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

Jolan E Walter, Lindsey B Rosen, Krisztian Csomos, Jacob M Rosenberg, Divij Mathew, Marton Keszei, Boglarka Ujhazi, Karin Chen, Yu Nee Lee, Irit Tirosh, Kerry Dobbs, Waleed Al-Herz, Morton J Cowan, Jennifer Puck, Jack J Bleesing, Michael S Grimley, Harry Malech, Suk See De Ravin, Andrew R Gennery, Roshini S Abraham, Avni Y Joshi, Thomas G Boyce, Manish J Butte, Kari C Nadeau, Imelda Balboni, Kathleen E Sullivan, Javeed Akhter, Mehdi Adeli, Reem A El-Feky, Dalia H El-Ghoneimy, Ghassan Dbaibo, Rima Wakim, Chiara Azzari, Paolo Palma, Caterina Cancrini, Kelly Capuder, Antonio Condino-Neto, Beatriz T Costa-Carvalho, Joao Bosco Oliveira, Chaim Roifman, David Buchbinder, Attila Kumanovics, Jose Luis Franco, Tim Niehues, Catharina Schuetz, Taco Kuijpers, Christina Yee, Janet Chou, Michel J Masaad, Raif Geha, Gulbu Uzel, Rebecca Gelman, Steven M Holland, Mike Recher, Paul J Utz, Sarah K Browne, Luigi D Notarangelo

Index: J. Clin. Invest. 125 , 4135-48, (2015)

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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-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.