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  • 1.
    Abdgawad, M.
    et al.
    Departments of Nephrology, Lund University, Lund, Sweden.
    Gunnarsson, L.
    Departments of Nephrology, Lund University, Lund, Sweden.
    Bengtsson, A. A.
    Departments of Rheumatology, Lund University, Lund, Sweden.
    Geborek, P.
    Departments of Rheumatology, Lund University, Lund, Sweden.
    Nilsson, L.
    Departments of Haematology, Lund University, Lund, Sweden.
    Segelmark, Mårten
    Departments of Nephrology, Lund University, Lund, Sweden.
    Hellmark, T.
    Departments of Nephrology, Lund University, Lund, Sweden.
    Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 161, no 1, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177–mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.

  • 2.
    Akesson, K.
    et al.
    Jonköping University, Sweden; Jonköping University, Sweden; Jonköping University, Sweden.
    Tompa, A.
    Jonköping University, Sweden; Jonköping University, Sweden.
    Ryden, A.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Novo Nordisk Inc, WA USA.
    Faresjo, M.
    Jonköping University, Sweden; Jonköping University, Sweden; Jonköping University, Sweden.
    Low expression of CD39(+)/CD45RA(+) on regulatory T cells (T-reg) cells in type 1 diabetic children in contrast to high expression of CD101(+)/CD129(+) on T-reg cells in children with coeliac disease2015In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 180, no 1, p. 70-82Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper (Th), T cytotoxic (Tc) and regulatory T cells (T-reg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells (Th:CD4(+) or Tc:CD8(+)); naive (CD27(+)CD28(+)CD45RA(+)CCR7(+)), central memory (CD27(+)CD28(+)CD45RA(-)CCR7(+)), effector memory (early differentiated; CD27(+)CD28(+)CD45RA(-)CCR7(-) and late differentiated; CD27(-)CD28(-)CD45RA(-)CCR7(-)), terminally differentiated effector cells (TEMRA; CD27(-)CD28(-)CD45RA(+)CCR7(-)) and T-reg (CD4(+)CD25(+)FOXP3(+)CD127(-)) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4(+) cells (Pless than005), but lower percentages of both early and late effector memory CD8(+) cells (Pless than005) compared to references. Children with exclusively T1D had lower median fluorescence intensity (MFI) of forkhead box protein 3 (FoxP3) (Pless than005) and also a lower percentage of CD39(+) and CD45RA(+) within the T-reg population (CD4(+)CD25(+)FOXP3(+)CD127(-)) (Pless than005). Children with exclusively coeliac disease had a higher MFI of CD101 (Pless than001), as well as a higher percentage of CD129(+) (Pless than005), in the CD4(+)CD25(hi) lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4(+) cells compared to CD8(+) cells. T1D children show signs of low CD39(+)/CD45RA(+) T-reg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101(+)/CD129(+) T-reg cells that may indicate suppressor activity.

  • 3.
    Backteman, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Natural killer (NK) cell deficit in coronary artery disease: no aberrations in phenotype but sustained reduction of NK cells is associated with low-grade inflammation2014In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 175, no 1, p. 104-112Article in journal (Refereed)
    Abstract [en]

    Although reduced natural killer (NK) cell levels have been reported consistently in patients with coronary artery disease (CAD), the clinical significance and persistence of this immune perturbation is not clarified. In this study we characterized the NK cell deficit further by determining (i) differentiation surface markers and cytokine profile of NK cell subsets and (ii) ability to reconstitute NK cell levels over time. Flow cytometry was used to analyse NK cell subsets and the intracellular cytokine profile in 31 patients with non-ST elevation myocardial infarction (non-STEMI), 34 patients with stable angina (SA) and 37 healthy controls. In blood collected prior to coronary angiography, the proportions of NK cells were reduced significantly in non-STEMI and SA patients compared with controls, whereas NK cell subset analyses or cytokine profile measurements did not reveal any differences across groups. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of metabolic syndrome. Moreover, interleukin (IL)-6 levels remained high in patients with sustained NK cell deficit, whereas a decline in IL-6 (P < 0·001) was seen in patients with a pronounced increase in NK cells. In conclusion, we found no evidence that reduction of NK cells in CAD patients was associated with aberrations in NK cell phenotype at any clinical stage of the disease. Conversely, failure to reconstitute NK cell levels was associated with a persistent low-grade inflammation, suggesting a protective role of NK cells in CAD.

  • 4. Blomqvist, M
    et al.
    Juhela, S
    Erkkila, S
    Korhonen, S
    Simell, T
    Kupila, A
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Simell, O
    Knip, M
    Ilonen, J
    Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life.2002In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 128, p. 511-515Article in journal (Refereed)
  • 5.
    Cederbrant, Karin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Characterization of mercuric mercury (Hg2+)-induced lymphoblasts from patients with mercury allergy and from healthy subjects2000In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 121, no 1, p. 23-30Article in journal (Refereed)
    Abstract [en]

    Hg2+ induces lymphocyte proliferation when added to cell cultures from both healthy and mercury-allergic subjects. Consequently, when measuring DNA synthesis a possible Hg2+-specific response, resulting from proliferating memory cells, cannot be discriminated from a non-allergic response. The mechanism behind this non-allergic response is unknown but a superantigenic effect of Hg2+ has been suggested. In this study, five mercury-allergic patients, with oral lichen planus (OLP) lesions adjacent to dental amalgam and a positive patch test to Hg0, and five healthy subjects without amalgam were examined. The immunophenotype and the T cell receptor Vβ (TCR Vβ) repertoire of Hg2+-induced lymphoblasts as well as the expression of the lymphocyte activation markers CD23 and CD134 were analysed for possible differences between healthy and allergic subjects. The mechanism of Hg2+-induced proliferation was examined by comparing the TCR Vβ expression of Hg- and staphylococcal enterotoxin B (SEB)-activated lymphoblasts, the latter used as a positive superantigen control. It was not possible to discriminate between mercury-allergic and healthy subjects using the immunophenotype or the TCR Vβ profile of the Hg2+-induced lymphoblasts or the expression of CD23 and CD134. However, Hg2+-induced CD4+ lymphoblasts showed a skewing towards Vβ2. This relative increase in Vβ2 was only detected in the CD4+ but not in the CD8+ lymphoblast population. In conclusion, Hg2+ induced a proliferation-dependent skewing towards CD4+ but not CD8+ lymphocytes expressing Vβ2. In this respect Hg2+ differs from the classical bacterial superantigen SEB, which also stimulates unique TCR Vβ families among CD8+ cells.

  • 6.
    Chéramy, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hampe, Christiane S.
    Department of Medicine, University of Washington, Seattle, WA, USA.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 171, no 3, p. 247-254Article in journal (Refereed)
    Abstract [en]

    Previous studies have indicated phenotypical differences in glutamic acid decarboxylase 65 autoantibodies (GADA) found in type 1 diabetes (T1D) patients, individuals at risk of developing T1D and stiff-person syndrome (SPS) patients. In a Phase II trial using aluminium-formulated GAD65 (GAD-alum) as an immunomodulator in T1D, several patients responded with high GADA titres after treatment, raising concerns as to whether GAD-alum could induce GADA with SPS-associated phenotypes. This study aimed to analyse GADA levels, immunoglobulin (Ig)G1–4 subclass frequencies, b78- and b96·11-defined epitope distribution and GAD65 enzyme activity in sera from four cohorts with very high GADA titres: T1D patients (n = 7), GAD-alum-treated T1D patients (n = 9), T1D high-risk individuals (n = 6) and SPS patients (n = 12). SPS patients showed significantly higher GADA levels and inhibited the in-vitro GAD65 enzyme activity more strongly compared to the other groups. A higher binding frequency to the b78-defined epitope was found in the SPS group compared to T1D and GAD-alum individuals, whereas no differences were detected for the b96·11-defined epitope. GADA IgG1–4 subclass levels did not differ between the groups, but SPS patients had higher IgG2 and lower IgG4 distribution more frequently. In conclusion, the in-vitro GADA phenotypes from SPS patients differed from the T1D- and high-risk groups, and GAD-alum treatment did not induce SPS-associated phenotypes. However, occasional overlap between the groups exists, and caution is indicated when drawing conclusions to health or disease status.

