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

Chen Wang¹, David Evan Potts², Bijun Sun³, Marta Toth², Boglarka Ujhazi², Svetlana Sharapova⁴, Rahim Miller², Lindsey Rosen¹, Melis Yilmaz², Kellie Larsen², Ottavia M Delmonte¹, Laura E Poskitt⁵, Eric J Allenspach⁶, Maria Teresa de la Morena⁶, Brant R Ward⁷, Joseph D Hernandez⁸, Christoph B Geier⁹, Hannie Zomer Bolanos¹⁰, Waleed Al-Herz¹¹, Taco W Kuijpers¹², Andrej A Petrov¹³, Sinisa Savic¹⁴, Karin Chen⁶, Emma Westermann-Clark², Cullen M Dutmer¹⁵, Maria G Kanariou¹⁶, Mehdi Adeli¹⁷, Paolo Palma¹⁸, Carmem Bonfim¹⁹, Evangelia Lycopoulou²⁰, Beata Wolska-Kusnierz²¹, Mayra de Barros Dorna²², Ghassan Dbaibo²³, Jack Bleesing²⁴, Despina Moshous²⁵, Francesco Licciardi²⁶, Benedicte Neven²⁷, Catharina Schuetz²⁸, Raif S Geha²⁹, Maurizio Miano³⁰, Stanton C Goldman³¹, Jason Raasch³², Luis Ignacio Gonzalez-Granado³³, Fatih Celmeli³⁴, Safa Baris³⁵, Roshini S Abraham³⁶, David K Buchbinder³⁷, Manish J Butte³⁸, Ji-Yang Wang³⁹, Xiaochuan Wang³, Kevin A Strauss⁵, Steven M Holland¹, Luigi D Notarangelo¹, Jolan E Walter²

Affiliations

¹ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
² Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St Petersburg, Fla.
³ Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁴ Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk region, Belarus.
⁵ Clinic for Special Children, Gordonville, Pa.
⁶ Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Wash.
⁷ Division of Allergy and Immunology, Children's National Medical Center, Washington, DC.
⁸ Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, Calif.
⁹ Division of Immunology, Faculty of Medicine and Health Sciences, Institute of Medical Genetics, Faculty of Medicine and Health Sciences, University Medicine Oldenburg, Oldenburg, Germany.
¹⁰ Department of Pediatrics, Children's Hospital at Montefiore and the Albert Einstein College of Medicine, Bronx, NY.
¹¹ Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City, Kuwait.
¹² Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
¹³ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa.
¹⁴ Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
¹⁵ Section of Allergy & Immunology, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colo.
¹⁶ Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies-Paediatric Immunology, "Aghia Sofia" Children's Hospital, Athens, Greece.
¹⁷ Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar.
¹⁸ Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
¹⁹ Hospital Pequeno Príncipe/Instituto de Pesquisa Pelé Pequeno Príncipe/Faculdades Pequeno Príncipe, Curitiba, Paraná, Brazil.
²⁰ 1st Department of Pediatrics, University of Athens, "Aghia Sofia" Children's Hospital, Athens, Greece.
²¹ Immunology Department, Children's Memorial Health Institute, Warsaw, Poland.
²² Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
²³ Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon.
²⁴ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio.
²⁵ Department of Pediatric Immunology, Hematology and Rheumatology, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, CEREDIH, French National Reference Centre for Primary Immunodeficiencies, Paris, France.
²⁶ Division of Pediatric Immunology and Rheumatology, Department of Public Health and Pediatrics, "Regina Margherita" Children Hospital, University of Turin, Turin, Italy.
²⁷ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Université Hospital, Assistance Publique-Hôpitaux de Paris, Paris, Italy.
²⁸ Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, and German Center for Child and Adolescent Health (DZKJ), partner site Dresden/Leipzig, Dresden, Germany.
²⁹ Division of Immunology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
³⁰ Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³¹ Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Medical City Children's Hospital, Dallas, Tex.
³² Midwest Immunology, Plymouth, Minn.
³³ Department of Pediatrics, 12 de Octubre Health Research Institute (imas12), Department of Public Health School of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
³⁴ Department of Allergy and Immunology, University of Medical Science, Antalya Education and Research Hospital, Antalya, Turkey.
³⁵ Department of Pediatric Allergy and Immunology, Faculty of Medicine, University of Marmara, Istanbul, Turkey.
³⁶ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
³⁷ Department of Hematology, Children's Hospital of Orange County, Orange, Calif.
³⁸ Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Calif.
³⁹ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China.

