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Título : Broad-spectrum Antibodies Against self-antigens and Cytokines in RAG Deficiency
Autor : Franco Restrepo, José Luis
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.
Bosco Oliveira, Joao Bosco
Roifman, Chaim
Buchbinder, David
Kumanovics, Attila
Niehues, Tim
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.
metadata.dc.subject.*: Broadly Neutralizing Antibodies
Anticuerpos ampliamente neutralizantes
Severe Combined Immunodeficiency
Inmunodeficiencia Combinada Grave
Fecha de publicación : 2015
Editorial : American Society for Clinical Investigation
Resumen : 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.
metadata.dc.identifier.eissn: 1558-8238
ISSN : 0021-9738
metadata.dc.identifier.doi: 10.1172/JCI80477
Aparece en las colecciones: Artículos de Revista en Ciencias Médicas

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