  • 7.
    Ekerfelt, Christina
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Andersson, M.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Olausson, Anna
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Bergström, S.
    Department of Microbiology, University of Umeå, Umeå, Sweden.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Faculty of Health Sciences.
    Mercury exposure as a model for deviation of cytokine responses in experimental Lyme arthritis: HgCl2 treatment decreases T helper cell type 1-like responses and arthritis severity but delays eradication of Borrelia burgdorferi in C3H/HeN mice2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 150, no 1, p. 189-197Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis is a complex infection, where some individuals develop so-called ‘chronic borreliosis’. The pathogenetic mechanisms are unknown, but the type of immune response is probably important for healing. A strong T helper cell type 1 (Th1)-like response has been suggested as crucial for eradication of Borrelia and for avoiding development of chronic disease. Many studies aimed at altering the Th1/Th2 balance in Lyme arthritis employed mice deficient in cytokine genes, but the outcome has not been clear-cut, due possibly to the high redundancy of cytokines. This study aimed at studying the importance of the Th1/Th2 balance in murine Borrelia arthritis by using the Th2-deviating effect of subtoxic doses of inorganic mercury. Ninety-eight C3H/HeN mice were divided into four groups: Borrelia-infected (Bb), Borrelia-infected exposed to HgCl2 (BbHg), controls exposed to HgCl2 alone and normal controls. Mice were killed on days 3, 16, 44 and 65 post-Borrelia inoculation. Arthritis severity was evaluated by histology, spirochaetal load determined by Borrelia culture, IgG2a- and IgE-levels analysed by enzyme-linked immunosorbemt assay (ELISA) and cytokine-secreting cells detected by enzyme-linked immunospot (ELISPOT). BbHg mice showed less severe histological arthritis, but delayed eradication of spirochaetes compared to Bb mice, associated with increased levels of IgE (Th2-induced) and decreased levels of IgG2a (Th1-induced), consistent with a Th2-deviation. Both the numbers of Th1 and Th2 cytokine-secreting cells were reduced in BbHg mice, possibly explained by the fact that numbers of cytokine-secreting cells do not correlate with cytokine concentration. In conclusion, this study supports the hypothesis that a Th1-like response is required for optimal eradication of Borrelia.

  • 8.
    Ekerfelt, Christina
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Weissert, R.
    Department of Medicine, Division of Neuroimmunology, Karolinska Institute, Stockholm, Sweden.
    Kvarnström, Maria
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Olsson, T.
    Department of Medicine, Division of Neuroimmunology, Karolinska Institute, Stockholm, Sweden.
    Ernerudh, Jan
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Transfer of myelin-specific cells deviated in vitro towards IL-4 production ameliorates ongoing experimental allergic neuritis2001In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 123, no 1, p. 112-118Article in journal (Refereed)
    Abstract [en]

    A causal role of IL-4 (Th2) production for recovery in experimental allergic neuritis (EAN) was indicated by experiments where Th1-like autoreactive cell populations, taken from the induction phase of the disease, were deviated to extensive secretion of IL-4 in a selective fashion, by ex vivo stimulation with autoantigen in the presence of IL-4. The deviated cells were adoptively transferred to EAN rats at a time just prior to the onset of clinical signs. This treatment ameliorated EAN compared with sham treatment. This therapeutic approach, with generation of autoreactive IL-4-secreting cells ex vivo followed by subsequent adoptive transfer, may become a new selective treatment of organ-specific autoimmune diseases since, in contrast to previous attempts, it is done in a physiological and technically easy way.

  • 9.
    Ekerfelt, Christina
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Forsberg, Pia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Svenvik, Maria
    Roberg, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Bergström, S.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    A symptomatic Borrelia-seropositive individuals display the same incidence of Borrelia-specific interferon-gamma (IFN-gamma)-secreting cells in blood as patients with clinical Borrelia infection.1999In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 115, p. 498-502Article in journal (Refereed)
  • 10.
    Eriksson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Andersson, Carina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjögren's syndrome, rheumatoid arthritis and healthy controls2004In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 137, no 3, p. 617-620Article in journal (Refereed)
    Abstract [en]

    Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1-like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL-18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL-18 as well as transforming growth factor (TGF) β1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American-European classification criteria. IL-18 and TGF-β1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL-18 were related (R = 0.52, P = 0.0005). No relation was found neither between IL-18 versus IgG2, IgG3 or IgA, nor between serum TGF-β1 versus any of the immunoglobulins. Since serum levels of IL-18 are related to serum IgG1, IL-18 may be of importance for IgG1 switch and/or release.

  • 11.
    Evaldsson, Chamilly
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Rydén, Ingvar
    Division of Clinical Chemistry, Kalmar County Hospital, Kalmar, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    4-Thiouridine induces dose-dependent reduction of oedema, leucocyte influx and tumour necrosis factor in lung inflammation2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 2, p. 330-338Article in journal (Refereed)
    Abstract [en]

    Recent reports demonstrate a role for nucleotides as inflammatory modulators. Uridine, for example, reduces oedema formation and leucocyte infiltration in a Sephadex-induced lung inflammation model. Tumour necrosis factor (TNF) concentration was also reduced. Previous in vivo observations indicated that 4-thiouridine might have similar effects on leucocyte infiltration and TNF release. The aim of this study was thus to investigate the effects of 4-thiouridine in greater detail. We used a Sephadex-induced acute lung inflammation model in Sprague-Dawley rats. The dextran beads were instilled intratracheally into the lungs, which were excised and examined after 24 h. Sephadex alone led to massive oedema formation and infiltration of macrophages, neutrophils and eosinophils. Microgranulomas with giant cell formations were clearly visible around the partially degraded beads. A significant increase in bronchoalveolar lavage fluid (BALF) content of TNF and leukotrienes was also seen. 4-Thiouridine co-administration affected all variables investigated in this model, i.e. oedema, microscopic and macroscopic appearance of lung tissue, total leucocyte and differential leucocyte counts in BALF, TNF and leukotrienes C-4 (LTC4), LTD4 and LTE4 in BALF, indicating a reproducible anti-inflammatory effect. In conclusion, we have demonstrated that 4-thiouridine has anti-inflammatory effects similar to those of uridine. To our knowledge, this is the first demonstration of pharmacological 4-thiouridine effects in vivo. The results suggest nucleoside/nucleotide involvement in inflammatory processes, warranting further studies on nucleoside analogues as attractive new alternatives in the treatment of inflammatory diseases.

  • 12.
    Frodlund, Martina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vikerfors, A.
    Karolinska Univ Hosp, Sweden; Swedish Med Prod Agcy, Sweden.
    Grosso, G.
    Karolinska Univ Hosp, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Elvin, K.
    Karolinska Inst, Sweden.
    Gunnarsson, I.
    Karolinska Univ Hosp, Sweden.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Ronnelid, J.
    Uppsala Univ, Sweden.
    Svenungsson, E.
    Karolinska Univ Hosp, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogrens syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

  • 13.
    Hartana, C. A.
    et al.
    Karolinska Inst, Sweden.
    Bergman, E. Ahlen
    Karolinska Inst, Sweden.
    Broome, A.
    Karolinska Inst, Sweden.
    Berglund, S.
    Karolinska Inst, Sweden.
    Johansson, M.
    Sundsvall Hosp, Sweden.
    Alamdari, F.
    Vastmanland Hosp, Sweden.
    Jakubczyk, T.
    Lanssjukhuset Ryhov, Sweden.
    Huge, Ylva
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Aljabery, Firas
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Palmqvist, K.
    Ostersund Cty Hosp, Sweden.
    Holmstroem, B.
    Akad Univ Hosp, Sweden.
    Glise, H.
    Karolinska Inst, Sweden.
    Riklund, K.
    Umea Univ, Sweden.
    Sherif, A.
    Umea Univ, Sweden.
    Winqvist, O.
    Karolinska Inst, Sweden.
    Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 39-53Article in journal (Refereed)
    Abstract [en]

    Tissue-resident memory T (T-RM) cells are CD8(+) T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in T-RM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in T-RM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate T-RM cell phenotypes. We discovered that tumour T-RM cells have low DNA methylation in the PRF1 locus (32amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9% methylation), which corresponds to increased numbers of perforin-expressing T-RM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour T-RM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that T-RM cells from tumours are not terminally exhausted. Moreover, a high number of T-RM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, T-RM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies T-RM cells as potential new targets for cancer immunotherapy.

