Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of aire-deficient mice

作者：Kuroda N; Mitani T; Takeda N; Ishimaru N; Arakaki R; Hayashi Y; Bando Y; Izumi K; Takahashi T; Nomura T; Sakaguchi S; Ueno T; Takahama Y; Uchida D; Sun SJ; Kajiura F; Mouri Y; Han HW; Matsushima A; Yamada G; Matsumoto M^*

来源：The Journal of Immunology, 2005, 174(4): 1862-1870.

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, a-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.

• 出版日期2005-2-15
• 单位RIKEN