Thymus, innate immunity and autoimmune arthritis: Interplay of gene and environment,10.1016/j.febslet.2011.10.026,Febs Letters,Shimon Sakaguchi,Satosh

Thymus, innate immunity and autoimmune arthritis: Interplay of gene and environment


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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.

Journal: Febs Letters - FEBS LETT

DOI: 10.1016/j.febslet.2011.10.026

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Thymus, innate immunity and autoimmune arthritis: Interplay of gene and environment,10.1016/j.febslet.2011.10.026,Febs Letters,Shimon Sakaguchi,Satosh