Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency
Jolan E. Walter, … , Sarah K. Browne, Luigi D. Notarangelo
Jolan E. Walter, … , Sarah K. Browne, Luigi D. Notarangelo
Published October 12, 2015
Citation Information: J Clin Invest. 2015;125(11):4135-4148. https://doi.org/10.1172/JCI80477.
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Research Article Immunology

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.

Authors

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

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Figure 1

Autoantibodies in RAG-deficient patients as detected by protein microarray.

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Autoantibodies in RAG-deficient patients as detected by protein microarr...
(A) IgG autoantibodies in 19 healthy controls (HCs) and 22 patients with RAG mutations. RAG-deficient patients were divided into 2 groups according to the severity of the clinical phenotype. Group 1 included patients with T–B– SCID, OS, and LS. Group 2 included patients with delayed presentation and/or a milder phenotype: CID-G/AI and TCL. MFI was normalized to that of healthy controls (mean + 2 SDs = 1), generating the RAR. Healthy controls had a lower percentage of positivity than did patients with RAG mutations (P = 0.0000008), and group 1 had a lower percentage of positivity than did group 2 (P = 0.028) as determined by Wilcoxon test with Holm’s adjustment. Samples that reacted to at least 20% of the self-antigens were defined as multireactive. (B) RAR to 11 autoantigens for which significantly higher levels of autoantibodies were found in the plasma of 5 CID-G/AI patients as compared with levels in 19 healthy controls. *P < 0.0005, **P < 0.0001, and ***P < 0.0001 by Wilcoxon test with Holm’s adjustment. Empty boxes indicate the range of RAR in healthy controls, with the bar representing the mean value. Hemo, hemocyanin; MPO, myeloperoxidase; PCNA, proliferating cell nuclear antigen; PL-12, alanyl-tRNA synthetase; PG, proteoglycan; RPLP, ribosomal phosphoprotein 0; Ro/SSA, ribonucleoprotein/Sjögren’s syndrome antigen A, 52 kDa; Tg, thyroglobulin; U1-BB’, U1 small nuclear ribonucleoprotein BB’ 9; U1-C, U1 small nuclear ribonucleoprotein C.