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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

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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