Autoimmune polyendokrine syndrome type I- model disease for autoimmunity

Autoimmune polyendocrine syndrome type I (APS-I) (OMIM 240300), is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. The disorder typically begins in early childhood and the patients gradually develop autoimm une destruction of different endocrine and non-endocrine tissues and, in addition, mucocutaneous candidiasis. The disease is characterized by autoantibodies against several, defined antigens, most often tissue-specific enzymes with important functions in the affected tissues and identical to those found in more common isolated autoimmune disorders such as type 1 diabetes mellitus and Addison?s disease. The expression of AIRE in the thymus indicates a central function in the negative selection of T cells . It is thought that AIRE somehow regulates the expression of tissue-specific proteins in the thymus. This promiscuous expression is probably necessary to remove autoreactive T cells against these various self-proteins. With defective AIRE function, autor eactive cells escape into the circulation, which later can trigger an autoimmune disease process. This key-role in T-cell selection indicates that AIRE may be an important determinant for more common organ-specific autoimmune diseases such as autoimmune t hyroid disease, type 1 diabetes and celiac disease. Using a European patient registry and bio bank, and international research network organised within EU?s 6th framework program and a 3-step integrated approach involving genetics, immunology and clinica l research, APS I will be used as a model to understand the pathogenesis of autoimmune diseases. We will focus on studies of patients and human samples. Other members of the network will study aire knock-out models. Hopefully this mouse-man cross talk wil l improve our understanding of the pathogenic mechanisms, which should lead to novel strategies for diagnosis, treatment and prevention of autoimmune diseases.