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Hypomorphic Rag mutations in humans cause Omenn Syndrome (OS) a severe immunodeficiency associated with autoimmune-like manifestations mediated by oligoclonal activated T and B cells. The clinical and immunological spectrum of OS presentation is extremely broad. However, the role played by environmental triggers in the disease pathogenesis remains largely unknown. We have recently shown in a murine model that gut microbiota has a substantial role in determining the distinctive immune dysregulation of OS. Here, we describe how dysbiosis and loss of T cell tolerance to commensals influence the expression of autoimmunity at the barrier site and beyond, and the disease hallmark hyper-IgE. We discuss how commensal antigens and gut-derived pathogenic T cells could potentially modulate skin immunity to determine cutaneous degenerations in OS. These mechanisms may have broader implications for a deeper understanding of the role of gut microbes in influencing barriers integrity and host physiology.

RAGs and BUGS : an alliance for autoimmunity / R. Rigoni, F. Grassi, A. Villa, B. Cassani. - In: GUT MICROBES. - ISSN 1949-0976. - 7:6(2016 Nov), pp. 503-511.

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