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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Walter Jolan E, Rosen Lindsey B, Csomos Krisztian, Rosenberg Jacob M, Mathew Divij, Keszei Marton, Ujhazi Boglarka, Chen Karin, Lee Yu Nee, Tirosh Irit, Dobbs Kerry, Al-Herz Waleed, Cowan Morton J, Puck Jennifer, Bleesing Jack J, Grimley Michael S, Malech Harry, De Ravin Suk See, Gennery Andrew R, Abraham Roshini S, Joshi Avni Y, Boyce Thomas G, Butte Manish J, Nadeau Kari C, Balboni Imelda,
Project Analysis of RAG-dependent immunodeficiency and autoimmunity
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Original article (peer-reviewed)

Journal The Journal of clinical investigation
Volume (Issue) 125(11)
Page(s) 4135 - 48
Title of proceedings The Journal of clinical investigation
DOI 10.1172/jci80477


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-α or anti-IFN-ω 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.