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FEBS Lett. 2011 Dec 1;585(23):3633-9. doi: 10.1016/j.febslet.2011.10.026. Epub 2011 Oct 21.

Thymus, innate immunity and autoimmune arthritis: interplay of gene and environment.

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  • 1Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. shimon@ifrec.osaka-u.ac.jp

Abstract

A hypomorphic mutation of the gene encoding zeta-associated protein-70 (ZAP-70), a signaling molecule in T cells, produces autoimmune arthritis in mice under a microbially conventional condition but not in a clean environment. The genetic anomaly alters thymic selection of self-reactive T cells as well as natural regulatory T cells and their respective functions. Highly self-reactive polyclonal T cells, including arthritogenic ones, thus produced by the thymus strongly recognize self-antigens presented by antigen-presenting cells, stimulate them to up-regulate co-stimulatory molecules and secrete cytokines that drive naïve self-reactive T cells to differentiate into autoimmune effector Th17 cells. Administration of microbial products and activation of complement can facilitate the differentiation, evoking clinically overt arthritis in a microbially clean environment. Furthermore, mutation-dependent graded attenuation of T cell receptor signaling alters disease phenotypes and the dependency of disease occurrence on the environment. These findings provide a model of how genetic and environmental factors, in association, cause autoimmune diseases such as rheumatoid arthritis.

Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

PMID:
22027617
[PubMed - indexed for MEDLINE]
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