PMID: 40697949
PMCID: PMC12281840
DOI: 10.1016/j.jacig.2025.100521

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

Chen Wang et al. J Allergy Clin Immunol Glob. 2025.

. 2025 Jun 23;4(3):100521.

doi: 10.1016/j.jacig.2025.100521. eCollection 2025 Aug.

Authors

Affiliations

¹ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
² Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St Petersburg, Fla.
³ Department of Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁴ Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk region, Belarus.
⁵ Clinic for Special Children, Gordonville, Pa.
⁶ Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Wash.
⁷ Division of Allergy and Immunology, Children's National Medical Center, Washington, DC.
⁸ Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, Calif.
⁹ Division of Immunology, Faculty of Medicine and Health Sciences, Institute of Medical Genetics, Faculty of Medicine and Health Sciences, University Medicine Oldenburg, Oldenburg, Germany.
¹⁰ Department of Pediatrics, Children's Hospital at Montefiore and the Albert Einstein College of Medicine, Bronx, NY.
¹¹ Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City, Kuwait.
¹² Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
¹³ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa.
¹⁴ Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
¹⁵ Section of Allergy & Immunology, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colo.
¹⁶ Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies-Paediatric Immunology, "Aghia Sofia" Children's Hospital, Athens, Greece.
¹⁷ Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar.
¹⁸ Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
¹⁹ Hospital Pequeno Príncipe/Instituto de Pesquisa Pelé Pequeno Príncipe/Faculdades Pequeno Príncipe, Curitiba, Paraná, Brazil.
²⁰ 1st Department of Pediatrics, University of Athens, "Aghia Sofia" Children's Hospital, Athens, Greece.
²¹ Immunology Department, Children's Memorial Health Institute, Warsaw, Poland.
²² Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
²³ Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon.
²⁴ Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio.
²⁵ Department of Pediatric Immunology, Hematology and Rheumatology, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, CEREDIH, French National Reference Centre for Primary Immunodeficiencies, Paris, France.
²⁶ Division of Pediatric Immunology and Rheumatology, Department of Public Health and Pediatrics, "Regina Margherita" Children Hospital, University of Turin, Turin, Italy.
²⁷ Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Université Hospital, Assistance Publique-Hôpitaux de Paris, Paris, Italy.
²⁸ Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, and German Center for Child and Adolescent Health (DZKJ), partner site Dresden/Leipzig, Dresden, Germany.
²⁹ Division of Immunology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
³⁰ Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³¹ Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Medical City Children's Hospital, Dallas, Tex.
³² Midwest Immunology, Plymouth, Minn.
³³ Department of Pediatrics, 12 de Octubre Health Research Institute (imas12), Department of Public Health School of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
³⁴ Department of Allergy and Immunology, University of Medical Science, Antalya Education and Research Hospital, Antalya, Turkey.
³⁵ Department of Pediatric Allergy and Immunology, Faculty of Medicine, University of Marmara, Istanbul, Turkey.
³⁶ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
³⁷ Department of Hematology, Children's Hospital of Orange County, Orange, Calif.
³⁸ Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Calif.
³⁹ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China.

PMID: 40697949
PMCID: PMC12281840
DOI: 10.1016/j.jacig.2025.100521

Abstract

Background: Autoantibodies against IFN-α (anti-IFN-α) 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-α IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation.

