Factors associated with and kinetics of anti-IFN-alpha autoantibodies in RAG1/2 deficiency.

Wang, C.; Potts, DE.; Sun, B.; Toth, M.; Ujhazi, B.; Sharapova, S.; Miller, R.; Rosen, L.; Yilmaz, M.; Larsen, K.; Delmonte, OM.; Poskitt, LE.; Allenspach, EJ.; de la Morena, MT.; Ward, BR.; Hernandez, JD.; Geier, CB.; Bolanos, HZ.; Al-Herz, W.; Kuijpers, TW.; Petrov, AA.; Savic, S.; Chen, K.; Westermann-Clark, E.; Dutmer, CM.; Kanariou, MG.; Adeli, M.; Palma, P.; Bonfim, C.; Lycopoulou, E.; Wolska-Kusnierz, B.; de Barros Dorna, M.; Dbaibo, G.; Bleesing, J.; Moshous, D.; Licciardi, F.; Neven, B.; Schuetz, C.; Geha, RS.; Miano, M.; Goldman, SC.; Raasch, J.; Gonzalez-Granado, LI.; Celmeli, F.; Baris, S.; Abraham, RS.; Buchbinder, DK.; Butte, MJ.; Wang, JY.; Wang, X.; Strauss, KA.; Holland, SM.; Notarangelo, LD.; Walter, JE.

Factors associated with and kinetics of anti-IFN-alpha autoantibodies in RAG1/2 deficiency.

All Authors

Wang, C.

Potts, DE.

Sun, B.

Toth, M.

Ujhazi, B.

Sharapova, S.

Miller, R.

Rosen, L.

Yilmaz, M.

Larsen, K.

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LTHT Author

Savic, Sinisa

LTHT Department

Pathology
Clinical Immunology & Allergy

Publication Date

2025

Item Type

Journal Article

Abstract

Background: Autoantibodies against IFN-alpha (anti-IFN-alpha) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined. Objective: We described the clinical and immunologic findings linked to anti-IFN-alpha IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation. Methods: We measured anti-IFN-alpha IgG by enzyme-linked immunosorbent assay in 80 RAG-deficient patients with curated clinical and immunologic data from a multinational collaboration. Results: Forty-eight patients (60.0%) had positive anti-IFN-alpha at baseline; these patients were typically older at time of testing, fulfilled the phenotype of delayed-onset combined immunodeficiency with granuloma and/or autoimmunity (70.8% vs 31.3%, P = .001), and had a history of more frequent viral infections, mainly from the Herpesviridae family (62.5% vs 21.9%, P < .001). These patients also showed higher levels of serum immunoglobulins and expanded populations of peripheral blood autoreactive-prone (CD19hiCD21lo) (14.3 vs 5.2%, P = .016) and double-negative (IgD-CD27-) B cells (12.8 vs 5.8%, P = .001). In cases with longitudinal evaluation, anti-IFN-alpha titers were largely stable, although an increase was observed with concurrent active cytomegalovirus infections. Despite some decline after transplantation, these autoantibodies persisted during follow-up. Conclusions: Anti-IFN-alpha autoantibodies reflect immune dysregulation in partial RAG deficiency. Their production is likely aggravated by environmental factors, especially frequent viral infections. Further studies are needed to define their pathogenic role in RAG deficiency.