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 4

Autoantibody reactivity in Rag1S723C/S723C (mut/mut) mice after stimulation with TLR3/MDA5, TLR7/-8, and TLR9 agonists.

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Autoantibody reactivity in Rag1S723C/S723C (mut/mut) mice after stimulat...
(A) Detection of IgG autoantibodies by protein microarray. Six- to eight-week-old mut/mut and WT/WT mice received a weekly i.p. injection of either PBS, low-dose poly(I:C), R848, or CpG. The presence of IgG antibodies against self-antigens in plasma samples was determined at day 0 and week 12 of treatment. Plasma pooled from lupus-prone NZM/MRL mice served as a positive control. Scale bars represent the MFI fold increase (blue to yellow) of autoantibody reactivity as compared with the mean + 2 SDs of the MFI in samples from WT/WT mice. (B) Frequency of autoantibodies in mut/mut mice after TLR/MDA5 stimulation. Multireactive samples were defined as containing autoantibodies against greater than or equal to 20% of 76 self-antigens. Wilcoxon test with Holm’s correction was used to compare results in WT/WT and mut/mut mice at baseline (week 0) and for each of the treatments and approached significance at week 0 (P = 0.0101). When comparing each of the 4 treatments with week 0 separately in WT/WT and in mut/mut mice, only CpG in WT/WT mice was significantly different (P = 0.0036). (C) Validation of dsDNA antibodies by ELISA. Plasma samples were diluted 200-fold. Wilcoxon test with Holm’s correction was used to compare results in WT/WT and mut/mut mice at baseline (week 0) and for each of the treatments as well as to compare each of the 4 treatments with week 0 separately in WT/WT and mut/mut mice. Results from 3 separate experiments were pooled.