Feb. 5, 2005 Omenn syndrome is a rare, inherited, and often-fatal immune disease associated with defective T and B cell development. It is caused by mutations in recombinase activating genes RAG1 or RAG2, which hamper B and T cell generation. As a result, patients with Omenn syndrome have only a small number of T cells that escape thymic selection, infiltrate peripheral tissues, and cause autoimmune reactions. The origin of the autoreactive T cells that cause autoimmunity in Omenn syndrome was previously unclear.
In a new Journal of Clinical Investigation report appearing online on February 3 in advance of publication in the March 1 print edition, Raffaele Badolato and colleagues at the University of Brescia study autoimmune regulator element (AIRE) expression in thymuses from three deceased infants with mutations in RAG - two with Omenn syndrome and one with a related immunodeficiency. They find that these thymuses have greatly reduced AIRE levels compared to thymuses from healthy children. AIRE is expressed in the thymus and helps establish central tolerance and prevent organ-specific autoimmunity. In the presence of AIRE, peripheral self-antigens are presented and autoreactive T cells are eliminated whereas in the absence of AIRE, such clones survive and lead to self-reactivity.
The authors propose that AIRE deficiency in Omenn syndrome causes a lack of expression of tissue-specific antigens in the thymus, with consequent loss of central tolerance. These results provide insight into the development of autoimmunity in immunodeficient patients.
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