Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency
Jolan E. Walter, et al.
Jolan E. Walter, et al.
View: Text | PDF | Corrigendum
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

×

Figure 2

Anti-cytokine antibodies in RAG-deficient patients.

Options: View larger image (or click on image) Download as PowerPoint
Anti-cytokine antibodies in RAG-deficient patients. (A) Heatmap of autoa...
(A) Heatmap of autoantibody reactivity. Plasma samples from 16 healthy controls (Ctr), 14 RAG-deficient patients (OS, n = 3; LS, n = 2; CID-G/AI, n = 8; idiopathic CD4+ TCL, n = 1), and 1 patient with APS-1 were tested for anti-cytokine antibodies. The complete array is shown in the left panel, and the area with the highest reactivity is magnified on the right. Antibodies against IFN-α, IFN-ω, and IL-12 (in red) were detected with high MFI in cluster 2, including RAG-deficient patients and APS-1 patients as a positive control. (B) Elevated levels of antibodies against TPO and IFN-α were detected in RAG-deficient patients as compared with healthy controls using SAM after 10,000 permutations of the data with an FDR of less than 0.00001. (C) Multiplex bead assay for anti-cytokine antibodies. Levels of antibodies targeting IFN-α, IFN-ω, IL-12p70, IFN-γ, IFN-β, TNF-α, and IL-22 in healthy controls (n = 15) and RAG-deficient patients (n = 23), grouped by phenotype: SCID, n = 3; LS, n = 3; OS, n = 5; CID-G/AI, n = 11; and TCL, n = 1. (D) Detection of anti–IFN-α-2A, –IFN-ω, and –IL-12p70 antibodies by ELISA. Plasma samples were assayed for IgG autoantibodies at a 200-fold dilution. RAG-deficient patients included those with SCID (n = 2); LS (n = 3); OS (n = 3); CID-G/AI (n = 9); and TCL (n = 1). In both C and D, floating bars indicate the range of values for each autoantibody in healthy controls (n = 15 in C; n = 6 in D).