  • 14.
    Havarinasab, Said
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Johansson, Uno
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Pollard, KM
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Gold causes genetically determined autoimmune and immunostimulatory responses in mice2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 150, no 1, p. 179-188Article in journal (Refereed)
    Abstract [en]

    Natrium aurothiomaleate (GSTM) is a useful disease-modifying anti-rheumatic drug, but causes a variety of immune-mediated adverse effects in many patients. A murine model was used to study further the interaction of GSTM with the immune system, including induction of systemic autoimmunity. Mice were given weekly intramuscular injections of GSTM and controls equimolar amounts of sodium thiomaleate. The effects of gold on lymphocyte subpopulations were determined by flow cytometry. Humoral autoimmunity was measured by indirect immunofluorescence and immunoblotting, and deposition of immunoglobulin and C3 used to assess immunopathology. Gold, in the form of GSTM, stimulated the murine immune system causing strain-dependent lymphoproliferation and autoimmunity, including a major histocompatibility complex (MHC)-restricted autoantibody response against the nucleolar protein fibrillarin. GSTM did not cause glomerular or vessel wall IgG deposits. However, it did elicit a strong B cell-stimulating effect, including both T helper 1 (Th1)- and Th2-dependent isotypes. All these effects on the immune system were dependent on the MHC genotype, emphasizing the clinical observations of a strong genetic linkage for the major adverse immune reactions seen with GSTM treatment. © 2007 British Society for Immunology.

  • 15.
    Havarinasab, Said
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences.
    Pollard, K M
    Scripps Research Institute.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Gold- and silver-induced murine autoimmunity - requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 3, p. 567-576Article in journal (Refereed)
    Abstract [en]

    Treatment with gold in the form of aurothiomaleate, silver or mercury (Hg) in genetically susceptible mouse strains (H-2(s) ) induces a systemic autoimmune condition characterized by anti-nuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin, as well as lymphoproliferation and systemic immune-complex (IC) deposits. In this study we have examined the effect of single-gene deletions for interferon (IFN)-gamma, interleukin (IL)-4, IL-6 or CD28 in B10.S (H-2(s) ) mice on heavy metal-induced autoimmunity. Targeting of the genes for IFN-gamma, IL-6 or CD28 abrogated the development of both anti-fibrillarin antibodies (AFA) and IC deposits using a modest dose of Hg (130 mu g Hg/kg body weight/day). Deletion of IL-4 severely reduced the IgG1 AFA induced by all three metals, left the total IgG AFA response intact, but abrogated the Hg-induced systemic IC deposits. In conclusion, intact IFN-gamma and CD28 genes are necessary for induction of AFA with all three metals and systemic IC deposits using Hg, while lack of IL-4 distinctly skews the metal-induced AFA response towards T helper type 1. In a previous study using a higher dose of Hg (415 mu g Hg/kg body weight/day), IC deposits were preserved in IL-4(-/-) and IL-6(-/-) mice, and also AFA in the latter mice. Therefore, the attenuated autoimmunity following loss of IL-4 and IL-6 is dose-dependent, as higher doses of Hg are able to override the attenuation observed using lower doses.

  • 16.
    Hedman Hjorth, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Impaired CD4+ and CD8+ T cell phenotype and reduced chemokine secretion in recent-onset type 1 diabetic children2008In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 153, no 3, p. 360-368Article in journal (Refereed)
    Abstract [en]

    Although the role of the T cell-mediated autoimmune reaction in type 1 diabetes (T1D) is conclusive, studies including data from human circulating CD4+ and CD8+ lymphocytes subsets during the disease onset and posterior development are scarce. Further, chemokines and chemokine receptors are key players in the migration of pathogenic T cells into the islets of NOD mice developing T1D, but few studies have investigated these markers in human T1D patients. We studied the expression of T helper 1 (Th1) and Th2 associated chemokine receptors, and the two isoforms of CD45 leukocyte antigen on CD4+ and CD8+ lymphocytes from T1D and healthy children, as well as the secretion of chemokines in cell supernatants in peripheral blood mononuclear cells. Our results showed increased expression of CCR7 and CD45RA, and reduced CD45RO on CD8+ cells among recent-onset T1D patients. The percentages of CD4+ cells expressing CXC chemokine receptor 3 (CXCR3), CXCR6 and CCR5, and the secretion of interferon-γ-induced protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1a and MIP-1β was lower among diabetics. Low expression of Th1-associated receptors and secretion of chemokines, together with an increased amount of CD8+ cells expressing CD45RA and CCR7 in T1D patients therefore might represent suboptimal Th function in T1D, leading to impaired T cytotoxic (Tc) responses or alternatively reflect a selective recruitment of Th1 cells into the pancreas.

  • 17.
    Hoxha, A.
    et al.
    University of Padua, Italy; Karolinska Institute, Sweden.
    Ruffatti, A.
    University of Padua, Italy.
    Ambrosi, A.
    Karolinska Institute, Sweden.
    Ottosson, V.
    Karolinska Institute, Sweden.
    Hedlund, M.
    Karolinska Institute, Sweden.
    Ottosson, L.
    Karolinska Institute, Sweden.
    Anandapadamanaban, Madhanagopal
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Sunnerhagen, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sonesson, S. -E.
    Karolinska Institute, Sweden.
    Wahren-Herlenius, M.
    Karolinska Institute, Sweden.
    Identification of discrete epitopes of Ro52p200 and association with fetal cardiac conduction system manifestations in a rodent model2016In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 186, no 3, p. 284-291Article in journal (Refereed)
    Abstract [en]

    Congenital heart block (CHB) is a potentially lethal condition characterized by a third-degree atrioventricular block (AVB). Despite anti-Ro52 antibodies being detected in nearly 90% of mothers of affected children, CHB occurs in only 1-2% of anti-Ro/Sjogrens-syndrome-related antigen A (SSA) autoantibody-positive pregnancies. Maternal antibodies have been suggested to bind molecules crucial to fetal cardiac function; however, it remains unknown whether a single antibody profile associates with CHB or whether several specificities and cross-reactive targets exist. Here, we aimed to define further the reactivity profile of CHB-associated antibodies towards Ro52p200 (amino acid 200-239). We first analysed reactivity of a monoclonal anti-Ro52 antibody shown to induce AVB in rats (7.8C7) and of sera from anti-Ro52p200 antibody-positive mothers of children with CHB towards a panel of modified Ro52p200 peptides, and subsequently evaluated their potential to induce AVB in rats upon transfer during gestation. We observed that CHB maternal sera displayed a homogeneous reactivity profile targeting preferentially the C-terminal part of Ro52p200, in contrast to 7.8C7 that specifically bound the p200 N-terminal end. In particular, amino acid D233 appeared crucial to maternal antibody reactivity towards p200. Despite low to absent reactivity towards rat p200 and different binding profiles towards mutated rat peptides indicating recognition of different epitopes within Ro52p200, immunoglobulin (Ig)G purified from two mothers of children with CHB could induce AVB in rats. Our findings support the hypothesis that several fine antibody specificities and cross-targets may exist and contribute to CHB development in anti-Ro52 antibody-positive pregnancies.

