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

Walter, J. E. and Rosen, L. B. and Csomos, K. and Rosenberg, J. M. and Mathew, D. and Keszei, M. and Ujhazi, B. and Chen, K. and Lee, Y. N. and Tirosh, I. and Dobbs, K. and Al-Herz, W. and Cowan, M. J. and Puck, J. and Bleesing, J. J. and Grimley, M. S. and Malech, H. and De Ravin, S. S. and Gennery, A. R. and Abraham, R. S. and Joshi, A. Y. and Boyce, T. G. and Butte, M. J. and Nadeau, K. C. and Balboni, I. and Sullivan, K. E. and Akhter, J. and Adeli, M. and El-Feky, R. A. and El-Ghoneimy, D. H. and Dbaibo, G. and Wakim, R. and Azzari, C. and Palma, P. and Cancrini, C. and Capuder, K. and Condino-Neto, A. and Costa-Carvalho, B. T. and Oliveira, J. B. and Roifman, C. and Buchbinder, D. and Kumanovics, A. and Franco, J. L. and Niehues, T. and Schuetz, C. and Kuijpers, T. and Yee, C. and Chou, J. and Masaad, M. J. and Geha, R. and Uzel, G. and Gelman, R. and Holland, S. M. and Recher, M. and Utz, P. J. and Browne, S. K. and Notarangelo, L. D.. (2015) Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. The Journal of Clinical Investigation, 125 (11). pp. 4135-4148.

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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-alpha or anti-IFN-omega 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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunodeficiency (Recher)
UniBasel Contributors:Recher, Mike
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:11 Dec 2018 16:45
Deposited On:11 Dec 2018 16:45

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