Journal of Allergy and Clinical Immunology: Global (Aug 2025)
Factors associated with and kinetics of anti–IFN-α autoantibodies in RAG1/2 deficiency
- Chen Wang, MD,
- David Evan Potts, MSc,
- Bijun Sun, MD,
- Marta Toth, PhD,
- Boglarka Ujhazi, MSc,
- Svetlana Sharapova, PhD,
- Rahim Miller, BS,
- Lindsey Rosen, PhD,
- Melis Yilmaz, BS,
- Kellie Larsen, MSc,
- Ottavia M. Delmonte, MD, PhD,
- Laura E. Poskitt, DO,
- Eric J. Allenspach, MD, PhD,
- Maria Teresa de la Morena, MD,
- Brant R. Ward, MD, PhD,
- Joseph D. Hernandez, MD, PhD,
- Christoph B. Geier, MD, MSc,
- Hannie Zomer Bolanos, MD,
- Waleed Al-Herz, MD,
- Taco W. Kuijpers, MD, PhD,
- Andrej A. Petrov, MD,
- Sinisa Savic, MBBS, PhD,
- Karin Chen, MD,
- Emma Westermann-Clark, MD,
- Cullen M. Dutmer, MD,
- Maria G. Kanariou, MD,
- Mehdi Adeli, MD,
- Paolo Palma, MD, PhD,
- Carmem Bonfim, MD, PhD,
- Evangelia Lycopoulou, MD,
- Beata Wolska-Kusnierz, PhD,
- Mayra de Barros Dorna, MD,
- Ghassan Dbaibo, MD,
- Jack Bleesing, MD, PhD,
- Despina Moshous, MD, PhD,
- Francesco Licciardi, MD,
- Benedicte Neven, MD, PhD,
- Catharina Schuetz, MD,
- Raif S. Geha, MD,
- Maurizio Miano, MD,
- Stanton C. Goldman, MD,
- Jason Raasch, MD,
- Luis Ignacio Gonzalez-Granado, MD,
- Fatih Celmeli, MD,
- Safa Baris, MD,
- Roshini S. Abraham, PhD,
- David K. Buchbinder, MD, MSHS,
- Manish J. Butte, MD, PhD,
- Ji-Yang Wang, PhD,
- Xiaochuan Wang, MD,
- Kevin A. Strauss, MD,
- Steven M. Holland, MD,
- Luigi D. Notarangelo, MD,
- Jolan E. Walter, MD, PhD
Affiliations
- Chen Wang, MD
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
- David Evan Potts, MSc
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Bijun Sun, MD
- Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Marta Toth, PhD
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Boglarka Ujhazi, MSc
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Svetlana Sharapova, PhD
- Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk region, Belarus
- Rahim Miller, BS
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Lindsey Rosen, PhD
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
- Melis Yilmaz, BS
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Kellie Larsen, MSc
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Ottavia M. Delmonte, MD, PhD
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
- Laura E. Poskitt, DO
- Clinic for Special Children, Gordonville, Pa
- Eric J. Allenspach, MD, PhD
- Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, Wash
- Maria Teresa de la Morena, MD
- Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, Wash
- Brant R. Ward, MD, PhD
- Division of Allergy and Immunology, Children’s National Medical Center, Washington, DC
- Joseph D. Hernandez, MD, PhD
- Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, Calif
- Christoph B. Geier, MD, MSc
- Division of Immunology, Faculty of Medicine and Health Sciences, Institute of Medical Genetics, Faculty of Medicine and Health Sciences, University Medicine Oldenburg, Oldenburg, Germany
- Hannie Zomer Bolanos, MD
- Department of Pediatrics, Children’s Hospital at Montefiore and the Albert Einstein College of Medicine, Bronx, NY
- Waleed Al-Herz, MD
- Department of Pediatrics, College of Medicine, Kuwait University, Kuwait City, Kuwait
- Taco W. Kuijpers, MD, PhD
- Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands
- Andrej A. Petrov, MD
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa
- Sinisa Savic, MBBS, PhD
- Department of Clinical Immunology and Allergy, St James’s University Hospital, Leeds, United Kingdom
- Karin Chen, MD
- Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, Wash
- Emma Westermann-Clark, MD
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla
- Cullen M. Dutmer, MD
- Section of Allergy & Immunology, Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, Colo
- Maria G. Kanariou, MD
- Department of Immunology—Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies—Paediatric Immunology, “Aghia Sofia” Children’s Hospital, Athens, Greece
- Mehdi Adeli, MD
- Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar
- Paolo Palma, MD, PhD
- Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children’s Hospital, Department of Systems Medicine, University of Rome “Tor Vergata,” Rome, Italy
- Carmem Bonfim, MD, PhD
- Hospital Pequeno Príncipe/Instituto de Pesquisa Pelé Pequeno Príncipe/Faculdades Pequeno Príncipe, Curitiba, Paraná, Brazil
- Evangelia Lycopoulou, MD
- 1st Department of Pediatrics, University of Athens, “Aghia Sofia” Children’s Hospital, Athens, Greece
- Beata Wolska-Kusnierz, PhD
- Immunology Department, Children’s Memorial Health Institute, Warsaw, Poland
- Mayra de Barros Dorna, MD
- Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Ghassan Dbaibo, MD
- Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
- Jack Bleesing, MD, PhD
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio
- Despina Moshous, MD, PhD
- 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
- Francesco Licciardi, MD
- Division of Pediatric Immunology and Rheumatology, Department of Public Health and Pediatrics, “Regina Margherita” Children Hospital, University of Turin, Turin, Italy
- Benedicte Neven, MD, PhD
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Université Hospital, Assistance Publique-Hôpitaux de Paris, Paris, Italy
- Catharina Schuetz, MD
- 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
- Raif S. Geha, MD
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Mass
- Maurizio Miano, MD
- Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Stanton C. Goldman, MD
- Department of Pediatric Hematology/Oncology/Stem Cell Transplantation, Medical City Children’s Hospital, Dallas, Tex
- Jason Raasch, MD
- Midwest Immunology, Plymouth, Minn
- Luis Ignacio Gonzalez-Granado, MD
- 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
- Fatih Celmeli, MD
- Department of Allergy and Immunology, University of Medical Science, Antalya Education and Research Hospital, Antalya, Turkey
- Safa Baris, MD
- Department of Pediatric Allergy and Immunology, Faculty of Medicine, University of Marmara, Istanbul, Turkey
- Roshini S. Abraham, PhD
- Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio
- David K. Buchbinder, MD, MSHS
- Department of Hematology, Children’s Hospital of Orange County, Orange, Calif
- Manish J. Butte, MD, PhD
- Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Calif
- Ji-Yang Wang, PhD
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Sci-Tech Inno Center for Infection & Immunity, Shanghai, China
- Xiaochuan Wang, MD
- Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Kevin A. Strauss, MD
- Clinic for Special Children, Gordonville, Pa
- Steven M. Holland, MD
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
- Luigi D. Notarangelo, MD
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; Luigi D. Notarangelo, MD, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 10, Rm 5-3750, 10 Centre Dr, Bethesda, MD 20892.
- Jolan E. Walter, MD, PhD
- Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, Fla; Corresponding authors: Jolan E. Walter, MD, PhD, Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St Petersburg, FL 33701.
- Journal volume & issue
-
Vol. 4,
no. 3
p. 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 (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-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.
