| 1. |
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| 2. |
- Andersson, Cecilia K, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes.
- 2011
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 44, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. Methods: A total of 686 patients diagnosed in 1996-2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 3. |
- Andersson, C, et al.
(författare)
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The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
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| 4. |
- Andersson, Kerstin, et al.
(författare)
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Patients with insulin-dependent diabetes but not those with non-insulin-dependent diabetes have anti-sulfatide antibodies as determined with a new ELISA assay
- 2002
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 35:7, s. 463-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In sera from newly diagnosed insulin-dependent diabetes mellitus patients (IDDM type 1) autoantibodies occur against different antigen determinants often shared with neural tissues. The role of these autoantibodies in the disease process is not yet clarified but they can be used as a diagnostic tool in the detection of IDDM patients. METHODS: We have analysed the occurrence of sulfatide autoantibodies in serum from patients with type 1 diabetes (n = 20), individuals with pre-type 1 diabetes (n = 6), patients with type 2 diabetes (n = 32) and controls (n = 43). The method used for the determination of the autoantibodies was a newly developed microtitre-ELISA assay utilizing a complex of sulfatide-albumin as the ligand. RESULTS: The new assay procedure for serum sulfatide autoantibodies showed good reproducibility. The total (day-to-day) imprecision based on analyses of three different serum samples with positive titres varied between 11 and 14% during an assay period of 6 months. None of the controls (0/43) had positive titres of sulfatide antibodies. Of the patients with type 1 diabetes, 85% displayed positive titres of anti-sulfatide antibodies while none of the type 2 patients did so. All individuals with pre-type 1 diabetes had positive titres of sulfatide antibodies. CONCLUSIONS: We conclude that sulfatide autoantibodies in serum can be reproducibly assayed by the newly developed microtitre-ELISA procedure. Elevated titres of sulfatide autoantibodies are a constant finding in newly diagnosed type 1 patients.
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| 5. |
- Andersson, Åsa, et al.
(författare)
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A genetic basis for shared autoimmunity in mouse models.
- 2005
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 38:3, s. 209-217
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Forskningsöversikt (refereegranskat)abstract
- Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.
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| 6. |
- Appelgren, Daniel, et al.
(författare)
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Active NET formation in Libman–Sacks endocarditis without antiphospholipid antibodies : A dramatic onset of systemic lupus erythematosus
- 2018
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 51:6, s. 310-318
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Tidskriftsartikel (refereegranskat)abstract
- Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman–Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman–Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p =.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r = 0.65, p =.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman–Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.
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| 7. |
- Baba, Akiyasu, et al.
(författare)
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Autoantibodies in atrial fibrillation: actor, biomaker or bystander?
- 2008
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Ingår i: Autoimmunity. - : Informa UK Limited. - 1607-842X .- 0891-6934. ; 41:6, s. 470-2
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Forskningsöversikt (refereegranskat)abstract
- Atrial fibrillation (AF) is one of the most common arrhythmias in patients with congestive heart failure, although the underlying mechanism has still to be determined. There is increasing evidence to suggest that autoimmunity may play an important role in the pathogenesis of AF. To date, at least three types of autoantibody have been found in AF: the anti-myosin heavy chain autoantibody, the anti-M2 muscarinic receptor autoantibody and the anti-heat shock protein autoantibody. The question is: are these autoantibodies actors, biomakers or merely bystanders? How much knowledge do we have?
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| 8. |
- Banday, Viqar Showkat, et al.
(författare)
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Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse
- 2017
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Ingår i: Autoimmunity. - : TAYLOR & FRANCIS LTD. - 0891-6934 .- 1607-842X. ; 50:6, s. 363-369
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Tidskriftsartikel (refereegranskat)abstract
- The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.
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| 9. |
- Brorsson, Caroline, et al.
(författare)
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Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:2, s. 107-114
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.
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| 10. |
- Brorsson, Caroline, et al.
(författare)
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Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 44:2, s. 107-114
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.
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| 11. |
- Bybrant, M. C., et al.
