different measurement frequencies, higher within-person variability, and experimental approaches are warranted.

  • 61. Arnheim, L
    et al.
    Dillner, Joakim
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden.
    Sanjeevi, CB
    A population-based cohort study of KIR genes and genotypes in relation to cervical intraepithelial neoplasia2005In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 65, no 3, p. 252-259Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are involved both in control of virus infections and in elimination of tumor cells. Killer immunoglobulin-like receptors (KIRs) either activate or inhibit NK cell-mediated cytolysis, protecting healthy cells from destruction while enabling killing of abnormal cells. To investigate whether KIR genes or genotypes are associated with cervical carcinogenesis, a nested case-control study of 65 case women with cervical intraepithelial neoplasia (CIN) diagnosed during a 6-year follow-up of 15,234 women and 150 control women from the same cohort that remained healthy was performed. More than 70 different genotypes were observed, and 33 of which had not been described previously. An A-genotype including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, and KIR2DS4 was associated with increased risk of CIN (OR 6.7; 95% CI 1.7-26.3), and KIR2DL5B*002 appeared to have an inverse association with disease (OR 0.5; 95% CI 0.5-2.9). There was no association of CIN with the number of activating KIR genes. There was also no association between KIR genes and type of human papilloma virus or with other CIN-related immune response genes. It was concluded that certain KIR genes and genotypes may associate with cervical neoplasia.

  • 62. Arruda, L. C. M.
    et al.
    Gaballa, A.
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, no 6, p. 1859-1870Article in journal (Refereed)
    Abstract [en]

    Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft γδ TCR repertoire on clinical outcomes following HSCT. Using a high-throughput sequencing platform, we sought to analyze the TCR γ-chain (TRG) repertoire of γδ T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV+/- The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV+ donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.

  • 63.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Kelly, Anne
    iRiSC-Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Karolinska University Hospital, Solna, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Demirel, Isak
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Fredlund, Hans
    iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Persson, Alexander
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent2019In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 6193186Article in journal (Refereed)
    Abstract [en]

    Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1 (IL-1), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanismpriming and licensing of inflammasome activationbut there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1 release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.

  • 64.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Sahdo, Berolla
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Balcha, Ermias
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Swedenital, Örebro, Sweden.
    Kelly, Anne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    C10X polymorphism in the CARD8 gene is associated with bacteraemia2014In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed)
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

  • 65.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ska obeprövade metoder få användas i svensk sjukvård?2017In: PIObladet, ISSN 1103-6249, no 2, p. 10-11Article in journal (Other academic)
  • 66.
    Assadi, G.
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Saleh, R.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Hadizadeh, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Vesterlund, L.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Törkvist, L.
    Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, A. S.
    Gatroenterology Unit, Department of Internal Medicine, Sahlgren's University Hospital/Östra, Göteborg, Sweden.
    Harris, H. E.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sundberg, E.
    Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, M.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis2016In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 17, no 4, p. 261-264Article in journal (Refereed)
    Abstract [en]

    The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

  • 67.
    Athlin, Simon
    et al.
    Örebro University Hospital.
    Kaltoft, Margit
    Statens Serum Institut, Copenhagen, Denmark.
    Slotved, Hans-Christian
    Statens Serum Institut, Copenhagen, Denmark.
    Herrmann, Björn
    Uppsala University, Uppsala, Sweden.
    Holmberg, Hans
    Örebro University Hospital.
    Konradsen, Helle Bossen
    Statens Serum Institut, Copenhagen, Denmark.
    Strålin, Kristoffer
    Örebro University Hospital, Örebro, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Association between serotype-specific antibody response and serotype characteristics in patients with pneumococcal pneumonia, with special reference to degree of encapsulation and invasive potential2014In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, no 11, p. 1541-1549Article in journal (Refereed)
    Abstract [en]

    We studied the immunoglobulin (Ig) response to causative serotype-specific capsular polysaccharides in adult pneumococcal pneumonia patients. The serotypes were grouped according to their degree of encapsulation and invasive potential. Seventy patients with pneumococcal pneumonia, 20 of whom were bacteremic, were prospectively studied. All pneumococcal isolates from the patients were serotyped, and the Ig titers to the homologous serotype were determined in acute- and convalescent-phase sera using a serotype-specific enzyme-linked immunosorbent assay. The Ig titers were lower in bacteremic cases than in nonbacteremic cases (P < 0.042). The Ig titer ratio (convalescent/acute titer) was ≥2 in 33 patients, 1 to 1.99 in 20 patients, and <1 in 17 patients. Patients ≥65 years old had a lower median Ig titer ratio than did younger patients (P < 0.031). The patients with serotypes with a thin capsule (1, 4, 7F, 9N, 9V, and 14) and medium/high invasive potential (1, 4, 7F, 9N, 9V, 14, and 18C) had higher Ig titer ratios than did patients with serotypes with a thick capsule (3, 6B, 11A, 18C, 19A, 19F, and 23F) and low invasive potential (3, 6B, 19A, 19F, and 23F) (P < 0.05 for both comparisons after adjustment for age). Ig titer ratios of <1 were predominantly noted in patients with serotypes with a thick capsule. In 8 patients with pneumococcal DNA detected in plasma, the three patients with the highest DNA load had the lowest Ig titer ratios. In conclusion, a high antibody response was associated with serotypes with a thin capsule and medium/high invasive potential, although a low antibody response was associated with serotypes with a thick capsule and a high pneumococcal plasma load.

