摘要:

To determine the role of TCR Vβgenes in a model of multiple sclerosis (MS), we studied Theiler's virus infection in congenic mice with deletion of TCR Vβchromosome. Congenic mice expressing the Vaβ[50% deletion of TCR Vβ] or Vcβ70% deletion of TCR Vβ] haplotype were generated in mice resistant [B10 (H-2b)], intermediate [B10.K (H-2k), B10.RIII (H-2r)] or susceptible [B10.S (H-2s), and B10.Q (H-2q)] to Theiler's virus induced demyelination. Deletion of TCR Vβgenes (Vaβor Vcβ) did not convert B10 or B10.K congenic mice to susceptibility. In contrast, congenic B10.RIII-Vcβdeveloped prominent demyelination and 10-to 100-fold increase in virus-antigen expression in spinal cord compared to B10.RIII mice. No effect on the extent of demyelination was observed in B10.S-Vaβ, B10.S-Vcβor B10.Q-Vcβmice. These experiments illustrate the critical interactions between MHC, TCR, and background genes in susceptibility to immune-mediated disease.

ISSN:0891-6934    

DOI:10.3109/08916939409071347

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

By using an immunoprecipitation assay, we analysed reactivity of autoantibodies to human recombinant GAD65and GAD67in sera from patients with autoimmune polyendocrine syndrome Type II (APS II) with and without Type 1 (insulin-dependent) diabetes mellitus (IDDM) compared to patients with organ-specific autoimmunity. Overall antibodies to GAD65were correlated with IDDM in all study groups, whereas GAD67antibodies were associated with IDDM when APS II coexists. Antibodies to GAD65and GAD67were detected in 13 (44.8%) and 7 (24.1%) out of 29 APS II patients with IDDM, but in only 4 (13.8%) and 2 (6.9%) out of 29 APS II patients without IDDM, respectively (p<0.05). In short-standing IDDM (<1 year), antibodies to GAD67were significantly more frequent in patients with APS II (5 of 9 [55.6%] subjects) compared to matched diabetic patients without coexisting polyendocrinopathy (1 of 18 [5.6%]subjects) (p<0.02). The levels of GAD65(142±90 AU) and GAD67antibodies (178±95 AU) were significantly higher in patients with polyglandular disease than in patients with isolated IDDM (91±85 AU and 93±57 AU) (p<0.02). Interestingly, all 11 GAD67antibody positive subjects also had GAD65antibodies (p<0.0001), and in 10 of 11 anti-GAD67positive sera the GAD67antibodies could be blocked by either GAD67or GAD65, suggesting the presence of cross-reactive autoantibodies. No correlation was observed between GAD antibodies and age, sex or any particular associated autoimmune disease, besides IDDM. GAD antibodies were present in only 1 of 6 (16.7%) patients with APS Type I, in 1 of 26 (3.9%) patients with autoimmune thyroid disease but in none of the patients with Addison's disease (n = 16), pernicious anaemia (n = 7) or normal controls (n = 50). Our data suggest distinct antibody specificities reactive to GAD isoforms in APS II and IDDM, which might reflect different mechanisms of autoimmune response in IDDM with coexisting autoimmune polyendocrine autoimmunity.

ISSN:0891-6934    

DOI:10.3109/08916939409071348

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Interleukin (IL)-l inhibits the function of insulin-producing rat pancreatic beta-cellsin vitroandin vivo, and it has been postulated that the IL-1 effect is mediated through the cytokine inducable nitric oxide (NO) synthase. IL-1 inhibits the function of cultured human thyroid cells too, and in this study human thyroid cell production of NO in response to the TSH-stimulated influence of IL-1β(105U/1) and TNF-α(106U/1), alone or in combination was measured. IL-1β, but not TNF-α, induced an increase in nitrite production, which was significantly reduced by the competitive inhibitor of nitric oxide synthase L-NG-monomethyl-arginine (L-NMMA) (0.1 mmol/L and 0.5 mmol/L). However, the nitrite production was unrelated to the IL-1β-induced inhibition of thyroglobulin (Tg) and cyclic AMP (cAMP) and the IL-1β-induced IL-6 production. Thus, it is unlikely that NO is a second mediator of the demonstrated effects of IL-1βand TNF-αon human thyroid cells in culture.

