| 1. |
- Ardesjö, Brita, et al.
(författare)
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Autoantibodies to glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases.
- 2008
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Ingår i: Journal of autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 30:4, s. 273-82
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Tidskriftsartikel (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is an enigmatic disorder with a suggested autoimmune basis. A variety of autoantigens have been suggested but no specific or highly directed epitope has been identified. To address this issue, we constructed a cDNA library from normal human choledochus and screened expressing clones with serum from a patient with PSC and inflammatory bowel disease (IBD). Based on this screening, glutathione S-transferase theta 1 (GSTT1) was identified as a potential autoantigenic target. To study the specificity of GSTT1, we determined immunoreactivity using a panel of 58 patients with PSC, with and without IBD, 57 patients with IBD, 31 patients with Hashimoto's thyroiditis, 30 patients with primary biliary cirrhosis (PBC), 20 patients with insulin dependent diabetes mellitus, 22 patients with autoimmune polyendocrine syndrome type I, 10 patients with systemic lupus erythematosus (SLE), 20 patients with Sjögren's syndrome, 12 patients with autoimmune pancreatitis, 28 patients with Addison's disease, 27 patients with Grave's disease, 17 with myasthenia gravis, and 118 healthy controls. Reactivity against GSTT1 was found with PSC and IBD as well as some patients with other autoimmune pathology, indicating that this population of antibodies is neither specific nor a sensitive serologic marker for PSC, but the frequency was clearly higher in autoimmune patients than controls. GSTT1-antibodies have been described in persons with GSTT1-null genotype and are suggested to develop as an alloimmune response to blood transfusions from GSTT1-positive donors or pregnancies with GSTT1-positive children. Therefore, two IBD patients with and 15 PSC patients without GSTT1-antibodies were genotyped for GSTT1 to investigate if the presence of GSTT1-antibodies was associated with the GSTT1-null genotype and possibly caused by an alloimmune response. Both IBD patients and three of the PSC patients were of the GSTT1-null genotype. We note that the frequency of GSTT1-antibodies in this study is more than 100-fold higher than the frequency described earlier in patients with autoimmune diseases. We also observe an increased frequency of GSTT1-antibodies in patients with autoimmune diseases compared to healthy controls. This increased frequency can be explained by an autoimmune phenotype which increases susceptibility to such autoantibodies, or by a high frequency of the GSTT1-null genotype in autoimmune disease.
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| 2. |
- Martinsson, Klara, et al.
(författare)
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The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity.
- 2008
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 31:1, s. 22-29
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Tidskriftsartikel (refereegranskat)abstract
- Fc-receptors for IgG (Fc gamma R) link cellular and humoral immune responses, controlling the balance between activating and inhibitory immune responses, and are involved in autoimmune diseases. Mercury (Hg) induces an autoimmune condition in genetically (H-2(s,q,f)) susceptible mice characterized by lymphoproliferation, hypergammaglobulinemia and IgG antinucleolar antibodies (ANoA). Here we investigate the role of activating (Fc gamma RI, Fc gamma RIII) and inhibitory (Fc gamma RIIb) Fc-receptors on mercury-induced autoimmunity (HgIA) using DBA/1 mice (H-2(q))(-) with targeted Fc gamma R mutations and wild type (wt) mice. Mice deficient for the FcR gamma-chain or FcyRIII and treated with 15 mg/L HgCl2 showed a delayed and attenuated IgG1, IgG2a and IgG2b ANoA response compared to wt mice. Female Hg-treated FcyRIIB(-/-) mice showed a significant increased of lgG2b ANoA development compared to wt mice. The total serum IgG1 response due to Hg was attenuated in FcR gamma(-/-) and Fe gamma RIII-/- mice compared to wt mice. Hg-treated Fc gamma RIIB-/- mice showed an increase of both serum IgG1 and IgE compared to wt mice. We conclude that FcyRIII is of importance for the rapidity and final strength of the ANoA response and the increase in serum IgG1 in HgIA, while lack of Fc gamma RIIb increases the IgG2b ANoA response and the serum IgG1 and IgE response.
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| 3. |
- Motta, Vinicius, et al.
(författare)
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The NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells.
- 2007
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 28:4, s. 216-223
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Tidskriftsartikel (refereegranskat)abstract
- Recent data have suggested that non-obese diabetic (NOD) mice display a defect in negative thymic selection. Using mixed bone marrow chimeras, we demonstrate that the NOD allele of the diabetes susceptibility region 5 (Idd5) locus on chromosome 1, confers defective negative selection in response to endogenous superantigens (SAg) Mtv8 and Mtv9. We generated mixed bone marrow (BM) chimeras in which the donor cells of NOD and C3H or NOD.Idd5(b10) and C3H coexist and are similarly exposed to the Mtv8 and Mtv9 SAg. Under these conditions, SAg-mediated deletion of Vbeta11+ T cells is less efficient in chimeric mice reconstituted with NOD+C3H BM, compared with chimeras reconstituted with NOD.Idd5(b10)+C3H BM. Interestingly, the observed discrepancy was not T cell autonomous but was found to be mediated by a BM derived cellular subset, and under control of a gene(s) in the Idd5 region.