(författare)
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Tissue transglutaminase autoantibodies in children with newly diagnosed type 1 diabetes are related to human leukocyte antigen but not to islet autoantibodies: A Swedish nationwide prospective population-based cohort study
- 2018
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 51:5, s. 221-227
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study explored the association between tissue transglutaminase autoantibody (tTGA), high-risk human leucocyte antigen (HLA) genotypes and islet autoantibodies in children with newly diagnosed type 1 diabetes (T1D).Patients and methods: Dried blood spots and serum samples were taken at diagnosis from children <18years of age participating in Better Diabetes Diagnosis (BDD), a Swedish nationwide prospective cohort study of children newly diagnosed with T1D. We analyzed tTGA, high-risk HLA DQ2 and DQ8 (DQX is neither DQ2 nor DQ8) and islet auto-antibodies (GADA, IA-2A, IAA, and three variants of Zinc transporter; ZnT8W, ZnT8R, and ZnT8QA).Results: Out of 2705 children diagnosed with T1D, 85 (3.1%) had positive tTGA and 63 (2.3%) had borderline values. The prevalence of tTGA was higher in children with the HLA genotypes DQ2/2, DQ2/X or DQ2/8 compared to those with DQ8/8 or DQ8/X (p=.00001) and those with DQX/X (p.00001). No significant differences were found in relation to islet autoantibodies or age at diagnosis, but the presence of tTGA was more common in girls than in boys (p=.018).Conclusion: tTGA at T1D diagnosis (both positive and borderline values 5.4%) was higher in girls and in children homozygous for DQ2/2, followed by children heterozygous for DQ2. Only children with DQ2 and/or DQ8 had tTGA. HLA typing at the diagnosis of T1D can help to identify those without risk for CD.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Christensen, Ulla Bjerre, et al.
(författare)
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Different islet protein expression profiles during spontaneous diabetes development vs. allograft rejection in BB-DP rats
- 2006
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 39:4, s. 315-321
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) is characterized by selective autoimmune destruction of the insulin producing beta-cells in the islets of Langerhans. When the beta-cells are destroyed exogenous administration of insulin is necessary for maintenance of glucose homeostasis. Allogeneic islet transplantation has been used as a means to circumvent the need for insulin administration and has in some cases been able to restore endogenous insulin production for years. However, long life immunosuppression is needed to prevent the graft from being rejected and destroyed. Changes in protein expression pattern during spontaneous diabetes development in the diabetes prone BioBreeding rat (BB-DP) have previously been described. In the present study, we have investigated if any of the changes seen in the protein expression pattern during spontaneous diabetes development are also present during allograft rejection of BB-DP rat islets. Two hundred neonatal islets were syngeneically transplanted under the kidney capsule of 30 day old BB-DP rats and removed prior to and at onset of diabetes. Allogeneically transplanted islets from BB-DP rats were removed before onset of allograft rejection and at maximal islet graft inflammation (rejection). The protein expression profiles of the transplants were visualised by two-dimensional gel (2-DG) electrophoresis, analysed and compared. In total, 2590 protein spots were visualised and of these 310 changed expression ( p < 0.01) in syngeneic islet transplants in the BB-DP rats from 7 days after transplantation until onset of diabetes. In BB-DP islets transplanted to WK rats 53 protein spots ( p < 0.01) showed changes in expression when comparing islet grafts removed 7 days after transplantation with islet grafts removed 12 days after transplantation where mononuclear cell infiltration is at its maximum. Only four protein spots (1%) were significantly changed in both syngeneic (autoimmune) and allogeneic islet destruction. When comparing protein expression changes in syngeneic BB-DP islet transplants from 37 days after transplantation to onset of diabetes with protein expression changes in allografts from day 7 to 12 after transplantation only three spot were found to commonly change expression in both situations. In conclusion, a large number of protein expression changes were detected in both autoimmune islet destruction and allogeneic islet rejection, only two overlaps were detected, suggesting that autoimmune islet destruction and allogeneic islet rejection may result from different target cell responses to signals induced by the cellular infiltrate. Whether this reflects activation of distinct signalling pathways in islet cells is currently unknown and need to be further investigated.
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| 16. |
- Daka, Bledar, 1976, et al.
(författare)
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Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.
- 2009
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Ingår i: Autoimmunity. - : Informa UK Limited. - 1607-842X .- 0891-6934. ; 42:6, s. 507-14
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.
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| 17. |
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| 18. |
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| 19. |
- Finke, Doreen, et al.
(författare)
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Endogenous type I interferon inducers in autoimmune diseases
- 2009
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 42:4, s. 349-352
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Forskningsöversikt (refereegranskat)abstract
- Type I interferon (IFN) is produced by the innate immune system in several autoimmune diseases, such as systemic lupus erythematosus (SLE), polymyositis, and systemic sclerosis. In these diseases, immune complex (IC)-containing DNA or RNA may act as endogenous IFN inducers. The abilities of these IC to reach the endosomes in the plasmacytoid dendritic cells (PDC) cause the intracellular toll-like receptor (TLR) to initiate a cascade of transcription factors--a critical step in triggering type I IFN production. A special configuration of the nucleic acid (NA), such as CpG-rich non-methylated DNA or GU-rich RNA, appears crucial. However, other components of the IC, like HMGB1, may also be necessary. Studies regarding the genetic background of autoimmune diseases suggest that variants of genes involved in both IFN production and response are associated with disease susceptibility. This knowledge is important for the development of new therapeutic strategies in autoimmune diseases.