  • 68.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Seminal Influence on the Oviduct: Mating and/or semen components induce gene expression changes in the pre-ovulatory functional sperm reservoir in poultry and pigs2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Internal fertilization occurs in birds and eutherian mammals. Foetal development, however, is either extra- respectively intra-corpore (egg vs uterus). In these animal classes, the female genital tract stores ejaculated spermatozoa into a restricted oviductal segment; the functional pre-ovulatory sperm reservoir, where they survive until ovulation/s occur. Paradoxically, this immunologically foreign sperm suspension in seminal fluid/plasma, often microbiologically contaminated, ought to be promptly eliminated by the female local immune defence which, instead, tolerates its presence. The female immune tolerance is presumably signalled via a biochemical interplay of spermatozoa, as well as the peptides and proteins of the extracellular seminal fluid, with female epithelial and immune cells. Such interplay can result in gene expression shifts in the sperm reservoir in relation to variations in fertility. To further aid our understanding of the underlying mechanisms, this thesis studied the proteome of the seminal fluid (using 2D SDS-PAGE and mass spectrometry) including cytokine content (using Luminex and/or ELISA) of healthy, sexually mature and fertile boars and cocks. As well, gene expression changes (using cDNA microarray) in the oviductal sperm reservoirs of sexually-mature females, mated or artificially infused with homologous sperm-free seminal fluid/plasma were studied. Pigs were of commercial, fertility-selected modern breeds (Landrace), while chicken belonged to the ancestor Red Junglefowl (RJF, low egg laying-capacity), a selected egg-layer White Leghorn (WL) and of their Advanced Intercross Line (AIL). Ejaculates were manually collected as single sample in cocks or as the sperm-rich fraction [SRF] and the post- SRF fraction in boars to harvest seminal fluid/plasma for proteome/cytokine and infusion-studies. Oviducts were retrieved for gene-expression analyses via microarray immediately post-mortem (chicken) or at surgery (pig), 24 h after mating or genital infusion. In pigs, the protein-rich seminal plasma showed the highest amounts of cytokines [interferon-γ, interferon gamma-induced protein 10 (IP-10/CXCL10), macrophage derived chemokine (MDC/CCL22), growth-regulated oncogene (GRO/CXCL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemo-attractant protein-1 (MCP-1/ CCL2), interleukin (IL)-6, IL-8/CXCL8, IL-10, IL-15, IL-17 and transforming growth factor (TGF)-β1-3) in the larger, protein-rich and sperm-poor post-SRF, indicating its main immune signalling influence. Chicken showed also a plethora of seminal fluid proteins with serum albumin and ovotransferrin being conserved through selection/evolution. However, they showed fewer cytokines than pigs, as the anti-inflammatory/immune-modulatory TGF-β2 or the pro-inflammatory CXCL10. The RJF contained fewer immune system process proteins and lacked TGF-β2 compared to WL and AIL, suggesting selection for increased fertility could be associated with higher expression of immune-regulating peptides/proteins. The oviductal sperm reservoir reacted in vivo to semen exposure. In chicken, mating significantly changed the expression of immune-modulatory and pH-regulatory genes in AIL. Moreover, modern fertile pigs (Landrace) and chicken (WL), albeit being taxonomically distant, shared gene functions for preservation of viable sperm in the oviduct. Mating or SP/SF-infusion were able to change the expression of comparable genes involved in pH-regulation (SLC16A2, SLC4A9, SLC13A1, SLC35F1, ATP8B3, ATP13A3) or immune-modulation (IFIT5, IFI16, MMP27, ADAMTS3, MMP3, MMP12). The results of the thesis demonstrate that both mating and components of the sperm-free seminal fluid/plasma elicit gene expression changes in the pre-ovulatory female sperm reservoir of chickens and pigs, some conserved over domestication and fertility-selection.

  • 69. Attarha, Sanaz
    et al.
    Roy, Ananya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation2017In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 37, p. 81-92Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.

  • 70.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, S.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm Univ, Dept Neurochem, S-10691 Stockholm, Sweden.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 35, p. 100-111Article in journal (Refereed)
    Abstract [en]

    Acrylamide is a well-known neurotoxic compound and people get exposed to the compound by food consumption and environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed resulting in a risk for developmental neurotoxicity. In this study, the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as alerting indicators for developmental neurotoxicity. For both cell lines, acrylamide reduced the number of viable cells by reducing proliferation and inducing cell death in undifferentiated cells. Acrylamide concentrations starting at 10 fM attenuated the differentiation process in SH-SY5Y cells by sustaining cell proliferation and neurite outgrowth was reduced at concentrations from 10 pM. Acrylamide significantly reduced the number of neurons starting at 1 mu M and altered the ratio between the different phenotypes in differentiating C17.2 cell cultures. Ten micromolar of acrylamide also reduced the expression of the neuronal and astrocyte biomarkers. Although the neurotoxic concentrations in the femtomolar range seem to be specific for the SH-SY5Y cell line, the fact that micromolar concentrations of acrylamide seem to attenuate the differentiation process in both cell lines raises the interest to further investigations on the possible developmental neurotoxicity of acrylamide.

  • 71.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Studies on Plasmodium falciparum asexual blood stage antigens: RAP-2/RSP-2 and Pf332 in focus2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The life cycle of the malaria parasite is very complex and provides a number of potential targets for vaccination. In this thesis, data on two plasmodial asexual blood stage antigens (RAP-2 and Pf332) are presented.

    A partial aim of the work presented herein was to investigate the mechanisms responsible for the destruction of erythroid cells in anaemia, and more specifically to define the role of the rhoptry associated protein (RAP)-2 and other members of the RAP complex, RAP-1 and -3 in processes resulting in anaemia. Antibodies to the RAP complex were shown to have the potential to mediate the destruction of RAP-2-tagged erythroid cells by phagocytosis or by complement activation and lysis. In addition, antibodies to RAP-1 and RAP-2 could induce the apoptotic death of RAP-2- tagged erythroblasts. The frequency and functionality of naturally occurring RAP-2 antibodies in the sera of anaemic and non-anaemic Cameroonian children were also investigated. All sera tested contained RAP-2-reactive antibodies by both immunofluorescence and flow cytometry. The anaemic group of children had higher levels of IgG than the non-anaemic ones, while the levels of IgM were similar. With respect to IgG subclasses, higher levels of IgG3 were seen in the non-anaemic individuals as compared to anaemic subjects. The non-anaemic individuals recognised a greater proportion of RAP-2-tagged RBCs and activated complement to a greater extent than the anaemic ones.

