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Publication : Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

First Author	Walter JE	Year	2015
Journal	J Clin Invest	Volume	125
Issue	11	Pages	4135-48
PubMed ID	26457731	Mgi Jnum	J:227482
Mgi Id	MGI:5700581	Doi	10.1172/JCI80477
Citation	Walter JE, et al. (2015) Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest 125(11):4135-48

abstractText

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-alpha or anti-IFN-omega antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

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Publication : Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.

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