Thymus, innate immunity and autoimmune arthritis: interplay of gene and environment.
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.
Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. shimon@ifrec.osaka-u.ac.jp
Shimon
S
Sakaguchi
Satoshi
S
Tanaka
Atsushi
A
Tanaka
Yoshinaga
Y
Ito
Shinji
S
Maeda
Noriko
N
Sakaguchi
Motomu
M
Hashimoto
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D059647:Gene-Environment Interaction; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*