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

  • Author(s): 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;
  • Sullivan, Kathleen E;
  • Akhter, Javeed;
  • Adeli, Mehdi;
  • El-Feky, Reem A;
  • El-Ghoneimy, Dalia H;
  • Dbaibo, Ghassan;
  • Wakim, Rima;
  • Azzari, Chiara;
  • Palma, Paolo;
  • Cancrini, Caterina;
  • Capuder, Kelly;
  • Condino-Neto, Antonio;
  • Costa-Carvalho, Beatriz T;
  • Oliveira, Joao Bosco;
  • Roifman, Chaim;
  • Buchbinder, David;
  • Kumanovics, Attila;
  • Franco, Jose Luis;
  • Niehues, Tim;
  • Schuetz, Catharina;
  • Kuijpers, Taco;
  • Yee, Christina;
  • Chou, Janet;
  • Masaad, Michel J;
  • Geha, Raif;
  • Uzel, Gulbu;
  • Gelman, Rebecca;
  • Holland, Steven M;
  • Recher, Mike;
  • Utz, Paul J;
  • Browne, Sarah K;
  • Notarangelo, Luigi D
  • et al.

Published Web Location

https://doi.org/10.1172/jci80477
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.

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