Class Ii Antigens and Disease Susceptibility

Nepom, Gerald T.

doi:10.1146/annurev.med.46.1.17

Cited by 51 publications

(5 citation statements)

References 30 publications

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“…In most autoimmune diseases, MHC genes are the chief genetic determinants, and this underlies the phenomenon of HLA association with disease (21,22). Given the crucial role of MHC molecules in presenting antigenic peptides to T cells, a key role of T cells in the pathogenesis of HLA-associated disorders has been invoked (1,2). Yet for most human diseases, the antigen presented by HLA molecules, and hence driving the pathogenic T cell response, remains elusive (23).…”

Section: Discussionmentioning

confidence: 99%

“…As T cells recognize peptide antigen with their TCRs in the context of MHC (HLA in humans) molecules, T cells very likely play a central role in HLA-associated disorders (1,2). Each naive T cell has a unique αβTCR as a result of gene recombination of different V, D, and J germline segments and random deletion or insertion of nongermline nucleotides at the V(D)J junction.…”

Section: Introductionmentioning

confidence: 99%

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Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease

Risnes

Christophersen²,

Dahal‐Koirala

et al. 2018

Journal of Clinical Investigation

104

139

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Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer-sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR-α and -β genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined. Persistence of the same clonotypes was seen in both compartments over decades, with up to 53% overlap between samples obtained 16 to 28 years apart. Further, we observed that the recall response following oral gluten challenge was dominated by preexisting CD4+ T cell clonotypes. Public features were frequent among gluten-specific T cells, as 10% of TCR-α, TCR-β, or paired TCR-αβ amino acid sequences of total 1813 TCRs generated from 17 patients were observed in 2 or more patients. In established celiac disease, the T cell clonotypes that recognize gluten are persistent for decades, making up fixed repertoires that prevalently exhibit public features. These T cells represent an attractive therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease

Risnes

Christophersen²,

Dahal‐Koirala

et al. 2018

Journal of Clinical Investigation

104

139

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“…T cell-mediated destruction of the islets is clearly involved in T1D pathogenesis; in fact, in both animal models and human patients, the disease is strongly linked to polymorphisms in MHC class II (3,4). However, despite the use of autoantibodies as both diagnostic and prognostic markers of T1D (5–7), the direct involvement of autoreactive B cells in disease pathogenesis remains controversial (8).…”

Section: Introductionmentioning

confidence: 99%

Cellular Requirements for Diabetes Induction in DO11.10xRIPmOVA Mice

Wesley¹,

Sather

Perdue³

et al. 2010

The Journal of Immunology

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Type 1 Diabetes (T1D3) results from the immune-mediated destruction of the insulin producing β-islet cells in the pancreas. The genetic and environmental mechanisms promoting the development of this disease remain poorly understood. We have explored the cellular requirements for T1D development in DO11.10xRIP-OVA (DORmO) mice, which carry a T cell receptor transgene specific for an MHC class II-restricted epitope from ovalbumin (OVA) and express membrane-bound OVA in the pancreas under the control of the rat insulin promoter. We found that DORmO.RAG2−/− mice do not develop insulitis and are completely protected from diabetes, demonstrating that endogenous lymphocyte receptor rearrangement is required for disease development. Diabetes in DORmO mice is preceded by the development of OVA-specific autoantibodies, and is delayed in B cell-deficient DORmO.JHD−/− mice, demonstrating that B cells contribute to disease progression. In addition, transfer of CD8+ T cells from diabetic animals into DORmO.RAG2−/− mice promoted insulitis by OVA-specific CD4+ T cells. Finally, although diabetes develops in DORmO mice in the presence of a significant population of Foxp3+ OVA-specific regulatory T cells, boosting regulatory T cell numbers by injecting IL-2 immune complexes dampens autoantibody production and prevents development of insulitis and overt diabetes. These results help define the events leading to diabetes in DORmO mice, and provide new insights into the cellular interactions required for disease development in an antigen-specific model of T1D.

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“… 14 HLA- DQB1∗02 which has shown a significant association with RHD in our study also poses a strong risk for insulin-dependent diabetes mellitus. 26 …”

Section: Association Of Hla- Dr With Rhdmentioning

confidence: 99%