Methods: We measured anti-IFN-α 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-α 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 (CD19^hiCD21^lo) (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-α 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-α 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.

Keywords: RAG deficiency; anti–IFN-α autoantibodies; viral infection.

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Conflict of interest statement

L.D.N. is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, 10.13039/100000002National Institutes of Health (NIH, grant ZIA AI001222). J.E.W. is supported by the 10.13039/100000060National Institute of Allergy and Infectious Diseases, National Institutes of Health 5K08AI103035, sub-R01AI100887-05 and R01AI153830-05, Robert A. Good Endowment at 10.13039/100008900University of South Florida, and 10.13039/100001245Jeffrey Modell Foundation. L.I.G.-G. is supported by the Instituto de Salud Carlos III (ISCIII) through project FIS-PI21/01642, cofunded by the 10.13039/501100000780European Union. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Research laboratory studies were performed on deidentified samples under institutional review board–approved protocols at the University of South Florida (USF-Pro00035468, USF-Pro00025693), and Johns Hopkins Medical Institute/Johns Hopkins All Children’s Hospital (JHMI-IRB00175372). Disclosure of potential conflict of interest: J. E. Walter reports receiving grant, research, and/or clinical trial support from Takeda, Janssen, Chiesi, MustangBio, ADMA Biologicals, and Octapharma; serving on consultant and/or advisory boards for Takeda, X4-Pharmaceuticals, CSL-Behring, Grifols, ADMA Biologicals, Enzyvant, and Regeneron; and serving on the speakers’ bureau for Takeda. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

**Fig 1**
Cohort characteristics. **(A)** Distribution of different clinical and immunologic phenotypes. **(B)** Frequency of positive anti–IFN-α IgG based on age of testing. **(C)** Comparison of clinical features in RAG-deficient patients with and without anti–IFN-α IgG. **(D)** Correlation matrix between key clinical/laboratory findings and positive anti–IFN-α IgG. Pearson r values are shown in each box, with cell borders indicating statistically significant correlations (P < .05).

**Fig 2**
Immunologic findings in RAG-deficient patients with and without anti–IFN-α IgG. **(A)** Serum IgG levels before IgRT. **(B)** Serum IgA levels. **(C)** Serum IgM levels. **(D)** Percentages of autoreactive-prone B cells (CD19^hiCD21^lo). **(E)** Percentages of double-negative B cells (IgD⁻CD27⁻). *IgRT,* Immunoglobulin replacement therapy.

**Fig 3**
Longitudinal titers of anti–IFN-α IgG in RAG-deficient patients. **(A)** No HCT during follow-up (n = 6). **(B)** HCT during follow-up (n = 4). Age when HCT was performed for each patient is indicated in parentheses (years old [yo]). **(C)** Correlation between anti–IFN-α IgG titers and acute CMV infection in *RAG1*-deficient patient. Age when indicated event happened is shown in *parentheses.* Ranges of anti–IFN-α IgG titers considered normal are shaded in *gray.*

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References

1. Notarangelo L.D., Kim M.S., Walter J.E., Lee Y.N. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016;16:234–246. - PMC - PubMed
1. Delmonte O.M., Schuetz C., Notarangelo L.D. RAG deficiency: two genes, many diseases. J Clin Immunol. 2018;38:646–655. - PMC - PubMed
1. Bosticardo M., Dobbs K., Delmonte O.M., Martins A.J., Pala F., Kawai T., et al. Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature. Sci Immunol. 2025;10 - PMC - PubMed
1. Walter J.E., Rucci F., Patrizi L., Recher M., Regenass S., Paganini T., et al. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med. 2010;207:1541–1554. - PMC - PubMed
1. Walter J.E., Rosen L.B., Csomos K., Rosenberg J.M., Mathew D., Keszei M., et al. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest. 2015;125:4135–4148. - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Research Materials