title: Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.
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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mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology*; D053487:DEAD-box RNA Helicases / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; D051193:Toll-Like Receptors; C064658:RAG-1 protein; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1