    Earlier studies observed that humans continuously exposed to malaria, recognised Pf332 extensively. Further studies revealed that Pf332 antibodies were able to inhibit parasite growth and cytoadherence in vitro. Making use of Pf332-C231, a sub-fragment of Pf332, we studied the effects/mode of action of C231-specific antibodies on P. falciparum parasite growth and development in vitro. The antibodies appeared to act mainly on late stage parasites by two main mechanisms: 1) through the induction of abnormal/pyknotic parasites, and, 2) RBC lysis (disintegration of RBCs), thus limiting parasite growth and development. The antibody isotype in this context was IgG. Following the removal of immune pressure, parasites resumed growth, albeit at a much slower rate. The results suggest that during natural infections, antibodies to C231 could play a role in parasite control.

    In summary, these data suggest that antibodies to both antigens could be instrumental in immune responses leading to disease control, but could also mediate pathology.

  • 72.
    Awah, Nancy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Achidi, E.
    Mariuba, L. A.
    Nogueira, P. A.
    Orlandi, P.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Gysin, J.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Antibodies to the Plasmodium falciparum rhoptry protein RAP-2/RSP-2 in relation to anaemia in Cameroonian children2011In: Parasite immunology (Print), ISSN 0141-9838, E-ISSN 1365-3024, Vol. 33, no 2, p. 104-115Article in journal (Refereed)
    Abstract [en]

    Previous studies have implicated reactive antibodies to the low molecular weight rhoptry-associated proteins (RAP-1, RAP-2/RSP-2 and RAP-3) in erythroid cell destruction during Plasmodium falciparum infection. In this pilot study, the frequency, specificity and functional capacity of naturally acquired anti-RAP-2/RSP-2 antibodies were investigated in the sera of anaemic and nonanaemic malaria-infected Cameroonian children. All sera recognized RAP-2/RSP-2 by FACS, irrespective of the clinical status of the subjects. However, the anaemic children showed higher levels of IgG antibodies than the nonanaemic group, while both groups showed similar levels of IgM antibodies. Only few individuals had detectable levels of RAP-2/RSP-2-specific IgG1 and IgG3 subclass antibodies, while no IgG2 and IgG4 subclass antibodies were detected in these subjects. By ELISA, the anaemic group tended to show higher levels of antibodies to RAP-2/RSP-2 regarding all antibody classes tested, except for IgG4 and IgE. Unexpectedly, sera from the nonanaemic group activated complement to a greater extent than those from the anaemic group. These results need to be confirmed in extended studies but indicate that the effector functions of the RAP-2/RSP-2-reactive antibodies may be more important than their amounts. Such antibodies could play a role in both immunity and pathogenesis during P. falciparum infection.

  • 73. Ayoglu, Burcu
    et al.
    Chaouch, Amina
    Lochmueller, Hanns
    Politano, Luisa
    Bertini, Enrico
    Spitali, Pietro
    Hiller, Monika
    Niks, Eric H.
    Gualandi, Francesca
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bushby, Kate
    Aartsma-Rus, Annemieke
    Schwartz, Elena
    Le Priol, Yannick
    Straub, Volker
    Uhlen, Mathias
    Cirak, Sebahattin
    't Hoen, Peter A. C.
    Muntoni, Francesco
    Ferlini, Alessandra
    Schwenk, Jochen M.
    Nilsson, Peter
    Szigyarto, Cristina Al-Khalili
    Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies2014In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 6, no 7, p. 918-936Article in journal (Refereed)
    Abstract [en]

    Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavo-protein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies.

  • 74. Babiker, Adil A
    et al.
    Magnusson, Peetra U
    Ronquist, Gunnar
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mapping Pro- and Antiangiogenic Factors on the Surface of Prostasomes of Normal and Malignant Cell Origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis.

    METHODS. VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy.

    RESULTS. VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy.

    CONCLUSIONS. Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 75.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Prostasome Involvement in the Development and Growth of Prostate Cancer2010In: The Open Prostate Cancer Journal, ISSN 1876-8229, Vol. 3, p. 1-13Article, review/survey (Refereed)
    Abstract [en]

    Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen after secretion. Even dedifferentiated prostate cancer cells have preserved their ability to produce and export prostasomes to the extracellular space. The precise physiological role of prostasomes is not known, although some of their properties assign them to important physiological and patho-physiological functions that could be exploited in prostate cancer growth and development. In this review, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes will be discussed.

    There are typical differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) as well as in the transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes). CD59, protein kinases and TF exhibit characteristic patterns of overexpression by malignant cell prostasomes. A high ATPase activity is recognized on seminal prostasomes with minimal activity on malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins are phosphorylated by prostasomal protein kinases, namely, complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF is identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes are demonstrated. DU145 and PC-3 cell-derived prostasomes exert a higher clotting effect on whole blood and plasma compared to LNCaP cell-derived and seminal prostasomes.

    In conclusion, malignant cell prostasomes show an increased ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation and inactivation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

  • 76. Babiker, Adil A
    et al.
    Ronquist, Gunnar
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Prostasome Involvement in the Development and of Prostate Cancer2010In: Open Prostate Cancer Journal, ISSN 1876-8229, Vol. 3, p. 1-13Article, review/survey (Refereed)
    Abstract [en]

    Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen after secretion. Even dedifferentiated prostate cancer cells have preserved their ability to produce and export prostasomes to the extracellular space. The precise physiological role of prostasomes is not known, although some of their properties assign them to important physiological and patho-physiological functions that could be exploited in prostate cancer growth and development. In this review, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes will be discussed.There are typical differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) as well as in the transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes). CD59, protein kinases and TF exhibit characteristic patterns of overexpression by malignant cell prostasomes. A high ATPase activity is recognized on seminal prostasomes with minimal activity on malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins are phosphorylated by prostasomal protein kinases, namely, complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF is identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes are demonstrated. DU145 and PC-3 cell-derived prostasomes exert a higher clotting effect on whole blood and plasma compared to LNCaP cell-derived and seminal prostasomes.In conclusion, malignant cell prostasomes show an increased ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation and inactivation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

  • 77.
    Babiker, Adil Abdelgadir
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions with Focus on Prostate Cancer2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen. Their precise physiological role is not known, although some of their properties assign them to important physiological and patho-physiological functions. In this thesis, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes have been identified.

    Differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) have been characterized. The transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes) has been established. CD59, protein kinases and TF were overexpressed by malignant cell prostasomes. ATPase activity was highest on seminal prostasomes with minimal expression by malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins were phosphorylated by prostasomal protein kinases, viz. complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF was identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes were established. DU145 and PC-3-derived prostasomes exerted a higher clotting effect on whole blood and plasma compared to LNCaP and seminal prostasomes.

    In conclusion, malignant cell prostasomes showed higher ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

  • 78.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Iliadou, Anastasia
    Granath, Fredrik
    Ekbom, Anders
    Amini, Rose-Marie
    Feltelius, Nils
    Enblad, Gunilla
    Sundström, Christer
    Klareskog, Lars
    Askling, Johan
    Rosenquist, Richard
    Diffuse large B-cell lymphomas in rheumatoid arthritis display a predominance of non-germinal center typeManuscript (Other academic)
    Abstract
  • 79.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Ekbom, Anders
    Sparén, Pär
    Feltelius, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Klareskog, Lars
    Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study1998In: British Medical Journal, Vol. 317, p. 180-181Article in journal (Refereed)
  • 80.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekbom, Anders
    Catrina, Anca
    Biberfeld, Peter
    Feltelius, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Klareskog, Lars
    Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma2003In: Arthritis & Rheumatism, Vol. 48, no 6, p. 1543-1550Article in journal (Refereed)
  • 81. Baharom, Faezzah
    et al.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smed-Sorensen, Anna
    Human Lung Mononuclear Phagocytes in Health and Disease2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 499Article, review/survey (Refereed)
    Abstract [en]

    The lungs are vulnerable to attack by respiratory insults such as toxins, allergens, and pathogens, given their continuous exposure to the air we breathe. Our immune system has evolved to provide protection against an array of potential threats without causing collateral damage to the lung tissue. In order to swiftly detect invading pathogens, monocytes, macrophages, and dendritic cells (DCs)-together termed mononuclear phagocytes (MNPs)-line the respiratory tract with the key task of surveying the lung microenvironment in order to discriminate between harmless and harmful antigens and initiate immune responses when necessary. Each cell type excels at specific tasks: monocytes produce large amounts of cytokines, macrophages are highly phagocytic, whereas DCs excel at activating naive T cells. Extensive studies in murine models have established a division of labor between the different populations of MNPs at steady state and during infection or inflammation. However, a translation of important findings in mice is only beginning to be explored in humans, given the challenge of working with rare cells in inaccessible human tissues. Important progress has been made in recent years on the phenotype and function of human lung MNPs. In addition to a substantial population of alveolar macrophages, three subsets of DCs have been identified in the human airways at steady state. More recently, monocyte-derived cells have also been described in healthy human lungs. Depending on the source of samples, such as lung tissue resections or bronchoalveolar lavage, the specific subsets of MNPs recovered may differ. This review provides an update on existing studies investigating human respiratory MNP populations during health and disease. Often, inflammatory MNPs are found to accumulate in the lungs of patients with pulmonary conditions. In respiratory infections or inflammatory diseases, this may contribute to disease severity, but in cancer patients this may improve clinical outcomes. By expanding on this knowledge, specific lung MNPs may be targeted or modulated in order to attain favorable responses that can improve preventive or treatment strategies against respiratory infections, lung cancer, or lung inflammatory diseases.

  • 82.
    Bailey, Leslie
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Chlamydia pneumoniae infection results in generalized bone loss in mice2008In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 10-11, p. 1175-1181Article in journal (Refereed)
  • 83.
    Balogun, Halima A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Immunological characteristics of recombinant fragments of the Plasmodium falciparum blood-stage antigen Pf3322011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Effective malaria vaccine might help improve control strategies against malaria, but the complexity of interactions between the parasite and its hosts poses challenges. The asexual blood stage P. falciparum antigen Pf332 has potentials as one of the proteins in understanding the complex host-parasite interactions. The interest in Pf332 as a target for parasite neutralizing antibodies, evolved from previous studies demonstrating that Pf332-reactive antibodies inhibits parasite growth in vitro. The presence of natural P. falciparum infection also indicated that Pf332 has the ability to induce protective antibodies.

    In paper I, we identified and characterized the immunogenicity of a C-terminal region of Pf332. Immunological analyses carried out with this fragment revealed that rabbit anti-C231 antibodies possess parasite in vitro inhibitory capabilities. In paper II, the functional activity of C231 specific antibodies was confirmed with human-affinity purified antibodies, where the antibodies inhibited late stage parasite development, by the presence of abnormal parasites and disintegrated red cell membranes.

    Epidemiological data from malaria endemic area of Senegal (Paper III & IV), showed that antibodies were reactive with two different fragments of Pf332 (C231 and DBL). Distribution of anti-C231 antibodies in the IgG subclasses, gave similar levels of IgG2 and IgG3. The levels of anti-C231 antibodies were associated with protection from clinical malaria, but with DBL reactive antibodies IgG3 was associated with protection from clinical malaria.

    We hereby conclude that antigen Pf332 contains immunogenic epitopes, and is a potential target for parasite neutralizing antibodies. The Pf332 protein should thus be considered as a candidate antigen for inclusion in a subunit P. falciparum malaria vaccine.