ISSN:0891-6934    

DOI:10.3109/08916939409071349

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

Rheumatoid arthritis (RA) develops as a result of the interaction of both genetic and environmental factors. Among the genes in humans that have been suggested as candidate susceptibility genes in RA are those encoding the T cell receptor for antigen (TCR). A high prevalence and early age of onset of RA has previously been reported in Alaskan Tlingit Indians. In this study, the frequency of seven different restriction fragment length polymorphisms (RFLPs) in the TCR alpha and beta gene complexes were measured in a population of Alaskan Tlingit Indians. No statistically significant differences were noted when the frequencies of these RFLPs were compared between Tlingits with RA and healthy controls (p>0.05). These results do not support the hypothesis of an RA-susceptibility allele in the vicinity of these TCR alpha or beta genes. Since TCR RFLPs have not been extensively studied in native American populations, TCR polymorphism frequencies in the Tlingits were also compared to the frequencies observed in a second control group of healthy Caucasians. Statistically significant differences were observed in these comparisons implying a different distribution of individuals in these populations with different TCR repertoires.

ISSN:0891-6934    

DOI:10.3109/08916939409071350

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

The lymphoproliferativelprgene confers a lupus-like disease with lymphadenopathy, antinuclear antibody production, and glomerulonephritis in MRL-lpr/lprmice. Upregulation of ornithine decarboxylase (ODC) activity and polyamine levels have been observed in the kidney and lymphoid organs of this strain. Inhibition of ODC with 0.5–1.5% (w/v) difluoromethylornithine (DFMO) in drinking water prolonged life-span and ameliorated renal disease. Glomerulonephritis is a major cause of morbidity and mortality in human and murine lupus. In order to elucidate the mechanism(s) of ODC regulation in lupus nephritis, we characterized ODC at the protein and mRNA levels in 3 strains of autoimmune mice with thelprgenetic background (MRL-lpr/lpr, C3H-lpr/lprand C57BL/6J-lpr/lpr) using Western blotting, enzyme kinetics, turnover rate measurements, Northern blot hybridization, and reverse transcription-polymerase chain reaction (RT-PCR). Normal BALB/c mice were used as a control. We found that ODC activity in the kidney oflprstrains was 4-to 6-fold higher than that of BALB/c mice. The intensity of the major ODC protein band at 54 kD in Western blot was 4-fold higher in MRL-lpr/lprand C3H-lpr/lprkidney compared to that of BALB/c kidney. Putrescine levels were 2-to 4-fold higher in kidney oflprstrains than that of BALB/c and DFMO-treated MRL-lpr/lprmice. DFMO treatment significantly reduced ODC activity and polyamine levels. The half-life of ODC enzyme in MRL-lpr/lpr, C3H-lpr/lpr, B6-lpr/lprand BALB/c mouse kidneys was 15, 5, 8 and 23 min, respectively. There was no significant difference in the Kmvalues of different strains, whereas Vmaxvalues differed significantly. There was no difference in the level of SAMDC, another enzyme involved in the polyamine biosynthetic pathway, in various strain. Steady-state levels of ODC mRNA were lower inlprstrains compared to that of BALB/c mouse. Our results suggest that the basis for up-regulation of ODC is not at the transcriptional level, but may involve post-transcriptional modification(s) inlprstrains. The link between aberrant regulation of ODC and the immunopathogenesis of murine lupus nephritis indicates novel targets for lupus therapy.