  • 18.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Effects of deviating the Th2-response in murine mercury-induced autoimmunity towards a Th1-response2003In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 134, no 2, p. 202-209Article in journal (Refereed)
    Abstract [en]

    T-helper cells type 1 (Th1) and type 2 (Th2) play an important role in the pathogenesis of autoimmune diseases. In many Th1-dependent autoimmune models, treatment with recombinant interleukin-12 (rIL-12) accelerates the autoimmune response. Mercury-induced autoimmunity (HgIA) in mice is an H-2 regulated condition with antinucleolar antibodies targeting fibrillarin (ANoA), systemic immune-complex (IC) deposits and transient polyclonal B-cell activation (PBA). HgIA has many characteristics of a Th2 type of reaction, including a strong increase of IgE, but disease induction is critically dependent on the Th1 cytokine IFN-γ. The aim of this study was to investigate if a strong deviation of the immune response in HgIA towards Th1 would aggravate HgIA. Injections of both rIL-12 and anti-IL-4 monoclonal antibody (α-IL-4) reduced the HgCl2-(Hg-)induced concentration of the Th2-dependent serum IgE and IgG1, but increased the Th1-dependent serum IgG2a. The IgG-ANoA developed earlier and attained a higher titre after combined treatment, and the ANoA titre of the IgG1 isotype decreased while the ANoA titre of the Th1-associated IgG2a, IgG2b and IgG3-ANoA isotypes increased. Treatment with rIL-12 alone increased the Hg-induced IgG2a and IgG3 ANoA titres, the PBA, and the IC deposits in renal and splenic vessel walls, while treatment with α-IL-4 + Hg inhibited renal but not splenic vessel wall IC deposits. We conclude that manipulating the cytokine status, by altering the Th1/Th2 balance, will influence autoimmune disease manifestations. This might be an important way of modulating human autoimmune diseases.

  • 19.
    Häggqvist, Bo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Interleukin-10 in murine metal-induced systemic autoimmunity2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 3, p. 422-431Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown aetiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive functions in the immune system have lately received much interest. One of the cytokines in focus in this respect is interleukin (IL)-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on the induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation of the IL-10 gene in a strain resistant to heavy metal-induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A.SW strain during the induction of autoimmunity by metals. The wild-type C57BL/6 J (B6-WT) strain did not react with lymphoproliferation, polyclonal B cell activation, anti-nucleoar autoantibodies (ANoA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, serum IgG1 and IgE showed a modest increase during Hg treatment, while Ag caused a weak increase in IgE and IgG2a. The B6-129P2-Il10tm1Cgn/J strain (IL-10-deficient mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but showed a higher median titre of homogeneous ANA compared with Hg-treated B6-WT mice. Both control and Hg-treated (but not Ag-treated) IL-10-deficient mice showed an increase in splenic weight and serum IgG1 compared with B6-WT control and Hg-treated mice. An early, significant increase in serum IgE was seen in Hg-treated IL-10-deficient and WT mice compared with the controls, the increase was 42- and sixfold, respectively. During ongoing intense treatment with rIL-10 in combination with Hg the susceptible A.SW mice showed a reduced development of ANoA and antichromatin antibodies, as well as serum IgE, compared with mice receiving Hg but not rIL-10. In conclusion, IL-10 suppresses several aspects of HgIA, but is not crucial for resistance to heavy metal-induced autoimmunity. Peroral silver treatment suppresses the spontaneous immune activation seen in IL-10-deficient mice. © 2005 British Society for Immunology.

  • 20.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Interleukin-10 in murine mercury-induced systemic autoimmunity2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 3, p. 422-431Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.

    The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.

    The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.

  • 21.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Murine metal-induced systemic autoimmunity: baseline and stimulated cytokine mRNA expression in genetically susceptible and resistant strains2001In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 126, no 1, p. 157-164Article in journal (Refereed)
    Abstract [en]

    Cytokines play an important and complex role in the pathogenesis of systemic autoimmune diseases. In susceptible H-2s mice, inorganic mercury (Hg) induces lymphoproliferation, antinucleolar antibodies against the 34-kDa-protein fibrillarin, and systemic immune-complex (IC) deposits. Here, we report extensive analysis of cytokine mRNA levels in susceptible A.SW (H-2s) and resistant A.TL (H-2tl) mice under unstimulated conditions and during oral treatment with Hg and/or silver nitrate (Ag). Cytokine mRNA expression in lymphoid tissues was assessed using the ribonuclease protection assay and phosphorimaging. Baseline expression of IL-2 and IFN-γ mRNA was higher in A.SW than in A.TL mice. In A.SW mice, Hg treatment caused early up-regulation of IL-2 and IFN-γ levels, followed by substantial expression of IL-4 mRNA, which was significant compared to control A.SW and Hg-treated A.TL mice. Hg-exposed A.TL mice exhibited unchanged IFN-γ, reduced IL-2 and greatly increased IL-10 mRNA expression. Ag-treated A.SW mice, which develop antifibrillarin antibodies (AFA) but exhibit minimal immune activation and no IC deposits, showed an early increase in IL-2 and IFN-γ mRNA, but only a small and delayed rise in IL-4 mRNA. In conclusion, H-2-linked resistance to Hg-induced AFA is characterized by low constitutive expression of IL-2 and IFN-γ mRNA, which is not increased by Hg, and a marked increase in IL-10 expression. Conversely, the key features of H-2-linked susceptibility to Hg- and Ag-induced AFA are up-regulation of IL-2, IFN-γ and IL-4 mRNA expression, and down-regulation of IL-10 expression.

  • 22.
    Jarefors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 1, p. 18-27Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis (LB) can, despite adequate antibiotic treatment, develop into a chronic condition with persisting symptoms such as musculoskeletal pain, subjective alteration of cognition and fatigue. The mechanism behind this is unclear, but it has been postulated that an aberrant immunological response might be the cause. In this study we investigated the expression of the T helper 1 (Th1) marker interleukin (IL)-12Rβ2, the marker for T regulatory cells, forkhead box P3 (FoxP3) and the cytokine profile in patients with a history of chronic LB, subacute LB, previously Borrelia-exposed asymptomatic individuals and healthy controls. Fifty-four individuals (12 chronic LB, 14 subacute LB, 14 asymptomatic individuals and 14 healthy controls) were included in the study and provided a blood sample. Mononuclear cells were separated from the blood and stimulated with antigens. The IL-12Rβ2 and FoxP3 mRNA expression was analysed with real-time reverse transcription–polymerase chain reaction (RT–PCR). The protein expression of IL-12Rβ2 on CD3+, CD4+, CD8+ and CD56+ cells was assessed by flow cytometry. Furthermore, the secretion of interferon (IFN)-γ, IL-4, IL-5, IL-10, IL-12p70 and IL-13 was analysed by enzyme-linked immunospot (ELISPOT) and/or enzyme-linked immunosorbent assay (ELISA). Chronic LB patients displayed a lower expression of Borrelia-specific IL-12Rβ2 on CD8+ cells and also a lower number of Borrelia-specific IFN-γ-secreting cells compared to asymptomatic individuals. Furthermore, chronic LB patients had higher amounts of Borrelia-specific FoxP3 mRNA than healthy controls. We speculate that this may indicate that a strong Th1 response is of importance for a positive outcome of a Borrelia infection. In addition, regulatory T cells might also play a role, by immunosuppression, in the development of chronic LB.

  • 23.
    Jarefors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Karlsson, Marika
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Eliasson, I.
    Department of Clinical Microbiology, Kalmar County Hospital, Sweden .
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Reduced number of interleukin-12 secreting cells in patients with Lyme borreliosis previously exposed to Anaplasma phagocytophilum2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 2, p. 322-328Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis and human granulocytic ehrlichiosis are tick-borne diseases caused by Borrelia burgdorferi and Anaplasma phagocytophilum, respectively. Infection with A. phagocytophilum has been observed to induce immunosuppression and animal studies suggest that the bacteria might also have prolonged inhibitory effects on immune cells. The aim of this study was to investigate the cytokine secretion in patients exposed previously to A. phagocytophilum and currently infected with B. burgdorferi compared with patients infected with B. burgdorferi and seronegative for A. phagocytophilum. Eight patients with erythema migrans and antibodies against A. phagocytophilum, 15 patients with erythema migrans and negative A. phagocytophilum serology and 15 non-exposed healthy individuals were included in the study. Blood mononuclear cells were stimulated with Borrelia-antigen and the number of cytokine [interleukin (IL)-4, IL-5, IL-12, IL-13 and interferon (IFN)-γ]-secreting cells was detected by enzyme-linked immunospot (ELISPOT). This study shows that patients with a previous exposure to A. phagocytophilum and a current infection with B. burgdorferi have a lower number of Borrelia-specific cells secreting IL-12 compared to Ap seronegative patients infected with B. burgdorferi (P < 0·001), indicating impairment in the ability to mount strong Th1-responses. We suggest that this mirrors a reduced Th1 response caused by A. phagocytophilum which could influence the outcome of the Borrelia infection and, speculatively, may also have implications in other conditions.