  • 84.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse2017In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 6, p. 363-369Article in journal (Refereed)
    Abstract [en]

    The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.

  • 85.
    Bang, Charlotte Sahlberg
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Önnberg, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Medicine, Örebro University, Sweden.
    Multiresistant uropathogenic extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are susceptible to the carbon monoxide releasing molecule-2 (CORM-2).2014In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 66, p. 29-35Article in journal (Refereed)
    Abstract [en]

    Carbon monoxide (CO) releasing molecules (CO-RMs) have been shown to inhibit growth of commensal Escherichia coli (E. coli). In the present study we examined the effect of CORM-2 on uropathogenic E. coli (UPEC) that produces extended-spectrum β-lactamase (ESBL). Viability experiments showed that CORM-2 inhibited the growth of several different ESBL-producing UPEC isolates and that 500 μM CORM-2 had a bactericidal effect within 4 h. The bactericidal effect of CORM-2 was significantly more pronounced than the effect of the antibiotic nitrofurantoin. CORM-2 demonstrated a low level of cytotoxicity in eukaryotic cells (human bladder epithelial cell line 5637) at the concentrations and time-points where the antibacterial effect was obtained. Real-time RT-PCR studies of different virulence genes showed that the expression of capsule group II kpsMT II and serum resistance traT was reduced and that some genes encoding iron acquisition systems were altered by CORM-2. Our results demonstrate that CORM-2 has a fast bactericidal effect against multiresistant ESBL-producing UPEC isolates, and also identify some putative UPEC virulence factors as targets for CORM-2. CO-RMs may be candidate drugs for further studies in the field of finding new therapeutic approaches for treatment of uropathogenic ESBLproducing E. coli.

  • 86.
    Barathan, Muttiah
    et al.
    University of Malaya, Malaysia.
    Mohamed, Rosmawati
    University of Malaya, Malaysia.
    Vadivelu, Jamuna
    University of Malaya, Malaysia.
    Yen Chang, Li
    University of Malaya, Malaysia.
    Vignesh, Ramachandran
    University of Kuala Lumpur, Malaysia.
    Krishnan, Jayalakshmi
    CUTN, India.
    Sigamani, Panneer
    CUTN, India.
    Saeidi, Alireza
    University of Malaya, Malaysia.
    Ravishankar Ram, M.
    University of Malaya, Malaysia.
    Velu, Vijayakumar
    Emory Vaccine Centre, GA 30329 USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia; CUTN, India; University of Malaya, Malaysia.
    CD8+T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides2017In: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 313Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray (TM) following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-beta 1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-alpha, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence. (C) 2016 Elsevier Inc. All rights reserved.

  • 87.
    Barbu, Andreea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The role of complement factor C3 in lipid metabolism2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 101-107Article, review/survey (Refereed)
    Abstract [en]

    Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.

  • 88.
    Barcenilla, Hugo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Mass Cytometry Identifies Distinct Subsets of Regulatory T Cells and Natural Killer Cells Associated With High Risk for Type 1 Diabetes2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 982Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin producing beta-cells. The time from onset of islet autoimmunity to manifest clinical disease can vary widely in length, and it is fairly uncharacterized both clinically and immunologically. In the current study, peripheral blood mononuclear cells from autoantibody-positive children with high risk for T1D, and from age-matched healthy individuals, were analyzed by mass cytometry using a panel of 32 antibodies. Surface markers were chosen to identify multiple cell types including T, B, NK, monocytes, and DC, and antibodies specific for identification of differentiation, activation and functional markers were also included in the panel. By applying dimensional reduction and computational unsupervised clustering approaches, we delineated in an unbiased fashion 132 phenotypically distinct subsets within the major immune cell populations. We were able to identify an effector memory Treg subset expressing HLA-DR, CCR4, CCR6, CXCR3, and GATA3 that was increased in the high-risk group. In addition, two subsets of NK cells defined by CD16(+) CD8(+) CXCR3(+) and CD16(+) CD8(+) CXCR3(+) CD11c(+) were also higher in the same subjects. High-risk individuals did not show impaired glucose tolerance at the time of sampling, suggesting that the changes observed were not the result of metabolic imbalance, and might be potential biomarkers predictive of T1D.

  • 89.
    Barratt-Due, Andreas
    et al.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Pischke, Søren Erik
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway.
    Mollnes, Tom Eirik
    Norwegian University of Science and Technology, Norway ; Nordland Hospital, Norway ; University of Tromsø, Norway.
    Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets.2017In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 101, no 1, p. 193-204Article in journal (Refereed)
    Abstract [en]

    The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by "dual blockade" of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.

