Organ-specific autoimmunity in humanized murine models of autoimmune polyendocrine syndrome type-I (APS-I).

Autoimmune polyendocrine syndrome type-I (APS-I) is one of very few monogenic autoimmune diseases. It usually presents in childhood and affects multiple organs. The clinical diagnosis requires two or more of the main components: hypoparathyroidism, primar y adrenal failure and chronic mucocutanous candidiasis, but a number of other endocrine and non-endocrine tissues are affected. The disease is characterized by autoantibodies against several defined antigens, most often tissue-specific key enzymes. Likewi se, T cells show affinity towards discrete structures in the same tissues. APS-I is caused by mutations in the AUTOIMMUNE REGULATOR (AIRE) gene, and studies of both humans and Aire-knockout mouse models have proved APS-I to be a powerful model for autoimm une disease. Studies in mice have revealed that Aire is an important transcriptional regulator of protein expression in thymic medullary epithelial cells, regulating the expression of an array of proteins not normally found in the thymus, but in other tis sues of the body. This shadow of self is presented to immature T cells, and autoreactive cells are purged from the T cell repertoire. When Aire is defective, such cells escape to the periphery, giving rise to autoimmune disease. Although there are clear similarities between the disease in Aire-knockout mice and man, there are also important differences as to which organs are affected and the severity of manifestations. To bridge this gap we will develop novel Aire-knockout models with partially humanize d immune systems to see if more human-like APS-I phenotypes develop. The advantage of humanized Aire-knockout models is potentially far-reaching. A closer replica of the human disease thus generated in mice, would teach us much more about the autoimmune p rocess in humans. Novel modalities of diagnosis and treatment could be tested, ultimately helping us to devise improved diagnostic and therapeutic approaches for patients with APS-I and other autoimmune diseases.