Journal Article

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

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

2015

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adenoviruses / Adolescent / Adult / Age / Animals / Antibodies, Neutralizing - blood / Antibodies, Neutralizing - immunology / Antibody Specificity / Autoantibodies / Autoantibodies - blood / Autoantibodies - immunology / Autoantigens - immunology / Autoimmune diseases / Autoimmune Diseases - genetics / Autoimmune Diseases - immunology / Biomedical research / Child / Child, Preschool / Children & youth / Cytokines - immunology / DEAD-box RNA Helicases - immunology / Disease Models, Animal / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / Female / Gene mutations / Genetic aspects / Granulomatous Disease, Chronic - genetics / Granulomatous Disease, Chronic - immunology / Granulomatous Disease, Chronic - therapy / Health aspects / Homeodomain Proteins - genetics / Homeodomain Proteins - immunology / Humans / Identification and classification / Immune system / Immunoglobulins / Infant / Infections / Interferon-Induced Helicase, IFIH1 / Lymphocytes / Male / Methods / Mice / Mice, Inbred Strains / Nuclear Proteins - deficiency / Nuclear Proteins - genetics / Patients / Phenotype / Psoriasis / Severe Combined Immunodeficiency - genetics / Severe Combined Immunodeficiency - immunology / Severe Combined Immunodeficiency - therapy / Toll-Like Receptors - agonists / Toll-Like Receptors - immunology / Viral infections / Virus Diseases - immunology / Vitiligo / Young Adult