  • 90.
    Bartlett, Stephen T.
    et al.
    Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA..
    Markmann, James F.
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Johnson, Paul
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hering, Bernhard J.
    Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Scharp, David
    Prodo Labs LLC, Irvine, CA USA.;Scharp Lacy Res Inst, Irvine, CA USA..
    Kay, Thomas W. H.
    St Vincents Hosp, St Vincents Inst Med Res, Dept Med, Fitzroy, Vic 3065, Australia.;Univ Melbourne, Melbourne, Vic 3010, Australia..
    Bromberg, Jonathan
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Odorico, Jon S.
    Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Div Transplantat, Madison, WI USA..
    Weir, Gordon C.
    Joslin Diabet Ctr, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Bridges, Nancy
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Kandaswamy, Raja
    Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Stock, Peter
    Univ San Francisco, Med Ctr, Div Transplantat, San Francisco, CA 94117 USA..
    Friend, Peter
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Gotoh, Mitsukazu
    Fukushima Med Univ, Dept Surg, Fukushima, Japan..
    Cooper, David K. C.
    Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA..
    Park, Chung-Gyu
    Seoul Natl Univ, Coll Med, Dept Biomed Sci, Xenotransplantat Res Ctr,Dept Microbiol & Immunol, Seoul, South Korea..
    O'Connell, Phillip
    Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Transplant & Renal Res, Westmead, NSW 2145, Australia..
    Stabler, Cherie
    Univ Miami, Sch Med, Diabet Res Inst, Coral Gables, FL 33124 USA..
    Matsumoto, Shinichi
    Natl Ctr Global Hlth & Med, Tokyo, Japan.;Otsuka Pharmaceut Factory Inc, Naruto, Japan..
    Ludwig, Barbara
    Tech Univ Dresden, Dept Med 3, D-01062 Dresden, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Ctr, Paul Langerhans Inst Dresden, Dresden, Germany.;DZD German Ctr Diabet Res, Dresden, Germany..
    Choudhary, Pratik
    Kings Coll London, Weston Educ Ctr, Diabet Res Grp, London WC2R 2LS, England..
    Kovatchev, Boris
    Univ Virginia, Ctr Diabet Technol, Charlottesville, VA USA..
    Rickels, Michael R.
    Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA..
    Sykes, Megan
    Coulmbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA..
    Wood, Kathryn
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Kraemer, Kristy
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Hwa, Albert
    Juvenile Diabet Res Fdn, New York, NY USA..
    Stanley, Edward
    Murdoch Childrens Res Inst, Parkville, Vic, Australia.;Monash Univ, Melbourne, Vic 3004, Australia..
    Ricordi, Camillo
    Univ Miami, Sch Med, Diabet Res Inst, Coral Gables, FL 33124 USA..
    Zimmerman, Mark
    BetaLogics, Raritan, NJ USA..
    Greenstein, Julia
    Juvenile Diabet Res Fdn, Discovery Res, New York, NY USA..
    Montanya, Eduard
    Univ Barcelona, Hosp Univ Bellvitge, CIBERDEM, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain..
    Otonkoski, Timo
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Biomedicum Stem Cell Ctr, Helsinki, Finland..
    Report from IPITA-TTS Opinion Leaders Meeting on the Future of beta-Cell Replacement2016In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 100, p. S1-S44Article in journal (Refereed)
  • 91.
    Bas, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Extrathymic T cell receptor gene rearrangement in human alimentary tract2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    T lymphocytes regulate the initiation, duration, and magnitude of adaptive immune responses and function as effector cells in cell mediated immunity. To become immunologically competent they must generate functional antigen receptors. This process takes place in the thymus and requires somatic recombination of T cell receptor (TCR) genes. It is mediated by the endonucleases recombination activating gene-1 (RAG1) and RAG2. Although the thymus regresses at puberty, T cells are present throughout life implying that other tissues must provide the proper milieu for T cell development. This thesis describes extrathymic T cell maturation in man. RAG1, RAG2, and the preTα-chain (pTα), which is exclusively utilized in developing T cells, were used as markers for TCR gene rearrangement. Two new exons (1A and 1B) encoding sequences in the 5’ untranslated region (5’UTR) of mRNA were discovered in the human RAG1 gene. The previously described 5’UTR exon (renamed 1C) was located between the new exons and exon 2, the latter containing the entire coding sequence. We found that small intestinal lymphocytes of the T cell lineage expressed the new exons in three different splice forms. RAG1 mRNA containing the 1C exon was not expressed in small intestinal lymphocytes. In contrast, splice forms containing the 1A exon were not expressed in thymocytes. RAG1 and pTα mRNA expressing lymphocytes were seen both within the epithelium and in lamina propria. Thymocyte-like CD2+CD7+CD3-, CD4+CD8+, CD1a+, and IL7-R+ lymphocytes were identified in the small intestinal mucosa. CD2+CD7+CD3- cells had the highest expression levels of mRNA for RAG1 and pTα, suggesting that the small intestinal mucosa is indeed a site for T cell maturation. Small intestinal T lymphocytes were also shown to kill via the Fas/FasL pathway in a TCR/CD3 independent manner and via the perforin/granzyme pathway in a TCR/CD3 dependent manner. The Fas/FasL-mediated cytotoxicity may reflect an ongoing selection process of extrathymically maturated T cells.

    The nasopharyngeal tonsil is the major inductive site for immune reactions against inhaled antigens. Previous demonstration of RAG1 expression in tonsillar B cells was interpreted as antigen driven receptor revision. The present study confirms the expression of RAG1 in B cells. We also found that RAG1, RAG2, and pTa mRNAs were expressed in lymphocytes of the T cell lineage. A small population of cells with the immature phenotype CD2+CD7+CD3- was demonstrated. This population had the highest expression levels of mRNA for RAG1, RAG2, pTα and terminal deoxynucleotidyl transferase. All four splice-forms of RAG1 mRNA were expressed. RAG1 and pTα mRNA expressing cells were mainly located in the proximity of the surface epithelium and in the outer rim of the follicles. These results suggest that the nasopharyngeal tonsil is a site where extrathymic T cell development and antigen driven TCR revision are occurring in parallel.

    Celiac disease (CD) is a small intestinal enteropathy characterized by permanent intolerance to gluten. Gluten reactive intestinal T cells are central in the pathogenesis and CD can be regarded as a failure to maintain tolerance to this food antigen. Expression of the RAG1 1A/2 splice form was significantly decreased in small intestinal T cell subsets of CD patients suggesting that impaired TCR gene rearrangement could contribute to failure of maintain tolerance in CD.

    Together, these findings show that both small intestinal and nasopharyngeal tonsillar lymphocytes of T cell lineage have the molecular machinery for antigen receptor rearrangement and that thymocyte-like lymphocytes are present in both tissues. Thus these organs are likely sites of T lymphocyte ontogeny as well as for secondary T cell receptor rearrangement in man.