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| 20. |
- Fransson, Moa, et al.
(författare)
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T regulatory cells lacking CD25 are increased in MS during relapse
- 2010
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 43:8, s. 590-597
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of inflammatory responses is considered to be a key element in autoreactive immune responses. T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4(+)CD25(+)FoxP3(+) Tregs in autoimmunity has been extensively investigated. Recently, it was shown that Tregs in systemic lupus erythematosus lacked CD25 but were biologically functional. These data warrants for further investigation of CD25(- ) Tregs in human autoimmunity. We analyzed relapsing-remitting multiple sclerosis (MS) patients by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3, and the IL7R (CD127). Further, the level of Tregs was compared in remitting and relapsing patients and correlated with disease duration. Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls (p < 0.05), indicating that Tregs attempt to restrain immune activity during relapse. The proportion of Tregs tended to be decreased with disease duration, while CD25(+)CD4(+) and CD25(+)CD8(+) effector T-cell proportions were elevated and positively correlated with overall disease duration (p < 0.05). In conclusion, while MS patients in remission have normal levels of Tregs of different phenotype, relapsing patients show an increased proportion of systemic CD25(- )FoxP3(+) Tregs. With time, the proportion of Tregs decrease while effector T cells expand.
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| 21. |
- Fu, Michael, 1963
(författare)
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Autoimmunity and idiopathic dilated cardiomyopathy: where we stand?
- 2008
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Ingår i: Autoimmunity. - : Informa UK Limited. - 1607-842X .- 0891-6934. ; 41:6, s. 415-8
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Forskningsöversikt (refereegranskat)abstract
- Idiopathic dilated cardiomyopathy (DCM) with its heterogeneous phenotype and genotype remains one of the leading causes of severe heart failure particularly in the younger. Even in the elderly, it appears around 15% of heart failure is due to DCM. Despite great improvements in heart failure therapy, prognoses remains poor. One of the most important reasons is that the present heart failure management is aimed mostly at restoration of neurohormonal balance, rather than targeting primary causes of the disease. As a matter of fact, a substantial subgroup of DCM and chronic heart failure is accompanied by autoimmune mechanism, in particular a wide spectrum of autoantibodies. For almost two decades, the autoimmune hypothesis has been considered a "fairy tale". Today, we have better understanding of autoimmune mechanism in DCM. This focused issue is aimed to summarize what has happened in the last two decades in the context of basic understanding of underlying mechanisms and clinical relevance.
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| 22. |
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| 23. |
- Goncalves, Isabel, et al.
(författare)
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Effects of simvastatin on circulating autoantibodies to oxidized LDL antigens : relation with immune stimulation markers
- 2009
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Ingår i: AUTOIMMUNITY. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 42:3, s. 203-208
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Tidskriftsartikel (refereegranskat)abstract
- Statins exert a number of anti-inflammatory and immunomodulatory effects in vitro. However, the immunomodulatory effects in vivo are less clarified. In the present study, we investigated whether simvastatin treatment changed the levels of autoantibodies against specific oxidized LDL (oxLDL) antigens as well as their association with leukocyte activation markers. Eighty volunteers with mild-to-moderate hypercholesterolemia were randomized to either simvastatin 40mg or placebo for 6 weeks. Autoantibodies against apo B peptide antigens, C-reactive protein (CRP) and interleukin (IL)-6 in plasma were determined by ELISA. Subsets of circulating B and T cells were studied by flow cytometry. Simvastatin significantly reduced CRP by 26%, whereas IL-6 remained unchanged. Levels of IgG against the apo B peptide P-240 (amino acids 3586-3605) increased by 16% (p=0.03) in the simvastatin group whereas autoantibody levels to other apo B peptides did not change. At baseline and after 6 weeks, the P-240 IgG levels were significantly correlated with the number of CD57+CD28-CD8+T cells but not to other lymphocyte subsets or inflammatory markers. The P-240 IgG levels after 6 weeks simvastatin therapy was strongly correlated to the relative increase in CD57+CD28-CD8+T cells (p=0.003). Simvastatin treatment induced an increase in autoantibodies against an oxLDL antigen. The effect was related to an expansion of a CD8+T cell subset and may involve an immunostimulation by simvastatin.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Herold, K C, et al.
