Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes

Kaufman, Daniel L.; Clare‐Salzler, Michael; Tian, Jide; Forsthuber, Thomas G.; Ting, Gong; Robinson, Philip; Atkinson, Mark A.; Sercaz, E. E.; Tobin, Allan J.; Lehmann, Paul

doi:10.1007/bf03347754

Cited by 156 publications

(240 citation statements)

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“…Amplification of T-cell responses at extratumorous sites might occur by activation of autoreactive T cells, and diversification may occur by intramolecular and intermolecular determinant spreading. 29,30 The resulting heterogeneity of T-cell specificity might lead to the broad autoantibody repertoire seen in patients with paraneoplastic MG. 8,9 A more detailed analysis of the autoantibody repertoire in these patients, however, would be helpful in supporting this view.…”

Section: (C) Significant Weak Positive Correlation Between T-cell Resmentioning

confidence: 99%

Neurofilament is an autoantigenic determinant in myasthenia gravis

et al. 1999

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Intratumorous expression of a 153‐kd protein (p153), which contains an acetylcholine receptor‐like epitope, is the only tumor marker described to date that significantly associates with thymoma in paraneoplastic myasthenia gravis (MG). Here, we report that p153 is identical to the midsize neurofilament, as verified by immunohistochemistry, immunofluorescence, and western blot analysis. Furthermore, the acetylcholine receptor‐like epitope of the midsize neurofilament (NF‐M) was identified by peptide epitope mapping. We also show, using T‐cell proliferation assays, a significantly increased response of intratumorous T cells to a recombinant midsize neurofilament fragment in thymoma patients with MG compared with MG patients with thymic follicular hyperplasia or thymoma patients without MG. The T cells of thymic follicular hyperplasia and thymoma patients without MG seem to be unresponsive to NF‐M. In contrast, we found increased T‐cell responses to recombinant acetylcholine receptor fragments in MG patients in general compared with non‐MG patients. Increased T‐cell responses to NF‐M in patients with paraneoplastic MG might be the result of an abnormal positive selection of immature T cells within thymomas, caused by the expression of NF‐M in neoplastic thymic epithelial cells. Our results offer further evidence that NF‐M expression in thymomas is an autoantigenic determinant in MG. Ann Neurol 1999;46:167–175

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Section: (C) Significant Weak Positive Correlation Between T-cell Resmentioning

confidence: 99%

Neurofilament is an autoantigenic determinant in myasthenia gravis

et al. 1999

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“…In NOD mice, it was found that the initial immune response against pancreatic islets is a Th1 response against a confined region of GAD (peptides 509 -528 and 524-543) and that later responses are directed against another region of GAD and against other autoantigens, such as HSP65 and insulin [89]. Therefore, prevention of this early immune response could be achieved by immunization with purified GAD65 protein, which tolerized the Tcell-mediated immune response against other autoanti- gens such as HSP65 and CPH in pancreatic b cells and prevented or delayed insulitis and diabetes in NOD mice [89].…”

Section: Cell-mediated Immune Response To Gadmentioning

confidence: 99%

“…Therefore, prevention of this early immune response could be achieved by immunization with purified GAD65 protein, which tolerized the Tcell-mediated immune response against other autoanti- gens such as HSP65 and CPH in pancreatic b cells and prevented or delayed insulitis and diabetes in NOD mice [89]. There is also direct evidence that GAD-reactive T cells are diabetogenic in NOD mice.…”

Section: Cell-mediated Immune Response To Gadmentioning

confidence: 99%

“…2), and Coxsackie B4 virus has been shown to be associated with the development of T1DM in humans [102]. Splenic T cells in NOD mice also showed a high proliferative response to the GAD peptide homologous to the Coxsackie B4 sequence [89]. Human data are more inconsistent, however; some reports support this hypothesis [98,[103][104][105], but others do not.…”

Section: Molecular Mimicry Between Gad and Viral Antigensmentioning

confidence: 99%

“…In many cases, the preventive effect was found to be associated with a Th2 shift [116]. Immunization with purified GAD65 protein at an early age either intrathymically or intravenously can tolerize the T-cell-mediated immune response against pancreatic b cells in NOD mice, thus preventing insulitis and diabetes [85,89]. Moreover, tolerization with GAD65 could prevent the development of other immune reactions that usually occur in NOD mice, such as those against HSP65 and CPH.…”

Section: Therapeutic Uses Of Gadmentioning

confidence: 99%

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Role of glutamic acid decarboxylase in the pathogenesis of type 1 diabetes

Lee¹,

Khil²,

Yoon³

2002

CMLS, Cell. Mol. Life Sci.

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Glutamic acid decarboxylase (GAD) is considered to be one of the strongest candidate autoantigens involved in triggering beta-cell-specific autoimmunity. The majority of recent onset type 1 diabetes patients and pre-diabetic subjects have anti-GAD antibodies in their sera, as do nonobese diabetic (NOD) mice, one of the best animal models for human type I diabetes. Immunization of young NOD mice with GAD results in the prevention or delay of the disease as a result of tolerizing autoreactive T cells. Autoimmune diabetes can also be prevented by the suppression of GAD expression in antisense GAD transgenic mice backcrossed with NOD mice for seven generations. These results support the hypothesis that GAD plays an important role in the development of T-cell-mediated autoimmune diabetes. However, there is some controversy regarding the role of GAD in the pathogenesis of diabetes. Whether GAD truly plays a key role in the initiation of this disease remains to be determined. The examination of the development of insulitis and diabetes in beta-cell-specific GAD knockout NOD mice will answer this remaining question.

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Anti-120-kDa α-fodrin immune response with Th1-cytokine profile in the NOD mouse model of Sjögren's syndrome

et al. 1998

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Our recent study suggested that the 120-kDa alpha-fodrin molecule may be an important autoantigen in the pathogenesis of Sjögren's syndrome, and anti-120-kDa alpha-fodrin antibodies have been detected in patients with Sjögren's syndrome. Here we have analyzed anti-120-kDa alpha-fodrin immune responses during development of spontaneous autoimmune sialadenitis in NOD mice as a model of Sjögren's syndrome. We found specific autoantibody production against 120-kDa alpha-fodrin, and its production correlated closely with autoimmune sialadenitis. A specific T cell response of splenocytes against the 120-kDa alpha-fodrin autoantigen was observed in NOD mice from the early onset of autoimmune sialadenitis. In addition, production in vitro by splenic T cells of cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), but not IL-4, was detected by enzyme-linked immunosorbent assays. We found up-regulation of local cytokine genes, including those of Th1 type (IL-1beta, TNF-alpha, IL-2, IFN-gamma, IL-6), as well as IL-10 and IL-12(p40), in the tissue-infiltrating cells during the course of autoimmune sialadenitis. These findings suggest that in spontaneous autoimmune sialadenitis in NOD mice, there may be a specific anti-120-kDa alpha-fodrin immune response in the development of autoimmune lesions resembling human Sjögren's syndrome, and that the autoreactive Th1 cells possess an up-regulated cytokine profile besides IL-10 and IL-12.

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Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes

Cited by 156 publications

References 0 publications

Neurofilament is an autoantigenic determinant in myasthenia gravis

Neurofilament is an autoantigenic determinant in myasthenia gravis

Role of glutamic acid decarboxylase in the pathogenesis of type 1 diabetes

Anti-120-kDa α-fodrin immune response with Th1-cytokine profile in the NOD mouse model of Sjögren's syndrome

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