  • 24.
    Jonson, Carl-Oscar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Nyholm, Caroline
    CRC, Lund University, Department of Clinical Sciences, Malmö, Sweden.
    Cilio, Corrado M
    CRC, Lund University, Department of Clinical Sciences, Malmö, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Regulatory T-cell associated activity in Photopheresis-induced Immune tolerance in Recent Onset Type 1 Diabetes Children2008In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 153, no 2, p. 174-181Article in journal (Refereed)
    Abstract [en]

    Extracorporeal photochemotherapy (ECP) has demonstrated immunological effects. The proposed cytotoxic lymphocyte antigen 4 (CTLA-4) involvement, together with forkhead box P3 (FoxP3) and transforming growth factor (TGF)-β are associated with regulatory T cell activity. The aim of the study was to evaluate the regulatory T cell-associated effect of ECP in recent onset type 1 diabetic (T1D) children. Children (n = 20) with T1D received photopheresis 8-methoxypsoralen + ECP or placebo + shampheresis. Peripheral blood mononuclear cells (PBMC) collected pretreatment (day 1) and post-treatment (day 90) were stimulated with phytohaemagglutinin (PHA) and T1D-associated glutamic acid decarboxylase 65 (GAD65) peptide a.a. 247–279. CTLA-4, sCTLA-4, FoxP3 and TGF-β mRNA transcription was quantified. Photopheresis-treated individuals' relative mRNA expression was generally maintained during the course of the study. Placebo individuals increased in spontaneous CTLA-4 mRNA (P < 0·05) but decreased in expression after stimulation with GAD65-peptide (P < 0·05) and PHA (P < 0·05). Spontaneous TGF-β (P < 0·05) increased whereas PHA- (P < 0·01) and GAD65-peptide (P < 0·01)-induced TGF-β expression decreased in the placebo group, whereas it was maintained in the treated group. Without intervention, expression of CTLA-4 and TGF-β, stimulated with PHA and GAD65 peptide, decreased with time, with a parallel reduction of GAD65-peptide and PHA-stimulated TGF-β expression. These parameters were counteracted by ECP. In conclusion, our results indicate that ECP maintains regulatory T cell-associated activity in recent-onset T1D.

  • 25.
    Kastbom, Alf
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Roos Ljungberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ziegelasch, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Martinsson, Klara
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 3, p. 391-399Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic inflammatory disease where serum analysis of anti-citrullinated peptide/protein antibodies (ACPA) is an important diagnostic/prognostic tool. Levels and changes of ACPA in RA patients have been studied previously in relation to disease course and therapy response, but less is known regarding ACPA isotype changes in early RA. Hence, recent-onset RA patients (n = 231) were subjected to a 3-year clinical and radiological follow-up. Serum samples were serially collected and ACPA isotypes were analysed using the second-generation cyclic citrullinated peptide (CCP) as capture antigen. Changes in ACPA isotype levels and status were related to disease course and pharmacotherapy. At inclusion, 74% of the patients tested positive for ACPA IgG; 55% for immunoglobulin (Ig)A, 37% for secretory IgA (SIgA) and 35% for IgM. The proportion of positive patients decreased significantly at follow-up regarding ACPA SIgA, IgM and IgA. During the initial 3 months, reduction of the 28-joint disease activity score (DAS28) correlated with reduced levels of ACPA IgG (Rho = 0 center dot 242, P = 0 center dot 003), IgA (Rho = 0 center dot 260, P = 0 center dot 008), IgM (Rho = 0 center dot 457, P amp;lt; 0 center dot 001) and SIgA (Rho = 0 center dot 402, P amp;lt; 0 center dot 001). Levels of ACPA SIgA (P = 0 center dot 008) and IgM (P = 0 center dot 021) decreased significantly among patients with good response to treatment, which was not seen regarding ACPA IgA or IgG. Changes in ACPA isotype levels were not associated with radiographic damage. In conclusion, ACPA SIgA and IgM declined rapidly upon anti-rheumatic therapy and correlated with decreased disease activity in recent-onset RA. This may indicate that down-regulation of mucosal immunity to citrullinated proteins/peptides and recruitment of new B cells are key features of therapy responses in early RA.

  • 26.
    Koch, Stefan
    et al.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Kucharzik, T.
    Department of Gastroenterology, Municipal Hospital of Lueneburg, Lueneburg.
    Heidemann, J.
    Department of Medicine B, University Hospital of Muenster, Muenster, Germany.
    Nusrat, A.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Luegering, A.
    Department of Medicine B, University Hospital of Muenster, Muenster, Germany.
    Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 161, no 2, p. 332-341Article in journal (Refereed)
    Abstract [en]

    Infiltrating monocytes and macrophages contribute to the initiation and perpetuation of mucosal inflammation characteristic for human inflammatory bowel disease (IBD). Peripheral blood monocytes expressing the low-affinity Fcgamma receptor CD16 have been identified previously as a major proinflammatory cell population, based on their unique cytokine secretion profile. However, the contribution of these cells to the pathogenesis of inflammatory bowel disease remains to be elucidated. Thus, in this study we investigated whether the peripheral CD16(+) monocyte count correlates with common IBD disease parameters, and whether these cells infiltrate the intestinal mucosa under inflammatory conditions. We observed that CD16(+) peripheral blood monocytes are increased significantly in active Crohn's disease, particularly in patients with high Crohn's disease activity index and colonic involvement. Furthermore, we found that CD16(+) cells are a major contributor to the inflammatory infiltrate in Crohn's disease mucosa, although their spontaneous migration through primary human intestinal endothelial cells is limited. Our data suggest that lamina propria, but not peripheral blood, CD16(+) monocytes are a crucial proinflammatory cell population in IBD, and a potential target for anti-inflammatory therapy.

  • 27.
    Kurz, Tino
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Weiner, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Skoglund, Camilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Basnet, Sandeep
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    A myelopoiesis gene signature during remission in ANCA associated vasculitis does not predict relapses but seems to reflect ongoing prednisolone therapy2014In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 175, no 2, p. 215-226Article in journal (Refereed)
    Abstract [en]

    A myelopoiesis gene signature in circulating leucocytes, exemplified by increased myeloperoxidase (MPO) and proteinase 3 (PR3) mRNA levels, has been reported in patients with active anti-neutrophil cytoplasm antibody associated vasculitis (AAV) and to a lesser extent during remission. We hypothesized that this signature could predict disease relapse. mRNA levels of PR3, MPO, selected myelopoiesis transcription factors (CEBPA, CEBPB, SPIB, SPI1) and microRNAs (miRNAs) from patient and control peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) were analyzed and associated with clinical data. Patients in stable remission had higher mRNA levels for PR3 (PBMCs, PMNs) and MPO (PBMCs). PR3 and SPIB mRNA correlated positively in control but negatively in patient PBMCs. Statistically significant correlations existed between PR3 mRNA and several miRNAs in controls, but not in patients. PR3/MPO mRNA levels were not associated with previous or future relapses but correlated to steroid treatment. Prednisolone doses were negatively linked to SPIB and miR-155-5p, miR-339-5p (PBMCs) and to miR-221, miR-361, miR-505 (PMNs). PR3 mRNA in PBMCs correlated with time since last flare, blood leucocyte count and estimated glomerular filtration rate. Our results show that elevated leucocyte PR3 mRNA levels in AAV patients in remission do not predict relapse. The origin seems multifactorial, but to an important part explainable by prednisolone action. Gene signatures in patients with AAV undergoing steroid treatment should therefore be interpreted accordingly.

