Intrathymic Expression of Genes Involved in Organ Specific Autoimmune Disease

Heath, Victoria L.; Moore, Nel C.; Parnell, Sonia M.; Mason, Don

doi:10.1006/jaut.1998.0210

Cited by 141 publications

(96 citation statements)

References 59 publications

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“…Tg/DC, but not OVA/DC, may activate and/or expand pre-existing, naturally occurring, Tg-specific CD25 ϩ T cells that have been positively selected in the thymus. This hypothesis is in agreement with recent data demonstrating that thymic expression of a self Ag facilitates the development of high numbers of Ag-specific Treg cells (9,29) and that Tg is known to be expressed intrathymically (30).…”

Section: Discussionsupporting

confidence: 93%

Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells

Verginis

Carayanniotis

2005

The Journal of Immunology

165

119

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Ex vivo treatment of bone marrow-derived dendritic cells (DCs) with TNF-α has been previously shown to induce partial maturation of DCs that are able to suppress autoimmunity. In this study, we demonstrate that i.v. administration of TNF-α-treated, semimature DCs pulsed with thyrogloblin (Tg), but not with OVA Ag, inhibits the subsequent development of Tg-induced experimental autoimmune thyroiditis (EAT) in CBA/J mice. This protocol activates CD4+CD25+ T cells in vivo, which secrete IL-10 upon specific recognition of Tg in vitro and express regulatory T cell (Treg)-associated markers such as glucocorticoid-induced TNFR, CTLA-4, and Foxp3. These CD4+CD25+ Treg cells suppressed the proliferation and cytokine release of Tg-specific, CD4+CD25− effector cells in vitro, in an IL-10-independent, cell contact-dependent manner. Prior adoptive transfer of the same CD4+CD25+ Treg cells into CBA/J hosts suppressed Tg-induced EAT. These results demonstrate that the tolerogenic potential of Tg-pulsed, semimature DCs in EAT is likely to be mediated through the selective activation of Tg-specific CD4+CD25+ Treg cells and provide new insights for the study of Ag-specific immunoregulation of autoimmune diseases.

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Section: Discussionsupporting

confidence: 93%

Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells

Verginis

Carayanniotis

2005

The Journal of Immunology

165

119

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“…The level of this thymic expression of tissue-specific autoantigens may be crucial to immune tolerance, at least in the case of insulin: the second strongest genetic association with type 1 diabetes (after HLA) is with a polymorphism upstream of the insulin gene, whose type 1 diabetes-predisposing alleles are associated with substantially lower thymic insulin expression [10][11][12]. This concept is supported by mouse models, which demonstrate a strong relationship between a tissue representation by 'promiscuous' gene expression in the thymus and the development of tissue-specific autoimmune response [13][14][15][16][17][18]. Most work in the past few years on the regulation of this atypical expression process has been on the autoimmune regulator (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) (AIRE) transcription factor, which has a major role in the expression of most self-antigens in the thymus.…”

Section: Introductionmentioning

confidence: 98%

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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Aims/hypothesis The expression of tissue-specific selfantigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature. Methods Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-γ and cell-tocell contact with thymocytes in co-culture. Results Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-γ, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, coculture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression. Conclusions/interpretation We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulinspecific mechanisms.

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“…Nevertheless, T cells that recognize peripheral-tissue antigens (PTAs) were long-thought to be tolerized in the periphery (4). This dichotomous paradigm channeled immunologists' thinking for years, being challenged only recently, when the thymus was found to be capable of ectopically expressing PTAs (6)(7)(8). In essence, PTAs project a veritable self-shadow in the thymus, primarily in medullary epithelial cells (MECs) of the stroma (9).…”

mentioning

confidence: 99%

Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity

Gavanescu

Kessler

Ploegh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Both humans and mice with a mutation in the autoimmune regulator (aire) gene develop multiorgan autoimmune disease. Aire was shown to exert its critical function in medullary epithelial cells of the thymus by promoting ectopic expression of peripheral tissue antigens. It was hypothesized that the widespread autoimmunity of Aire-deficient individuals reflects a lack of tolerance induction to the repertoire of peripheral tissue antigens expressed in the thymus of normal individuals. Here, we substantiate this hypothesis by identifying Mucin 6 as a stomach-specific antigen targeted by autoantibodies in gastritisprone mice lacking thymic expression of aire and demonstrate that transcription of the Mucin 6 gene in thymic medullary epithelial cells is indeed Aire-dependent.central tolerance ͉ self-antigen ͉ inflammation

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Intrathymic Expression of Genes Involved in Organ Specific Autoimmune Disease

Cited by 141 publications

References 59 publications

Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells

Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity

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