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| 4. |
- Mäkelä, Miia, et al.
(författare)
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Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin
- 2006
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 27:1, s. 54-61
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Tidskriftsartikel (refereegranskat)abstract
- Enteral virus infections may trigger the development of β-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of β-cell specific autoimmunity and type 1 diabetes. © 2006 Elsevier Ltd. All rights reserved.
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| 5. |
- Nilsson, Bengt-Olof, 1954-, et al.
(författare)
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Antinuclear antibodies in the oldest-old women and men
- 2006
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Ingår i: Journal of Autoimmun. - : Elsevier. ; 27:4, s. 281-288
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the prevalence of antinuclear antibodies (ANA) in very old individuals (>/=86years of age) with healthy younger (18-68years) blood donors (n=200) regarding gender, health status, ratio of circulating CD4/CD8 cells and cytomegalovirus (CMV) serology. Frozen plasma was used for ANA detection in two study groups, i.e. 'OCTO' (97 persons aged 86-92years, 65% women) and 'NONA' (136 persons aged 86-95years, 70% women). OCTO participants were recruited on the basis that they were healthy or moderately healthy according to a selection protocol. No exclusion criteria regarding health status were applied in the NONA sample. The prevalence of ANA was significantly higher in the oldest-old samples compared to blood donors. There was no association between health status and the presence of ANA in the oldest-old. The difference across age was most pro-nounced in men, with low levels at younger age, whereas the prevalence among the oldest-old men reached similar levels as in women. There were no associations between the presence of ANA and CD4/CD8 ratio or with CMV status in the oldest-old. Our findings confirm an in-creased prevalence of ANA in the oldest-old, and emphasize the importance of taking gender and age into consideration when evaluating ANA.
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| 6. |
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| 7. |
- Ola, Thomas O, et al.
(författare)
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Importin beta : A novel autoantigen in human autoimmunity identified by screening random peptide libraries on phage
- 2006
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 26:3, s. 197-207
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Tidskriftsartikel (refereegranskat)abstract
- By screening random peptide libraries (RPLs) with sera of Type 1 diabetes (T1D) patients, we previously identified 5 disease-specific 'mimotopes' displayed on phages (phagotopes). We already characterised 1 phagotope (CH1p), as an epitope of human osteopontin, an autoantigen expressed within the somatostatin cells of human islets. In this paper, we report the characterization of the second phagotope, 195Dyn, by immunohistochemistry, Western Blotting and screening of a human islet cDNA library using rabbit anti-195Dyn antibodies. The 195Dyn mimotope was detected in human islets. The screening of a λgt11 cDNA library from human islets has identified a clone, which corresponded to human importin beta. ELISA detected autoantibodies against this protein in sera of around 60% of TD1 patients and in 30% of patients affected by other autoimmune diseases. In summary, RPLs technology proved again successful in identifying another novel autoantigen (importin beta), whose significance in the autoimmune process remains to be fully elucidated. © 2006 Elsevier Ltd. All rights reserved.
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| 8. |
- Pöntynen, Nora, et al.
(författare)
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Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients
- 2006
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 27:2, s. 96-104
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.
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| 9. |
- Sundström, Mia, 1980-, et al.
(författare)
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Idd-linked genetic regulation of TACIhigh expressing B cells in NOD mice
- 2007
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 29:2-3, s. 116-124
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Tidskriftsartikel (refereegranskat)abstract
- In NOD mice, B cells play a key role in the initiation of type 1 diabetes pathogenesis. We have identified a novel NOD-specific B cell-related trait, i.e. the increased percentage of TACI(high)-expressing splenic B cells, by comparing NOD mice with non-autoimmune C57BL/6 mice. Using athymic NOD mice, we determined that this trait was T cell independent. We mapped the loci contributing to the increased proportion of TACI(high) expressing splenic B cells and found that the control of TACI expression was strongly linked to chromosome 1, in a region which includes the insulin-dependent diabetes (Idd) 5 loci. Moreover, another locus potentially involved was detected in the vicinity of Idd22 on chromosome 8. Interestingly, when analyzing age-dependent contribution to the obtained LOD scores we observed that the linkage to chromosome 8 was explained solely by mice > or =61 days of age, suggesting a temporal genetic regulation of TACI expression. In addition, analysis of genetic interaction between chromosome 1 and chromosome 8 indicated that the two loci acted in an additive fashion. Our findings corroborate the notion that B cell deviations contribute to type 1 diabetes development, and suggest a temporal regulation of TACI(high) expression, possibly influenced by the ongoing autoimmune process.
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| 10. |
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