ISSN:0891-6934    

DOI:10.3109/08916939409071351

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

HLA-DR haplotypes in patients with scleroderma and vasculitis were compared with those in healthy controls from the Scottish population to investigate whether any associations exist between MHC antigens and development of specific autoantibodies.In patients with systemic vasculitis the presence of any antibodies against neutrophil cytoplasmic antigens (ANCA) was associated with an increased frequency of DR8 [p<0.004], and no patients expressed the DR5 antigen. However, no significant differences were observed when these patients were subdivided into those with anti-myeloperoxidase (MPO) antibodies or anti-proteinase-3 (PR3) antibodies.Scleroderma patients as a whole showed a lower frequency of DR7 than controls [5.1% cf 28% in control population, p<0.002], Following subdivision by autoantibody profile, patients with circulating anti-centromere antibody (ACA) showed an increased frequency of DR1 compared to the control population [p<0.001]. No scleroderma patient without ACA expressed this haplotype.Associations between MHC and some autoantibodies suggest that antigen presentation could lead to their production.

ISSN:0891-6934    

DOI:10.3109/08916939409071352

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

We have analyzed the human T-cell receptor (hTcR) Va gene repertoire in thyroid tissue transplants of a patient with hyperthyroid Graves' disease. Blocks of thyroid tissue were transplanted subcutaneously into 10 mice with severe immunodeficiency (scid) and 4 weeks later 5 of the mice were injected intraperitoneally with autologous peripheral blood mononuclear cells (PBMC) (107cells per mouse). After a further 3 weeks, mice were sacrificed and total cellular RNA and cDNA prepared from each of the explants. We used specific olingonucleotides in polymerase chain reactions (PCR) to amplify 18 different human hTcR Va gene families and the identity of the PCR fragments was confirmed by Southern blot analysis.Different samples of the donor thyroid tissue consistently expressed 9–10 of the 18 hTcR Vαgene families screened (Vα1–7, 11, 12&15). A more marked bias in hTcR V gene family use was seen in each of the explants with a mean of only 2.8 Vαgene families detected. After 7 weeks of transplantation, the thyroid explants largely reflected some of the same genes seen in the hTcR V gene repertoire of the donor tissue with particularly pronounced expression of Vα2 and Vα3 gene families. The transplantation of PBMC into thescidmice showed evidence for their accumulation within the transplanted thyroid tissues as judged by the appearence of additional hTcR V gene families expressed in these samples although the specificity of such accumulation remains unclear. PCR fragment sequencing showed evidence that the hTcR Vα3 PCR products represented a mixture of clonaliy explanded and heterogeneous T cells while a randomly selected Vα13 product showed only evidence of heterogeneous T cells. Hence, at least the Vα3 gene family is likely to be involved in the etiopathogenesis of autoimmune thyroid disease in this particular patient.Our data underline the value of thescidmouse as anin vivomodel to study the human intrathyroidal lymphocyte population in Graves' disease and confirm the presence of selected T cells within the thyroid gland of patients with Graves' disease.

ISSN:0891-6934    

DOI:10.3109/08916939409071353

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

In a 56-year-old woman with granulomas of gold thioglucose in her hips, who developed insulin autoimmune syndrome, the relationships among the frequency or severity of hypoglycemic attacks, serum insulin (IRI) concentration, and characteristics of insulin antibodies were investigated during the clinical course with steroid treatment and two resection operations for the gold-thioglucose granulomas. When hypoglycemia was severe, the total IRI level was elevated, and Scatchard analysis showed that a high-affinity (k1), low-capacity (b1) population of antibodies had a relatively low affinity constant and very high binding capacity compared with the same population of antibodies in insulin-treated diabetic patients. When the attacks were relieved by steroid treatment and/or granuloma resection operation, the total IRI level was decreased and the high-affinity (k1), low-capacity (b1) population of antibodies showed a higher affinity constant and a lower binding capacity than those during the attacks. This indicated that the antibodies changed their characteristics to release insulin into the serum. The k1/b1 population of insulin antibodies with the lower affinity constant and higher binding capacity may easily release human insulin into the serum, leading to hypoglycemia. The longitudinal change of the k1/b1 population suggests a clonal change of the B cells producing the insulin antibody in insulin autoimmune syndrome.

ISSN:0891-6934    

DOI:10.3109/08916939409071354

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939409071355

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor