High incidence of spontaneous autoimmune thyroiditis in immunocompetent self-reactive human T cell receptor transgenic mice

Badami, Ester; Maiuri, Luigi; Quaratino, Sonia

doi:10.1016/j.jaut.2005.01.003

Cited by 16 publications

(10 citation statements)

References 25 publications

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“…Consistent with this interpretation is our observation that peripheral CD4−/CD8+ 164/Rag2 o/o T cells have less functional avidity to GAD65 555–567 stimulation than CD4+/CD8− 164/Rag2 o/o T cells. The skewing of class II restricted self antigen reactive T cells towards a CD8 lineage has been observed in other TcR transgenic models, also in the context of strong negative selection(7,8). …”

Section: Discussionmentioning

confidence: 55%

“…Central tolerance in the thymus is largely governed through the interaction of the T cell receptor with self-peptide-MHC complexes, in which high avidity T cells are eliminated through apoptosis(1–3) or potentially differentiated into CD4+/CD25+/Foxp3 expressing regulatory T cells (Treg)(4,5). Strategies by which autoreactive T cells may escape central tolerance to self antigens include down modulation of receptor or costimulatory molecules (6) and skewing of CD4/CD8 coreceptor expression (7,8). These mechanisms are incomplete, however, such that self reactivity by some peripheral T cells is an intrinsic property of normal immunity, perhaps required to enable the immune repertoire to respond to the diverse nature of foreign antigens (9).…”

Section: Introductionmentioning

confidence: 99%

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Restricted Autoantigen Recognition Associated with Deletional and Adaptive Regulatory Mechanisms

Gebe¹,

Yue

Unrath

et al. 2009

The Journal of Immunology

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Autoimmune diabetes (T1D) is characterized by CD4+ T cell reactivity to a variety of islet-associated Ags. At-risk individuals, genetically predisposed to T1D, often have similar T cell reactivity, but nevertheless fail to progress to clinically overt disease. To study the immune tolerance and regulatory environment permissive for such autoreactive T cells, we expressed TCR transgenes derived from two autoreactive human T cells, 4.13 and 164, in HLA-DR4 transgenic mice on a C57BL/6-derived “diabetes-resistant” background. Both TCR are responsive to an immunodominant epitope of glutamic acid decarboxylase 65555–567, which is identical in sequence between humans and mice, is restricted by HLA-DR4, and is a naturally processed self Ag associated with T1D. Although both TCR use the identical Vα and Vβ genes, differing only in CDR3, we found stark differences in the mechanisms utilized in vivo in the maintenance of immune tolerance. A combination of thymic deletion (negative selection), TCR down-regulation, and peripheral activation-induced cell death dominated the phenotype of 164 T cells, which nevertheless still maintain their Ag responsiveness in the periphery. In contrast, 4.13 T cells are much less influenced by central and deletional tolerance mechanisms, and instead display a peripheral immune deviation including differentiation into IL-10-secreting Tr1 cells. These findings indicate a distinct set of regulatory alternatives for autoreactive T cells, even within a single highly restricted HLA-peptide-TCR recognition profile.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Restricted Autoantigen Recognition Associated with Deletional and Adaptive Regulatory Mechanisms

Gebe¹,

Yue

Unrath

et al. 2009

The Journal of Immunology

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“…Another interesting possibility to explain our apparent paradoxical results is that once immune tolerance is broken and the inflammatory/destructive phenomenon is ongoing, the activity of effector T cells would overcome the suppressive effect of T REG cells (33). In this regard, it has been described that CD4ϩCD25Ϫ T cells from rheumatoid arthritis synovial fluid are more difficult to suppress than cells from the peripheral blood (34).…”

Section: Discussionmentioning

confidence: 96%

Regulatory T Cells in Human Autoimmune Thyroid Disease

Marazuela

García-López

Figueroa-Vega

et al. 2006

The Journal of Clinical Endocrinology &Amp; Metabolism

182

132

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“…Also, in contrast to Tg, relatively few studies have used TPO (protein or cDNA) to immunize mice (17)(18)(19)(20)(21). Remarkably, even though the transgenic expression in mice of a pathogenic human TPO-specific T-cell receptor induces thyroiditis and hypothyroidism (22,23), there is no evidence that TPOAbs arise in these animals (23).…”

mentioning

confidence: 99%

Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin Antibodies

et al. 2010

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Hashimoto's thyroiditis, a common autoimmune disease, is associated with autoantibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO). TPO, unlike abundant and easily purified Tg, is rarely investigated as an autoantigen in animals. We asked whether antibodies (Abs) develop to both TPO and Tg in thyroiditis that is induced (C57BL/6 and DBA/1 mice) or arises spontaneously (NOD.H-2h4 mice). Screening for TPOAbs was performed by flow cytometry using mouse TPOexpressing eukaryotic cells. Sera were also tested for binding to purified mouse Tg and human TPO. The antibody data were compared with the extent of thyroiditis. Immunization with mouse TPO adenovirus broke self-tolerance to this protein in C57BL/6 mice, but thyroiditis was minimal and TgAbs were absent. In DBA/1 mice with extensive granulomatous thyroiditis induced by Tg immunization, TPOAbs were virtually absent despite high levels of TgAbs. In contrast, antibodies to mouse TPO, with minimal cross-reactivity with human TPO, arose spontaneously in older (7-12 months) NOD.H-2h4 mice. Unexpectedly, TgAbs preceded TPOAbs, a time course paralleled in relatives of probands with juvenile Hashimoto's thyroiditis. These findings demonstrate a novel aspect of murine and human thyroid autoimmunity, namely breaking B cell self-tolerance occurs first for Tg and subsequently for TPO. (Endocrinology 151: 4583-4593, 2010)

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High incidence of spontaneous autoimmune thyroiditis in immunocompetent self-reactive human T cell receptor transgenic mice

Cited by 16 publications

References 25 publications

Restricted Autoantigen Recognition Associated with Deletional and Adaptive Regulatory Mechanisms

Restricted Autoantigen Recognition Associated with Deletional and Adaptive Regulatory Mechanisms

Regulatory T Cells in Human Autoimmune Thyroid Disease

Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin Antibodies

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