Thymus, innate immunity and autoimmune arthritis: interplay of gene and environment.
FEBS Lett
; 585(23): 3633-9, 2011 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-22027617
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arthritis, Rheumatoid
/
Thymus Gland
/
Autoimmunity
/
Gene-Environment Interaction
/
Immunity, Innate
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
FEBS Lett
Year:
2011
Type:
Article
Affiliation country:
Japan