(författare)
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Derivation of non-lymphopenic BB rats with an intercross breeding
- 1989
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 3:2, s. 83-93
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have suggested that the development of diabetes in the BB rats does not require the expression of T lymphopenia. In order to derive non-lymphopenic diabetic rats and define the relationship between the T cell abnormalities, MHC genotype, and diabetes, we performed a cross between BB/H and diabetes resistant BB/control followed by an intercross of the F1. In the F2, the overall incidence of diabetes and lymphopenia was 30% and 27%, respectively. Lymphopenia was strongly associated with diabetes (p less than 0.001) and was seen in 76% of the diabetic F2's. However, 6 of the diabetic were non-lymphopenic (24%) and 3 of the non-diabetics were lymphopenic (5%). In the non-lymphopenic diabetic animals, all T cell levels were within the normal range, but diabetes occurred at an earlier age than their lymphopenic littermates (p less than 0.001). In contrast to the strong association between the inheritance of lymphopenia and diabetes, no relationship between diabetes and Class I MHC restriction fragment length polymorphisms was found. We conclude: 1) Diabetes and lymphopenia are strongly associated inherited abnormalities in the BB rat and are not associated with Class I RFLP defined genotypes within the RTIu haplotype, 2) Animals in whom diabetes occurs in the absence of lymphopenia can be derived using this breeding approach 3) In our non-lymphopenic rats, diabetes occurred at an earlier age possibly reflecting the restoration of quantitative or qualitative T cell defects found in lymphopenic BB rats.
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| 29. |
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| 30. |
- Hultgren, O, et al.
(författare)
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Serum concentration of interleukin-18 is up-regulated in patients with ANCA-associated vasculitis
- 2007
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 40:7, s. 529-531
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Tidskriftsartikel (refereegranskat)abstract
- We investigated circulating interleukin-18 concentrations in patients with ANCA-associated vasculitis (ASV) and healthy control subjects, and included a group of hemodialysis patients, a patient group previously reported to show high IL-18 plasma levels. Anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO) serum levels were also measured. Interestingly we found significantly increased serum IL-18 concentrations in ASV patients as compared to healthy controls, 437 vs. 185 pg/ml (p < 0.0001). The increase of IL-18 production was similar irrespective of presence of autoantibodies to PR3 or MPO. As expected the hemodialysis patients also showed significantly increased circulating IL-18 concentrations as compared to control subjects.
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| 31. |
- Häggmark-Månberg, Anna, et al.
(författare)
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Autoantibody targets in vaccine-associated narcolepsy
- 2016
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Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 49:6, s. 421-433
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Tidskriftsartikel (refereegranskat)abstract
- Narcolepsy is a chronic sleep disorder with a yet unknown cause, but the specific loss of hypocretin-producing neurons together with a strong human leukocyte antigen (HLA) association has led to the hypothesis that autoimmune mechanisms might be involved. Here, we describe an extensive effort to profile autoimmunity repertoires in serum with the aim to find disease-related autoantigens. Initially, 57 serum samples from vaccine-associated and sporadic narcolepsy patients and controls were screened for IgG reactivity towards 10 846 fragments of human proteins using planar microarrays. The discovered differential reactivities were verified on suspension bead arrays in the same sample collection followed by further investigation of 14 antigens in 176 independent samples, including 57 narcolepsy patients. Among these 14 antigens, methyltransferase-like 22 (METTL22) and 5'-nucleotidase cytosolic IA (NT5C1A) were recognized at a higher frequency in narcolepsy patients of both sample sets. Upon sequence analysis of the 14 proteins, polymerase family, member 3 (PARP3), acyl-CoA-binding domain containing 7 (ARID4B), glutaminase 2 (GLS2) and cyclin-dependent kinase-like 1 (CDKL1) were found to contain amino acid sequences with homology to proteins found in the H1N1 vaccine. These findings could become useful elements of further clinical assays that aim towards a better phenotypic understanding of narcolepsy and its triggers.
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| 32. |
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| 33. |
- Isic, Azra, 1979, et al.
(författare)
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TNFalpha-antagonist neither improve cardiac remodelling or cardiac function at early stage of heart failure in diabetic rats.
- 2008
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Ingår i: Autoimmunity. - : Informa UK Limited. - 1607-842X .- 0891-6934. ; 41:6, s. 473-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Despite tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in patients with heart failure and previous preclinical study with TNFalpha-antagonist has been demonstrated to improve cardiac function in acute heart failure, recent clinical trials using TNFalpha-antagonist in patients with chronic severe heart failure have been disappointing. The aim was to study why TNFalpha-antagonist may not work during long-term treatment in chronic heart failure (CHF) in experimental model. METHODS: 49 rats were used at the age of 26 weeks: healthy Whistar Kyoto rats (WKY, n = 26) and diabetic (WKY+D, n = 23). Rats in each group received either a 12-week treatment with TNFalpha-antagonist (Etanercept) or NaCl injections. RESULTS: In diabetic rats, there were increased plasma glucose level and blood pressure. By use of echocardiography diabetic rats displayed not only enlarged and thinned left ventricles but also decreased both systolic and diastolic functions. Moreover, there are increased interleukin-6 (IL6) mRNA levels. However, TNFalpha-antagonist, etanercept, does not improve either cardiac remodelling or cardiac function. IL6 mRNA level remained unchanged after treatment of etanercept. CONCLUSION: Chronic treatment of TNFalpha-antagonist has no favourable effect on either cardiac remodelling or cardiac function. It is therefore inappropriate to use TNFalpha-antagonist in CHF in diabetes as underlying cause.