  • 92.
    Baygan, Arjang
    et al.
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Aronsson-Kurttila, Wictor
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Moretti, Gianluca
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Tibert, Babylonia
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Dahllöf, Göran
    Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Klingspor, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Department of Microbiology, Uppsala University Hospital, Uppsala, Sweden.
    Gustafsson, Britt
    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), Neuropediatrics/Paediatric oncology.
    Khoein, Bita
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Moll, Guido
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Hausmann, Charlotta
    Center for Allogeneic Stem Cell Transplantation, Department of Pathology/Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Svahn, Britt-Marie
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Westgren, Magnus
    Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.
    Remberger, Mats
    Center for Allogeneic Stem Cell Transplantation, Department of Pathology/Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Sadeghi, Behnam
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Ringden, Olle
    Translational Cell Therapy Research Group (TCR), Division of Therapeutic Immunology, Department of LabMed, Karolinska Institutet, Stockholm, Sweden.
    Safety and Side Effects of Using Placenta-Derived Decidual Stromal Cells for Graft-versus-Host Disease and Hemorrhagic Cystitis2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 795Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stromal cells (MSCs) are increasingly used in regenerate medicine. Placenta-derived decidual stromal cells (DSCs) are a novel therapy for acute graft-versus-host-disease (GVHD) and hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT). DSCs are more immunosuppressive than MSCs. We assessed adverse events and safety using DSCs among 44 treated patients and 40 controls. The median dose of infused cells was 1.5 (range 0.9–2.9) × 106 DSCs/kg. The patients were given 2 (1–5) doses, with a total of 82 infusions. Monitoring ended 3 months after the last DSC infusion. Three patients had transient reactions during DSC infusion. Laboratory values, hemorrhages, and transfusions were similar in the two groups. The frequency of leukemic relapse (2/2, DSC/controls) and invasive fungal infections (6/6) were the same in the two groups. Causes of death were those seen in HSCT patients: infections (5/3), respiratory failure (1/1), circulatory failure (3/1), thromboembolism (1/0), multiorgan failure (0/1), and GVHD and others (2/7). One-year survival for the DSC patients with GVHD was 67%, which was significantly better than achieved previously at our center. One-year survival was 90% in the DSC-treated HC group. DSC infusions appear safe. Randomized studies are required to prove efficacy.

  • 93. Belov, Katherine
    et al.
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Immunoglobulin genetics of Ornithorhynchus anatinus (platypus) and Tachyglossus aculeatus (short-beaked echidna).2003In: Comp Biochem Physiol A Mol Integr Physiol, ISSN 1095-6433, Vol. 136, no 4, p. 811-9Article in journal (Refereed)
  • 94. Belov, Katherine
    et al.
    Lam, Mary K P
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Colgan, Donald J
    Evolution of the major histocompatibility complex: Isolation of class II beta cDNAs from two monotremes, the platypus and the short-beaked echidna.2003In: Immunogenetics, ISSN 0093-7711, Vol. 55, no 6, p. 402-11Article in journal (Other scientific)
  • 95.
    Bengtsson, Torbjörn
    et al.
    Örebro University, School of Medical Sciences.
    Zhang, Boxi
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Selegård, Robert
    Örebro University, School of Medical Sciences. Division of Molecular Physics, Department of Physics, Chemistry and Biology (IFM), Linköping University, Linköping, Sweden.
    Wiman, Emanuel
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Aili, Daniel
    Division of Molecular Physics, Department of Physics, Chemistry and Biology (IFM), Linköping University, Linköping, Sweden.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Dual action of bacteriocin PLNC8 alpha beta through inhibition of Porphyromonas gingivalis infection and promotion of cell proliferation2017In: Pathogens and Disease, E-ISSN 2049-632X, Vol. 75, no 5, article id ftx064Article in journal (Refereed)
    Abstract [en]

    Periodontitis is a chronic inflammatory disease that is characterised by accumulation of pathogenic bacteria, including Porphyromonas gingivalis, in periodontal pockets. The lack of effective treatments has emphasised in an intense search for alternative methods to prevent bacterial colonisation and disease progression. Bacteriocins are bacterially produced antimicrobial peptides gaining increased consideration as alternatives to traditional antibiotics. We show rapid permeabilisation and aggregation of P. gingivalis by the two-peptide bacteriocin PLNC8 alpha beta. In a cell culture model, P. gingivalis was cytotoxic against gingival fibroblasts. The proteome profile of fibroblasts is severely affected by P. gingivalis, including induction of the ubiquitin-proteasome pathway. PLNC8 alpha beta enhanced the expression of growth factors and promoted cell proliferation, and suppressed proteins associated with apoptosis. PLNC8 alpha beta efficiently counteracted P. gingivalis-mediated cytotoxicity, increased expression of a large number of proteins and restored the levels of inflammatory mediators. In conclusion, we show that bacteriocin PLNC8 alpha beta displays dual effects by acting as a potent antimicrobial agent killing P. gingivalis and as a stimulatory factor promoting cell proliferation. We suggest preventive and therapeutical applications of PLNC8 alpha beta in periodontitis to supplement the host immune defence against P. gingivalis infection and support wound healing processes.

  • 96.
    Bennet, Sean M. P.
    et al.
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Polster, Annikka
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Törnblom, Hans
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Isaksson, Stefan
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Capronnier, Sandrine
    Department of Life Science, Danone Nutricia Research, Palaiseau, France.
    Tessier, Aurore
    Department of Life Science, Danone Nutricia Research, Palaiseau, France.
    Le Nevé, Boris
    Department of Life Science, Danone Nutricia Research, Palaiseau, France.
    Simrén, Magnus
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA.
    Öhman, Lena
    University of Skövde, School of Health and Education. Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Global Cytokine Profiles and Association With Clinical Characteristics in Patients With Irritable Bowel Syndrome2016In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 111, no 8, p. 1165-1176Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Evidence suggests that patients with irritable bowel syndrome (IBS) have an altered cytokine profile, although it is unclear whether cytokines are linked with symptom severity. We aimed to determine whether global serum and mucosal cytokine profiles differ between IBS patients and healthy subjects and whether cytokines are associated with IBS symptoms.