  • 28.
    Kvarnström, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Sidorova, E.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Joakim
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ekerfelt, Christina
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Vrethem, Magnus
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Söderberg, O.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Johansson, Malin
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Rosén, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Myelin protein P0-specific IgM producing monoclonal B cell lines were established from polyneuropathy patients with monoclonal gammopathy of undetermined significance (MGUS)2002In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 127, no 2, p. 255-262Article in journal (Refereed)
    Abstract [en]

    Monoclonal expansion of B cells and plasma cells, producing antibodies against ‘self’ molecules, can be found not only in different autoimmune diseases, such as peripheral neuropathy (PN), but also in malignancies, such as Waldenström’s macroglobulinaemia and B-type of chronic lymphocytic leukaemia (B-CLL), as well as in precancerous conditions including monoclonal gammopathy of undetermined significance (MGUS). About 50% of patients with PN-MGUS have serum antibodies against peripheral nerve myelin, but the specific role of these antibodies remains uncertain. The aims of the study were to establish, and characterize, myelin-specific B cell clones from peripheral blood of patients with PN-MGUS, by selection of cells bearing specific membrane Ig-receptors for myelin protein P0, using beads coated with P0. P0-coated magnetic beads were used for selection of cells, which subsequently were transformed by Epstein–Barr virus. The specificity of secreted antibodies was tested by ELISA. Two of the clones producing anti-P0 antibodies were selected and expanded. The magnetic selection procedure was repeated and new clones established. The cells were CD5+ positive, although the expression declined in vitro over time. The anti-P0 antibodies were of IgM-λ type. The antibodies belonged to the VH3 gene family with presence of somatic mutations. The IgM reacted with P0 and myelin-associated glycoprotein (MAG), and showed no evidence for polyreactivity, in contrast to other IgM CD5+ clones included in the study as controls. The expanded clones expressed CD80 and HLA-DR, which is compatible with properties of antigen-presenting cells. The immunomagnetic selection technique was successfully used for isolation of antimyelin protein P0-specific clones. The cell lines may provide useful tools in studies of monoclonal gammopathies, leukaemia, and autoimmune diseases, including aspects of antigen-presentation by these cells followed by T cell activation.

  • 29.
    Lahdenperä, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hölttä, V
    National Institute for Health and Welfare, Finland.
    Ruohtula, T
    National Institute for Health and Welfare, Finland.
    Salo, H M
    National Institute for Health and Welfare, Finland.
    Orivuori, L
    National Institute for Health and Welfare, Finland.
    Westerholm-Ormio, M
    Hospital for Children and Adolescents, University of Helsinki,.
    Savilahti, E
    Hospital for Children and Adolescents, University of Helsinki,.
    Fälth-Magnusson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Högberg, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Norrköping.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Vaarala, O
    National Institute for Health and Welfare, Finland.
    Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes2012In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 167, no 2, p. 226-234Article in journal (Refereed)
    Abstract [en]

    Up-regulation of interleukin (IL)-17 in small intestinal mucosa has been reported in coeliac disease (CD) and in peripheral blood in type 1 diabetes (T1D). We explored mucosal IL-17 immunity in different stages of CD, including transglutaminase antibody (TGA)-positive children with potential CD, children with untreated and gluten-free diet-treated CD and in children with T1D. Immunohistochemistry was used for identification of IL-17 and forkhead box protein 3 (FoxP3)-positive cells and quantitative polymerase chain reaction (qPCR) for IL-17, FoxP3, retinoic acid-related orphan receptor (ROR)c and interferon (IFN)-γ transcripts. IL-1β, IL-6 and IL-17 were studied in supernatants from biopsy cultures. Expression of the apoptotic markers BAX and bcl-2 was evaluated in IL-17-stimulated CaCo-2 cells. The mucosal expression of IL-17 and FoxP3 transcripts were elevated in individuals with untreated CD when compared with the TGA-negative reference children, children with potential CD or gluten-free diet-treated children with CD (P andlt; 0·005 for all IL-17 comparisons and P andlt; 0·01 for all FoxP3 comparisons). The numbers of IL-17-positive cells were higher in lamina propria in children with CD than in children with T1D (P andlt; 0·05). In biopsy specimens from patients with untreated CD, enhanced spontaneous secretion of IL-1β, IL-6 and IL-17 was seen. Activation of anti-apoptotic bcl-2 in IL-17-treated CaCo-2 epithelial cells suggests that IL-17 might be involved in mucosal protection. Up-regulation of IL-17 could, however, serve as a biomarker for the development of villous atrophy and active CD.

  • 30.
    Locht, H
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology.
    Skogh, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Rheumatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Kihlström, Erik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Anti-lactoferrin antibodies and other types of anti-neutrophil cytoplasmic antibodies (ANCA) in reactive arthritis and ankylosing spondylitis. 1999In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 117, p. 568-573Article in journal (Refereed)
  • 31.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    The role of Fc-receptors in murine mercury-induced systemic autoimmunity2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 144, no 2, p. 309-318Article in journal (Refereed)
    Abstract [en]

    Inorganic mercury (Hg) in genetically susceptible mouse strains induces a T cell-dependent, systemic autoimmune condition (HgIA) characterized by immunostimulation, anti-nuclear antibodies (ANA) and systemic immune-complex (IC) deposits. The exact phenotypic expression of HgIA in different strains depends on H-2 and non-H-2 genes. Fc receptors (FcRs) are important in the development of many autoimmune diseases. In this study, the effect of targeted mutations for activating and inhibiting FcRs in the BALB/c model of HgIA was examined. Hg-treated BALB/c mice without mutation (wild-type, wt) showed heavy IC deposits in the renal glomerular mesangium, as well as in renal and splenic vessel walls. The renal mesangial IC deposits were severely reduced in Hg-treated BALB/c mice without the gamma-chain (lack of the activating receptors FcgammaRI, FcgammaRIII and FcinRI), but unchanged in mice lacking the inhibitory FcgammaRIIB. The Hg-induced vessel wall IC deposits present in wt mice were abolished and reduced in the FcRgamma and FcgammaRIIB strains, respectively. Hg-treated BALB/c wt mice and mice without the gamma-chain showed an increase in serum IgE, while the increase in IgG1 was attenuated in the latter strain. In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE. In conclusion, FcRs are important mainly for the induction of systmeic IC deposits in the HgIA model, but also affects serum IgG1 and IgE levels.

  • 32.
    Martinsson, Klara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Johansson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Immunoglobulin (Ig)G1 and IgG4 anti-cyclic citrullinated peptide (CCP) associate with shared epitope, whereas IgG2 anti-CCP associates with smoking in patients with recent-onset rheumatoid arthritis (the Swedish TIRA project).2017In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 188, no 1, p. 53-62Article in journal (Refereed)
    Abstract [en]

    Given the possible importance of anti-citrullinated peptide/protein antibodies (ACPA) for initiation and progression of rheumatoid arthritis (RA), extended knowledge about the different isotypes and subclasses is important. In the present study, we analysed the immunoglobulin (Ig)G subclasses regarding reactivity against cyclic citrullinated peptides (anti-CCP) among 504 clinically well-characterized patients with recent-onset RA in relation to smoking habits, shared epitope (SE) status and IgA and pan-IgG anti-CCP antibodies. All patients, regardless of pan-IgG anti-CCP status, were analysed for IgG1-4 CCP reactivity. Sixty-nine per cent were positive in any IgG anti-CCP subclass, and of these 67% tested positive regarding IgG1, 35% IgG2, 32% IgG3, and 59% IgG4 anti-CCP. Among ever-smokers the percentages of IgG2 anti-CCP (P = 0·01) and IgA anti-CCP (P = 0·002)-positive cases were significantly higher compared to never-smokers. A positive IgG anti-CCP subclass -negative cases. Combining SE and smoking data revealed that IgG1 and IgG4 anti-CCP were the IgG anti-CCP isotypes associated with expression of SE, although the lower number of patients positive for IgG2 or IgG3 anti-CCP could, however, have influenced the results. High levels of IgG2 anti-CCP were shown to correlate with expression of the 'non-SE' allele human leucocyte antigen (HLA)-DRB1*15. In conclusion, in this study we describe different risk factor characteristics across the IgG anti-CCP subclasses, where IgG2 appears similar to IgA anti-CCP regarding the predominant association with smoking, while IgG1 and IgG4 related more distinctly to the carriage of SE genes.