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| 34. |
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| 35. |
- Jonsdottir, Berglind, et al.
(författare)
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Childhood thyroid autoimmunity and relation to islet autoantibodies in children at risk for type 1 diabetes in the diabetes prediction in skåne (DiPiS) study
- 2018
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 51:5, s. 228-237
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim was to determine prevalence and age at seroconversion of thyroid autoimmunity in relation to islet autoantibodies, gender and HLA-DQ genotypes in children with increased risk for type 1 diabetes followed from birth. Methods: In 10-year-old children (n = 1874), blood samples were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase 65 (GADA), Zink transporter 8 (ZnT8R/W/QA), insulinoma-associated protein-2 (IA-2A), insulin (IAA) and HLA-DQ genotypes. Prospectively collected samples from 2 years of age were next analysed for TPOAb, and TGAb and, finally, in confirming samples at 11–16 years of age along with TSH and FT4. Frequencies were tested with Chi-square or Fischer’s exact tests, autoantibody levels with Wilcoxon and correlations between autoantibody levels with Spearman’s rank correlation test. Results: The prevalence of thyroid autoimmunity was 6.9%, overrepresented in girls (p <.001) also having higher TPOAb levels at 10 years (p =.049). TPOAb was associated with GADA (p =.002), ZnT8R/W/QA (p =.001) and IA-2A (p =.001) while TGAb were associated with ZnT8R/W/QA (p =.021). In boys only, TPOAb were associated with GADA (p =.002), IA-2A (p =.001), ZnT8R/W/QA (p =.001) and IAA (p =.009), and TGAb with GADA (p =.013), IA-2A (p =.005) and ZnT8R/W/QA (p =.003). Levels of IA-2A correlated to both TPOAb (p =.021) and to TGAb (p =.011). In boys only, levels of GADA and TGAb correlated (p =.009 as did levels of IA-2A and TPOAb (p =.013). The frequency and levels of thyroid autoantibodies increased with age. At follow-up, 22.3% had abnormal thyroid function or were treated with thyroxine. Conclusions: Thyroid autoimmunity and high TPOAb levels were more common in girls. In contrast, in boys only, there was a strong association with as well as correlation between levels of thyroid and islet autoantibodies. It is concluded that while girls may develop autoimmune thyroid disease (AITD) independent of islet autoantibodies, the risk for thyroid disease in boys may be linked to concomitant islet autoimmunity.
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| 36. |
- Jönsen, Andreas, et al.
(författare)
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Gene-environment interactions in the aetiology of systemic lupus erythematosus
- 2007
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 40:8, s. 613-617
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutathion S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.
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| 37. |
- Jönsson, Ida, et al.
(författare)
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High-titer GAD65 autoantibodies detected in adult diabetes patients using a high efficiency expression vector and cold GAD65 displacement.
- 2011
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Ingår i: Autoimmunity. - : Informa Healthcare. - 0891-6934 .- 1607-842X. ; 44:2, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- Adult type 2 diabetes patients with GAD65 autoantibodies (GADA) are known as latent autoimmune diabetes in adults (LADA). It has been suggested that GADA in LADA patients preferentially bind to the N-terminal end of GAD65. Using the N-terminal end extension of ³⁵S-GAD65 generated by the pEx9 plasmid, we tested the hypothesis that GADA in LADA patients preferentially react with ³⁵S-GAD65 from the pEx9 plasmid compared to the normal length pThGAD65 plasmid. Healthy control subjects (n = 250) were compared with type 1 (n = 23), type 2 (n = 290), and unspecified (n = 57) diabetes patients. In addition, radio-binding assays for GADA with ³⁵S-GAD65 generated from both the pEx9 and pThGAD65 plasmids were used in displacement assays with an excess of recombinant human GAD65 (2 μg/mL) to correct for non-specific binding. ³⁵S-GAD65 produced by either pEx9 or pThGAD65 did not differ in binding among the healthy controls and among the type 1 diabetes patients. Among the type 2 and unspecified patients, there were 4/290 and 3/57 patients, respectively, with binding to the pEx9 but not to the pThGAD65 generated ³⁵S-GAD65. In the displacement assay, we discovered 14 patients with very high-titer GADA among the type 1 (n = 3, 12,272-29,915 U/mL), type 2 (n = 7; 12,398-334,288 U/mL), and unspecified (n = 4; 20,773-4,053,580 U/mL) patients. All samples were fully displaced following appropriate dilution. We conclude that pThGAD65 is preferred for the coupled in vitro transcription translation of ³⁵S-GAD65 and that displacement with recombinant GAD65 may detect very high-titer GADA with possible clinical relevance.
