Thymus, innate immunity and autoimmune arthritis : interplay of gene and environment
Thymus, innate immunity and autoimmune arthritis : interplay of gene and environment
复制标题
胸腺、先天免疫和自身免疫性关节炎：基因和环境的相互作用
DOI：
10.1016/j.febslet.2011.10.026
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Shimon Sakaguchi
中科院分区：
文献类型：
--
作者：
S. Okuda;M. Rasti;T. Kawata. S. Obi;Shimon Sakaguchi
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.