  • 33.
    Mathsson, L.
    et al.
    Uppsala University.
    Åhlin, E.
    Uppsala University.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
    Rönnelid, J.
    Uppsala University.
    Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 3, p. 513-520Article in journal (Refereed)
    Abstract [en]

    Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.

  • 34.
    Nilsson, Lennart
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Kivling, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Jalmelid, M
    Fälth-Magnusson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Combinations of common chronic paediatric diseases deviate the immune response in diverging directions2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 146, no 3, p. 433-442Article in journal (Refereed)
    Abstract [en]

    The cytokine pattern of T lymphocytes has not been characterized in children with combinations of paediatric immunological disorders. We describe cytokine secretion in children with type 1 diabetes, coeliac disease and allergy and combinations of two of these diseases after stimulation with 'disease-specific' antigens. Peripheral blood mononuclear cells (PBMC) were collected from 68 children with type 1 diabetes, allergy or coeliac disease, two of these diseases in combination or none of these diseases. Using the enzyme-linked immunospot (ELISPOT) technique, interferon (IFN)-γ and interleukin (IL)-4 were analysed from fresh PBMC spontaneously and after in vitro stimulation with antigens associated with one or more of these diseases (insulin, gluten, birch and cat extract, β-lactoglobulin, ovalbumin and phytohaemagglutinin) in order to divide T helper (Th)1- from Th2-like lymphocytes. Stimulation with birch and cat extract caused increased IL-4 secretion in allergic children. A low IFN-γ response to insulin was found in type 1 diabetic children, whereas allergic children responded to insulin by increased IL-4 secretion. Children suffering from both type 1 diabetes (Th1-prone) and allergy (Th2-prone) reacted distinctly to general mitogen stimulation. Children suffering from two Th1-dominated diseases (type 1 diabetes and coeliac disease) showed hardly any response to either food or inhalation allergens. Our results indicate an important interplay between common immunological diseases in children. The combination of two Th1-deviated diseases is associated with a suppressed immune response, whereas a combination of Th1- and Th2-dominated diseases appears to increase the general immune response. © 2006 The Author(s).

  • 35.
    Ohlsson, S M
    et al.
    Lund University, Sweden .
    Pettersson, A
    Lund University, Sweden .
    Ohlsson, S
    Lund University, Sweden .
    Selga, D
    Lund University, Sweden .
    Bengtsson, A A
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Hellmark, T
    Lund University, Sweden .
    Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis2012In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 170, no 1, p. 47-56Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte-derived macrophages (M circle divide) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4.2 X 106 cells/l versus 10.4 X 106 cells/l, P andlt; 0.001). The number of neutrophils was increased (6.0 X 109 cells/l versus 3.8 X 109 cells/l, P andlt; 0.001). There were no differences found in the ability of M circle divide s to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of M circle divide s (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the M circle divide s or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability.

  • 36.
    Ohlsson, Susanne M.
    et al.
    Lund University, Sweden .
    Ohlsson, Sophie
    Lund University, Sweden .
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Lena
    Lund University, Sweden .
    Pettersson, Åsa
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Hellmark, Thomas
    Lund University, Sweden .
    Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies2014In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 176, no 3, p. 363-372Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibodies (ANCA) are thought to be pathogenic in ANCA-associated vasculitis (AAV) by stimulating polymorphonuclear leucocytes (PMNs) to degranulate and produce reactive oxygen species (ROS). The aim of this study was to investigate if PMNs from AAV patients are stimulated more readily by ANCA compared with PMNs from healthy controls (HCs). Differences in ANCA characteristics that can account for different stimulation potential were also studied. PMNs from five AAV patients and five HCs were stimulated with 10 different immunoglobulins (Ig)Gs, purified from PR3-ANCA-positive patients, and ROS production, degranulation and neutrophil extracellular trap (NET) formation was measured. ANCA levels, affinity and clinical data of the AAV donors were recorded. The results show that PMNs from AAV patients produce more intracellular ROS (P=0 center dot 019), but degranulate to a similar extent as PMNs from HCs. ROS production correlated with NET formation. Factors that may influence the ability of ANCA to activate PMNs include affinity and specificity for N-terminal epitopes. In conclusion, our results indicate that PMNs from AAV patients in remission behave quite similarly to HC PMNs, with the exception of a greater intracellular ROS production. This could contribute to more extensive NET formation and thus an increased exposure of the ANCA autoantigens to the immune system.

  • 37.
    Pihl, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Mallone, R.
    St Vincent Paul Hospital, France.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, no 3, p. 394-402Article in journal (Refereed)
    Abstract [en]

    Glutamic acid decarboxylase (GAD)65 formulated with aluminium hydroxide (GAD-alum) was effective in preserving insulin secretion in a Phase II clinical trial in children and adolescents with recent-onset type 1 diabetes. In addition, GAD-alum treated patients increased CD4+CD25hi forkhead box protein 3+ (FoxP3+) cell numbers in response to in-vitro GAD65 stimulation. We have carried out a 4-year follow-up study of 59 of the original 70 patients to investigate long-term effects on the frequency and function of regulatory T cells after GAD-alum treatment. Peripheral blood mononuclear cells were stimulated in vitro with GAD65 for 7 days and expression of regulatory T cell markers was measured by flow cytometry. Regulatory T cells (CD4+CD25hiCD127lo) and effector T cells (CD4+CD25CD127+) were further sorted, expanded and used in suppression assays to assess regulatory T cell function after GAD-alum treatment. GAD-alum-treated patients displayed higher frequencies of in-vitro GAD65-induced CD4+CD25+CD127+ as well as CD4+CD25hiCD127lo and CD4+FoxP3+ cells compared to placebo. Moreover, GAD65 stimulation induced a population of CD4hi cells consisting mainly of CD25+CD127+, which was specific of GAD-alum-treated patients (16 of 25 versus one of 25 in placebo). Assessment of suppressive function in expanded regulatory T cells revealed no difference between GAD-alum- and placebo-treated individuals. Regulatory T cell frequency did not correlate with C-peptide secretion throughout the study. In conclusion, GAD-alum treatment induced both GAD65-reactive CD25+CD127+ and CD25hiCD127lo cells, but no difference in regulatory T cell function 4 years after GAD-alum treatment.

  • 38.
    Rubér, Marie
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Berg, A
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Andersson, Roland
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Different cytokine profiles in patients with a history of gangrenous or phlegmonous appendicitis2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 143, no 1, p. 117-124Article in journal (Refereed)
    Abstract [en]

    Appendicitis is one of the most common and costly acute abdominal states of illnesses. Previous studies suggest two types of appendicitis which may be different entities, one which may resolve spontaneously and another that progresses to gangrene and perforation. Gangrenous appendicitis has a positive association to states of Th1 mediated immunity whereas Th2 associated immune states are associated with lower risk of appendicitis. This study investigated the inflammatory response pattern in patients previously appendicectomized for gangrenous (n = 7), or phlegmonous appendicitis (n = 8) and those with a non-inflamed appendix (n = 5). Peripheral blood mononuclear cells were analysed with ELISPOT analysis for number of spontaneous or antigen/mitogen stimulated IFN-γ, IL-4, IL-10 and IL-12 secreting cells or with ELISA for concentration of spontaneous or antigen/mitogen stimulated IFN-γ, IL-5 and IL-10. Spontaneously IL-10 secreting cells/100 000 lymphocytes were increased in the gangrenous group compared to the phlegmonous group (P = 0.015). The median concentration of IL-10 secreted after Tetanus toxoid (TT)-stimulation were higher in the gangrenous group and the control group, than the phlegmonous group (P = 0.048 and P = 0.027, respectively). The median concentration of TT induced IFN-γ secretion was higher for the gangrenous group compared to both the phlegmonous group and the control group (P = 0.037 and P = 0.003). Individuals with a history of gangrenous appendicitis demonstrated ability to increased IL-10 and IFN-γ production. The increased IFN-γ may support the notion of gangrenous appendicitis as an uncontrolled Th1 mediated inflammatory response and increased IL-10 may speculatively indicate the involvement of cytotoxic cells in the progression to perforation. © 2005 British Society for Immunology.

