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

JE Walter, LB Rosen, K Csomos… - The Journal of …, 2015 - Am Soc Clin Investig
JE Walter, LB Rosen, K Csomos, JM Rosenberg, D Mathew, M Keszei, B Ujhazi, K Chen
The Journal of clinical investigation, 2015Am Soc Clin Investig
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) …
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.
The Journal of Clinical Investigation