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

Lookup NU author(s): Professor Andrew GenneryORCiD

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Abstract

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 Rag1(5723C/5723C) mice, Le 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.


Publication metadata

Author(s): Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uze G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2015

Volume: 125

Issue: 11

Pages: 4135-4148

Print publication date: 01/11/2015

Online publication date: 12/10/2015

Acceptance date: 03/09/2015

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: Amerivan Society for Clinical Investigation

URL: http://dx.doi.org/10.1172/JCI80477

DOI: 10.1172/JCI80477


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Funding

Funder referenceFunder name
Manton Foundation
Intramural Research Program of the NIAID, NIH
Jeffrey Modell Foundation
5K08AI103035NIAID, NIH
5R01AI100887NIAID, NIH
T32GM007365NIAID, NIH
U54AI082973NIAID, NIH

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