  • 39. Ryan, EJ
    et al.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Kjellman, N-IM
    Gothefors, L
    Mills, KHG
    Booster immunization of children with an acellular pertussis vaccine enhances Th2 cytokine production and serum IgE responses against pertussis toxin but not against common allergens2000In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 121, no 2, p. 193-200Article in journal (Refereed)
    Abstract [en]

    Acellular pertussis vaccines (Pa) protect against severe pertussis in children. However, serum antibody responses decline quickly after immunization. Studies in animal models suggest that cell-mediated immunity also contributes to protection against Bordetella pertussis, and it has already been demonstrated that Pa induce T cells that secrete type-1 and type-2 cytokines in children. In this study we examined the persistence of the T cell response and the effect of booster immunization in 4-6-year-old children. Cell-mediated immunity to B. pertussis antigens was detected in a high proportion of children more than 42 months after their last immunization. Peripheral blood mononuclear cells (PBMC) from the majority of children secreted interferon-gamma (IFN-?) and a smaller proportion IL-5, in response to specific antigen stimulation in vitro. However, following booster immunization, significantly higher concentrations of IL-5, but not IFN-?, were produced by PBMC in response to B. pertussis antigens. Furthermore, plasma IL-4 and IL-5 concentrations were increased, whereas IFN-? concentrations were reduced following booster immunization. It has been suggested that childhood immunization with Th2-inducing vaccines may predispose some children to atopic disease. Although we found that pertussis toxin (PT)-specific IgE was significantly increased after booster immunization in both atopic and non-atopic children, the levels of IgE to common allergens and the prevalence of positive skin prick test were unaffected by the booster vaccination. Thus, despite the enhancement of type-2 responses to B. pertussis antigens, booster vaccination with Pa does not appear to be a risk factor for allergy.

  • 40.
    Sandin, Charlotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Medicine and Health Sciences.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    IgA- and SIgA anti-PR3 antibodies in serum versus organ involvement and disease activity in PR3-ANCA associated vasculitis.2016In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 184, no 2, p. 208-215Article in journal (Refereed)
    Abstract [en]

    Circulating IgA class anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA-associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3-ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3-ANCA and IgA PR3-ANCA with IgG PR3-ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3-ANCA at diagnosis, 84% tested positive for IgG PR3-ANCA, 47% for IgA-ANCA and 36% for SIgA PR3-ANCA at the time of sampling for the present study. IgA and IgG PR3-ANCA were similarly represented among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3-ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3-ANCA and SIgA PR3-ANCA positive patients were significantly higher as compared to inactive disease. Eight patients were prospectively sampled during 24 months from onset of active disease. In these patients, IgA PR3-ANCA and SIgA PR3-ANCA more often turned negative after remission induction as compared to IgG PR3-ANCA. Our findings suggest that serum IgA PR3-ANCA and SIgA PR3-ANCA are more closely related to disease activity in AAV as compared to IgG PR3-ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3-ANCA isotypes increased along with disease activity, suggesting a global B-cell activation during active disease. This article is protected by copyright. All rights reserved.

  • 41.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Complement C3 and C4 genotypes in systemic vasculits1999In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, no 116(2), p. 379-82Article in journal (Refereed)
  • 42.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Deficiency of the mannan-binding ledtin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. Feb, no 139(2), p. 306-13Article in journal (Refereed)
  • 43.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Epitope mapping of anti-PR3 antibodies usin chimeric human PR3/mouse PR3 recombinant proteins.2004In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. Jan, no 135(1), p. 164-72Article in journal (Refereed)
  • 44.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Increased circulating levels of proteinase 3 in patients with anti-neutrophilic cytoplasmic autoantibodies-associated systemic vasculitis in remission2003In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. Mar, no 131(3), p. 528-35Article in journal (Refereed)
  • 45.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Increased Membrane Expression and Plasma Concentrations of Proteianse 3 (PR3) in Vasculitis is not a Consequence of the -564 A/G Gene Promotor Polymorphism2006In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. Jul, no 145(1), p. 63-70Article in journal (Refereed)
  • 46.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Increased monocyte transcription of the proteianse 3 gene2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. Jul, no 141(1), p. 174-82Article in journal (Refereed)
  • 47.
    Segelmark, Mårten
    Universitetssjukhuset i Lund.
    Screening for ANCA: Is indirect immunofluorescence the method of choice1995In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, p. 486-492Article in journal (Refereed)
  • 48.
    Selga, D.
    et al.
    Department of Nephrology, Clinical Sciences in Lund, Lund University and Lund University Hospital, Sweden.
    Segelmark, Mårten
    Department of Nephrology, Clinical Sciences in Lund, Lund University and Lund University Hospital, Sweden.
    Gunnarsson, L.
    Department of Nephrology, Clinical Sciences in Lund, Lund University and Lund University Hospital, Sweden.
    Hellmark, T.
    Department of Nephrology, Clinical Sciences in Lund, Lund University and Lund University Hospital, Sweden.
    Epitope shift of proteinase-3 anti-neutrophil cytoplasmic antibodies in patients with small vessel vasculitis2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 160, no 3, p. 318-324Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibodies against proteinase 3 (PR3-ANCA) are used as diagnostic tools for patients with small vessel vasculitis (AASV). We have produced chimeric mouse/human PR3 molecules and investigate changes in reactivity over time and the possible relationship between epitope specificity and clinical course. Thirty-eight PR3-ANCA-positive patients diagnosed between 1990 and 2003 were followed until December 2005. Plasma was collected at each out-patient visit and older samples were retrieved retrospectively. Patients reacted with multiple epitopes at the time of diagnosis. At subsequent relapses 12 patients shifted reactivity, in 11 cases from epitopes located in the C-terminal towards epitopes in the N-terminal. Patients with reactivity against N-terminal parts of PR3 at diagnosis had a significantly lower relapse rate, 30% compared to 78% in the group with predominantly C-terminal reactivity (P = 0·04). The reactivity pattern did not correlate to outcome measured as death, end-stage renal disease or vasculitis activity index score (VDI) at 5 years. Further research is necessary to conclude if this is a general phenomenon.

  • 49.
    Sjöwall, Johanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Carlsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Bergstrom, S.
    Bergström, S., Department of Microbiology, University of Umeå, Umeå, Sweden.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Forsberg, Pia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Innate immune responses in Lyme borreliosis: Enhanced tumour necrosis factor-a and interleukin-12 in asymptomatic individuals in response to live spirochetes2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 1, p. 89-98Article in journal (Refereed)
    Abstract [en]

    Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, Interferon (INF)-? and tumour necrosis factor (TNF)-a in DCs and IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF-a, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a, MIP-1ß and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-a-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease. © 2005 British Society for Immunology.

  • 50.
    Stuemer, J.
    et al.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Biermann, M. H. C.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Knopf, J.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Magorivska, I.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv National Medical University, Ukraine.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Svärd, A.
    Falun Central Hospital, Sweden.
    Janko, C.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany; University Hospital Erlangen, Germany.
    Bilyy, R.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany; Danylo Halytsky Lviv National Medical University, Ukraine.
    Schett, G.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Herrmann, M.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Munoz, L. E.
    Friedrich Alexander University of Erlangen Nurnberg FAU, Germany.
    Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy2017In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 189, no 3, p. 372-382Article in journal (Refereed)
    Abstract [en]

    The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.

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