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| 38. |
- Kozyrev, Sergey V., et al.
(författare)
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The genetics and biology of Irf5-mediated signaling in lupus
- 2007
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 40:8, s. 591-601
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Tidskriftsartikel (refereegranskat)abstract
- Recently much attention was attracted to the importance of the type I interferon pathway in the initiation and development of the autoimmune disease systemic lupus erythematosus (SLE). Many SLE patients have increased serum levels of IFN-α and display an IFN gene expression "signature" characterized by strong overexpression of IFN-responsive genes in leukocytes and target tissues. Moreover, about 20% of cancer patients treated with IFN-α therapy manifest symptoms resembling SLE and some later develop the disease. One of the key genes of the IFN-α pathway, IRF5, was found to be strongly associated with SLE. Two functional SNPs lead to alternative splicing and altered steady-state level of IRF5 gene expression. Besides, the gene has a polymorphic inserion/deletion in exon 6, which contributes to the diversity in the isoform pattern of IRF5. Interestingly, recent studies have not found association of IRF5 with the other autoimmune diseases, such as rheumatoid arthritis or psoriasis, suggesting the unique role for IRF5 in the development of lupus. Here, we present the current knowledge on IRF5 genetics and its biological function and discuss the possible ways in which IRF5 contributes to susceptibility to SLE.
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| 39. |
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| 40. |
- Landin-Olsson, Mona, et al.
(författare)
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Appearance of islet cell autoantibodies after clinical diagnosis of diabetes mellitus
- 1999
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 29:1, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- Islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies (GAD65Ab) are often present at diagnosis of insulin dependent diabetes mellitus (type I diabetes) and are supposed to decline in level and frequency during the first years of disease. We have analysed ICA and GAD65Ab at onset and after one gear in 395 population based randomly selected 15-34 year old patients newly diagnosed with diabetes mellitus, to study how these autoantibodies persist, disappear and appear and their relation to C-peptide levels. Of the 395 samples 212 (54%) were positive for ICA, 250 (63%) were positive for GAD65Ab and 170 (43%) were positive for both. At follow up after one year, 27/183 (15%) of the ICA negative patients and 25/145 (17%) of the GAD65Ab negative patients had converted to positivity. Among the 103 patients negative for both ICA and GAD65Ab, 16 turned positive for one or both antibodies after one year. Patients converting to positivity for one or the other antibody after one year, had lower C-peptide levels after one year than patients who initially were and remained negative, supporting the hypothesis that these patients have a genuine type I diabetes. In conclusion, newly diagnosed patients may be negative for autoantibodies at diagnosis but develop these antibodies later on during the disease.
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| 41. |
- Leijon, Kristina, 1967-, et al.
(författare)
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Analysis of VH gene utilisation in the non-obese diabetic mouse
- 1993
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Ingår i: Autoimmunity. - : Harwood Academic. - 0891-6934 .- 1607-842X. ; 15:1, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- The immunoglobulin (Ig) heavy chain variable (VH) gene complexity and the VH gene utilisation pattern of the non-obese diabetic (NOD) mouse were investigated. We found that the NOD mouse displays a VH gene complexity which appears to be identical to that of the C57BL/6 mouse. Thus, Southern hybridisation using probes specific for 9 of the murine VH gene families revealed identical restriction fragment length polymorphism (RFLP) patterns in both mouse strains. As indicated by immunofluorescence analysis using allotype specific monoclonal antibodies the NOD mice were also found to carry the IgCH-1b allele. Collectively, these data suggest that the NOD mice carry an IgVH locus identical to that carried by C57BL/6. In contrast to the apparent identity at the level of germline VH gene repertoires, the pattern of VH gene utilisation differed considerably between these two mouse strains. Thus, in NOD mice the neonatal preference of D-proximal VH genes was found to be more pronounced than in C57BL/6 mice. Moreover, in contrast to adult C57BL/6 mice a D-proximal bias was evident also in adult NOD mice. On the basis of these findings we discuss the possibility that the distorted development of B cell repertoires in the NOD mouse could be directly or indirectly related to the T cell mediated, autoimmune process in the NOD mouse.
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| 42. |
- Lindberg, Bengt, et al.