    METHODS: Serum from 144 IBS patients and 42 healthy subjects was analyzed for cytokine levels of interleukin (IL)-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, interferon (IFN)-γ, and tumor necrosis factor (TNF) by MSD MULTI-ARRAY. In total, 109 IBS and 36 healthy sigmoid colon biopsies were analyzed for mRNA expression of IL-8, IL-10, TNF, and FOXP3 by quantitative reverse transcription PCR. Multivariate discrimination analysis evaluated global cytokine profiles. Rectal sensitivity, oroanal transit time, and psychological and gastrointestinal symptom severity were also assessed.

    RESULTS: Global cytokine profiles of IBS patients and healthy subjects overlapped, but cytokine levels varied more in IBS patients. Serum levels of IL-6 and IL-8 tended to be increased and levels of IFN-γ tended to be decreased in IBS patients. Mucosal mRNA expression of IL-10 and FOXP3 tended to be decreased in IBS patients. Within both the full study cohort and IBS patients alone, serum level of TNF was associated with looser stool pattern, while subjects with more widespread somatic symptoms had increased serum levels of IL-6. Although neither IBS bowel habit subgroups nor patients with possible post-infectious IBS were associated with distinct cytokine profiles, a small cluster of IBS patients with comparatively elevated immune markers was identified.

    CONCLUSIONS: Global cytokine profiles did not discriminate IBS patients from healthy subjects, but cytokine profiles were more varied among IBS patients than among healthy subjects, and a small subgroup of patients with enhanced immune activity was identified. Also, association of inflammatory cytokines with some clinical symptoms suggests that immune activation may be of importance in a subset of IBS patients.

  • 97. Bentham, James
    et al.
    Morris, David L
    Cunninghame Graham, Deborah S
    Pinder, Christopher L
    Tombleson, Philip
    Behrens, Timothy W
    Martín, Javier
    Fairfax, Benjamin P
    Knight, Julian C
    Chen, Lingyan
    Replogle, Joseph
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Graham, Robert R
    Wither, Joan E
    Rioux, John D
    Alarcón-Riquelme, Marta E
    Vyse, Timothy J
    Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, p. 1457-1464Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

  • 98.
    Berg, Aase
    et al.
    Stavanger University Hospital, Norway ; University of Bergen, Norway.
    Otterdal, Kari
    Oslo University Hospital Rikshospitalet, Norway.
    Patel, Sam
    Central Hospital of Maputo, Mozambique.
    Gonca, Miguel
    Central Hospital of Maputo, Mozambique.
    David, Catarina
    Central Hospital of Maputo, Mozambique.
    Dalen, Ingvild
    Stavanger University Hospital, Norway.
    Nymo, Stig
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson, Margareta
    Oslo University Hospital Rikshospitalet, Norway.
    Nordling, Sofia
    Uppsala University.
    Magnusson, Peetra U
    Uppsala University.
    Ueland, Thor
    Oslo University Hospital Rikshospitalet, Norway.
    Prato, Mauro
    University of Torino, Italy.
    Giribaldi, Giuliana
    University of Torino, Italy.
    Mollnes, Tom Eirik
    Oslo University Hospital Rikshospitalet, Norway.
    Aukrust, Pål
    Oslo University Hospital Rikshospitalet, Norway.
    Langeland, Nina
    University of Bergen, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria.2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 11, p. 1835-1840Article in journal (Refereed)
    Abstract [en]

    The impact of complement activation and its possible relation to cytokine responses during malaria pathology was investigated in plasma samples from patients with confirmed Plasmodium falciparum malaria and in human whole-blood specimens stimulated with malaria-relevant agents ex vivo. Complement was significantly activated in the malaria cohort, compared with healthy controls, and was positively correlated with disease severity and with certain cytokines, in particular interleukin 8 (IL-8)/CXCL8. This was confirmed in ex vivo-stimulated blood specimens, in which complement inhibition significantly reduced IL-8/CXCL8 release. P. falciparum malaria is associated with systemic complement activation and complement-dependent release of inflammatory cytokines, of which IL-8/CXCL8 is particularly prominent.

  • 99. Berg, Aase
    et al.
    Otterdal, Karl
    Patel, Sam
    Gonca, Miguel
    David, Catarina
    Dalen, Ingvild
    Nymo, Stig
    Nilsson, Margareta
    Nordling, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ueland, Thor
    Prato, Mauro
    Giribaldi, Giuliana
    Mollnes, Tom Eirik
    Aukrust, Pål
    Langeland, Nina
    Nilsson, Per
    Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria2015In: The Internet Journal of Infectious Diseases, ISSN 1528-8366, Vol. 212, no 11, p. 1835-1840Article in journal (Refereed)
    Abstract [en]

    The impact of complement activation and its possible relation to cytokine responses during malaria pathology was investigated in plasma samples from patients with confirmed Plasmodium falciparum malaria and in human whole-blood specimens stimulated with malaria-relevant agents ex vivo. Complement was significantly activated in the malaria cohort, compared with healthy controls, and was positively correlated with disease severity and with certain cytokines, in particular interleukin 8 (IL-8)/CXCL8. This was confirmed in ex vivo-stimulated blood specimens, in which complement inhibition significantly reduced IL-8/CXCL8 release. P. falciparum malaria is associated with systemic complement activation and complement-dependent release of inflammatory cytokines, of which IL-8/CXCL8 is particularly prominent.

  • 100.
    Bergfelt, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kozlowski, Piotr
    Ahlberg, Lucia
    Hulegardh, Erik
    Hagglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, Karin
    Markuszewska-Kuczymska, Alicja
    Tomaszewska-Toporska, Beata
    Smedmyr, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Astrom, Maria
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hallböök, Hélene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study2015In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 135Article in journal (Refereed)
    Abstract [en]

    The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

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