(författare)
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Prevalence of β-cell and Thyroid Autoantibody Positivity in Schoolchildren during Three-Year Follow-up
- 1999
-
Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 31:3, s. 175-185
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65Ab), insulin (IAA), islet cells (ICA), thyroid peroxidase (TPOAb) and thyroglob-ulin (TgAb), in relation to HLA-DR types, was assessed in 310 (HLA in 280) twelve-year-old children during three-year follow-up. Altogether, 26.8% (83?10) of the children were found to carry at least one autoantibody. The HLA-DR3/DR4 genotype was significantly more prevalent in the subgroup of children GAD65Ab-positive on at least one occasion than among GAD65Ab-negative children |33% (2/6) vs. 5% (12/274);? = 0.03|, as was the HLA-DR4/x genotype among children seropositive for at least one thyroid autoantibody, compared to the corresponding seronegative subgroup [52% (34/65) vs. 34% (74/215); p = 0.01]. The proportion of children seropositive in at least one of the three tests was 1.9% (6?10) for GAD65Ab, 2.6% (8?10) for IAA, 5.2% (16?10) for ICA, 11.3% (35?10) for TPOAb and 19.4% (60?10) for TgAb. All autoantibodies except GAD65Ab tended to disappear during follow-up, and at the three-year follow-up IAA had disappeared in 50% (2/4) of cases, ICA in 67% (6/9), TPOAb in 30% (6/20) and TgAb in 38% (18/47) of cases. The turnover of seropositive subjects and the large proportion of children seropositive for at least one islet or thyroid autoantibody during a three-year follow-up suggest transient autoantibodies to be more common than is discernible in cross-sectional investigations
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| 43. |
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| 44. |
- Lindehammer, Sabina, et al.
(författare)
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Early human pregnancy serum cytokine levels predict autoimmunity in offspring.
- 2011
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 44, s. 445-452
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Tidskriftsartikel (refereegranskat)abstract
- It is generally believed that pregnancy is mediated by a Th2 response, which includes cytokines that promote placental growth and are involved in inducing tolerance to the foetus. If the balance between Th1/and Th2-mediated cytokines is disrupted, systemic and local changes could predispose the foetus to future disease. Therefore, a shift in the Th1/Th2 balance during pregnancy, possibly caused by underlying environmental factors, could be associated with post-partum autoimmune disease in the offspring. Based on this presumption, we used celiac disease as a model to investigate whether autoimmunity is triggered in the foetus during early pregnancy, observed as changes in the mother's cytokine profile. Ten cytokines were measured by electro-chemi-luminescent multiplex ELISA in serum samples obtained from mothers during early pregnancy. Cases included women with children who had developed verified celiac disease before the age of 5, who were compared with other women as matched controls. We observed that 7 out of 10 cytokine levels were significantly increased in our case mothers when compared to controls. Five of these belonged to what is generally known as a Th1-mediated response (TNF?, IFN?, IL-2, IL-1? and IL-12) and two were Th2 cytokines (IL-13 and IL-10). However, the IL-10 cytokine is known to have features from both arms of the immune system. These results were confirmed in a logistic regression model where five out of the initial seven cytokines remained. This study suggests that increase in Th1 serum cytokines may be associated with celiac disease in offspring.
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| 45. |
- Lowe, Michael R., et al.
(författare)
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The length of the CTLA-4 microsatellite (AT)(N)-repeat affects the risk for type 1 diabetes
- 2000
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 32:3, s. 173-180
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Tidskriftsartikel (refereegranskat)abstract
- CTLA-4 is important to down-regulating T cell responses and has been implicated in type 1 (insulin dependent) diabetes mellitus in both linkage and association studies. The aim of our study was to relate the polymorphic (AT)(n) microsatellite in the 3' untranslated sequence of the CTLA-4 gene to diabetes risk. We studied 616 consecutively diagnosed 0-34 year-old Swedish patients and 502 matched controls by PCR-based genotyping to determine the length of the 3'-end (AT)(n)repeat region of the CTLA-4 gene and categorizing alleles as predominantly monomorphic short (S) or highly polymorphic (in length) long (L) alleles. The odds of type 1 diabetes of subjects with the L/L genotype was estimated to be 1.84 times that of subjects with the S/S genotype (95% CI 1.44-2.73, p=0.002). Further analysis of the long alleles, partitioned into intermediate (I) length and very long (VL) alleles, suggested that L alleles act recessively in conferring diabetes risk (p=0.0009). This study suggests that the 3'-end (AT)(n) repeat region of the CTLA-4 gene represents a recessive risk factor for type 1 diabetes.
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| 46. |
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| 47. |
- Matsui, Shinobu, et al.
(författare)
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Transfer of immune components from rabbit autoimmune cardiomyopathy into severe combined immunodeficiency (SCID) mice induces cardiomyopathic changes.
- 2006
-
Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 39:2, s. 121-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Growing evidence suggests that autoimmune mechanism plays an important role in the pathogenesis of cardiomyopathy. The purpose of this study was to investigate whether passive transfer of IgG and/or lymphocytes from rabbits with autoimmune cardiomyopathy is able to reproduce cardiomyopathic changes in severe combined immunodeficiency (SCID) mice. METHODS AND RESULTS: SCID mice were injected intraperitoneally with IgG and/or peripheral blood lymphocytes (PBL) from either rabbits immunized with both beta1-adrenoceptor peptide and M2-muscarinic receptor peptide (beta1+M2 group) or rabbits with adjuvant (N group). Thirty five SCID mice were divided into seven groups; N-IgG, N-PBL, N-IgG & PBL, (beta1+M2)-IgG, (beta1+M2)-PBL, (beta1+M2)-IgG & PBL and control groups. Heart weight in three (beta1+M2) groups were significantly increased. All mice in three (beta1+M2) groups showed high titer of rabbit anti-beta1 adrenoceptor autoantibodies, and 4 mice in the (beta1+M2)-PBL group and 3 mice in the (beta1+M2)-IgG & PBL group showed a significant increase in titer of rabbit anti-M2-muscarinic receptor autoantibodies. Focal infiltration of inflammatory cells in the myocardium was observed in the (beta1+M2)-IgG & PBL group. In the (beta1+M2)-PBL group and (beta1+M2)-IgG & PBL group, cardiomyocyte diameters were significantly increased. Some myocytes of the (beta1+M2)-IgG & PBL group exhibited intracellular edema, clumps of Z-band and increased numbers of mitochondria by using electron microscopy. CONCLUSION: Transfer of IgG and PBL from rabbits immunized with combined beta1 and M2 peptides was able to reproduce the early stage of cardiomyopathic changes in SCID mice.
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| 48. |
- Neiman, Maja, 1983-, et al.
(författare)
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Individual and stable autoantibody repertoires in healthy individuals
- 2019
-
Ingår i: Autoimmunity. - : TAYLOR & FRANCIS LTD. - 0891-6934 .- 1607-842X. ; 52:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- In the era towards precision medicine, we here present the individual specific autoantibody signatures of 193 healthy individuals. The self-reactive IgG signatures are stable over time in a way that each individual profile is recognized in longitudinal sampling. The IgG autoantibody reactivity towards an antigen array comprising 335 protein fragments, representing 204 human proteins with potential relevance to autoimmune disorders, was measured in longitudinal plasma samples from 193 healthy individuals. This analysis resulted in unique autoantibody barcodes for each individual that were maintained over one year's time. The reactivity profiles, or signatures, are person specific in regards to the number of reactivities and antigen specificity. Two independent data sets were consistent in that each healthy individual displayed reactivity towards 0-16 antigens, with a median of six. Subsequently, four selected individuals were profiled on in-house produced high-density protein arrays containing 23,000 protein fragments representing 14,000 unique protein coding genes. Based on a unique, broad and deep longitudinal profiling of autoantibody reactivities, our results demonstrate a unique autoreactive profile in each analyzed healthy individual. The need and interest for broad-ranged and high-resolution molecular profiling of healthy individuals is rising. We have here generated and assessed an initial perspective on the global distribution of the self-reactive IgG repertoire in healthy individuals, by investigating 193 well-characterized healthy individuals.
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| 49. |
- Nielsen, Lotte B., et al.
(författare)
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Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes
- 2011
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 44:8, s. 616-623
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibodies against the newly established autoantigen in type 1 diabetes, zinc transporter 8, ZnT8, are presented as two types, ZnT8RAb and ZnT8WAb. The rs13266634 variant of the SLC30A8 gene has recently been found to determine the type of ZnT8Ab. The aim of this study was to explore the impact of this genetic variant and the ZnT8Ab on the residual beta-cell function during disease progression the first year after disease diagnosis in children with newly diagnosed type 1 diabetes. This cohort consists of 257 children aged < 16 years, all patients were newly diagnosed with type 1 diabetes. A Boost-test was carried out at 1, 6, and 12 months to characterize the residual beta-cell function. Carriers of the CC and CT genotype groups of the rs13266634 SNP of the SLC30A8 gene had higher stimulated C-peptide levels the first year after onset compared with those of the TT genotype group (29%, p = 0.034). CC genotype carriers were highly associated with the presence of ZnT8RAb subtype during disease progression (compared with TT, p < 0.0001). On the other hand, the TT genotype was associated with the presence of ZnT8WAb subtype during disease progression (compared with CC, p < 0.0001). The C allele of the SLC30A8 gene is associated with preserved beta-cell function in type 1 diabetes patients. The genetic determination of the rs13266634 variant on the ZnT8Ab specificity is sustained the first 12 months after the diagnosis of type 1 diabetes in a pediatric cohort.
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| 50. |
- Nilsson, Jan, et al.
(författare)
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Atherosclerosis.
- 2004
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 37:4, s. 351-355
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Tidskriftsartikel (refereegranskat)
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