ArticleNature immunology2022
Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet
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Article in Nature immunology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28citing papers in PubMed
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28 citing papers in PubMed, 37 citations in OpenAlex.
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- Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections.Cell · 2026Article
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- Unique chicken B cell development: species-specific mechanisms and contradictory requirements of B cell receptor for post-hatched B cell development.Frontiers in immunology · 2026Review
- Cellular signatures of immune dysregulation in inborn errors of immunity: development of a quantitative immune balance score.Frontiers in immunology · 2026Article
- Identification of plasma cell infiltration-related gene signatures as a novel prognostic model for clear cell renal cell carcinoma.Clinical and experimental medicine · 2025Article
- Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency.The Journal of experimental medicine · 2025Article
- Factors associated with and kinetics of anti-IFN-α autoantibodies inThe journal of allergy and clinical immunology. Global · 2025Article
- Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.Journal of human immunity · 2025Article
- T-bet-expressing B cells promote atherosclerosis in apolipoprotein E-deficient mice.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans.Blood advances · 2025Article
- Hypomorphic RAG2 Deficiency Promotes Selection of Self-Reactive B Cells.Journal of clinical immunology · 2025Article
- Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.Science immunology · 2025Article
- Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement.The Journal of experimental medicine · 2024Article
- Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells.Biomedicines · 2024Article
- Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Clinical, immunological features, treatments, and outcomes of autoimmune hemolytic anemia in patients with RAG deficiency.Blood advances · 2024Article
- Emerging insights into atypical B cells in pediatric chronic infectious diseases and immune system disorders: T(o)-bet on control of B-cell immune activation.The Journal of allergy and clinical immunology · 2024Review
- The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome.Nature communications · 2023Article
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Authors and funding
50 authors at 20 institutions in 9 countries.
Krisztian CsomosDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA. kcsomos@usf.edu.
Boglarka UjhaziDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Peter BlazsoDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.ORCID 0000-0003-4404-8068
Jose L HerreraCancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Christopher M TiptonDepartment of Medicine, Division of Rheumatology, Emory University, Atlanta, GA, USA.
Tomoki KawaiLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Sumai GordonDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Maryssa EllisonDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Kevin WuDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Matthew StowellDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Lauren HaynesDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.ORCID 0000-0003-0011-3104
Rachel CruzDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Bence ZakotaDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Johnny NguyenDepartment of Pathology & Laboratory Medicine, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.
Michelle AltrichEurofins Viracor Laboratories, Lee Summit's, MO, USA.
Christoph B GeierImmunology Outpatient Clinic, Vienna, Austria.ORCID 0000-0003-4353-8663
Svetlana SharapovaBelarusian Research Center for Pediatric Oncology, Minsk, Belarus.
Joseph F DassoDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.ORCID 0000-0001-8917-8603
Jennifer W LeidingDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Grace SmithLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0001-6381-0391
Waleed Al-HerzDepartment of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.ORCID 0000-0003-4244-4489
Mayra de Barros DornaDepartment of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil.ORCID 0000-0002-0168-7807
Olajumoke FadugbaDivision of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
Eva FronkovaChildhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Veronika KanderovaChildhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Michael SvatonChildhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.ORCID 0000-0003-2966-3687
Sarah E HenricksonAllergy Immunology Division, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Joseph D HernandezDepartment of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
Taco KuijpersDeptartment of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, Netherlands.
Snezhina Mihailova KandilarovaDepartment of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria.
Elizaveta NaumovaDepartment of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria.
Tomas MilotaDepartment of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.
Anna SedivaDepartment of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.
Despina MoshousUniversité de Paris, Paris, France.ORCID 0000-0001-6719-3693
Benedicte NevenUniversité de Paris, Paris, France.
Tara SacoWindom Allergy, Asthma and Sinus, Sarasota, FL, USA.
Ravishankar SargurDepartment of Immunology and Allergy, Sheffield Teaching Hospitals, Sheffield, UK.
Sinisa SavicDepartment of Clinical Immunology and Allergy, St James's University Hospital, Leeds, UK.
John SleasmanDivision of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC, USA.
Gauri SunkersettCancer and Blood Disorder Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Brant R WardDivision of Allergy and Immunology, Children's Hospital of Richmond, Virginia Commonwealth University, Richmond, VA, USA.
Masanobu KomatsuCancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Stefania PittalugaLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0001-7688-1439
Attila KumanovicsDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Manish J ButteDivision of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Los Angeles, CA, USA.ORCID 0000-0002-4490-5595
Michael P CancroDepartment of Pathology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
Shiv PillaiRagon Institute of Massachusetts General Hospital, Massachusetts Institute of technology and Harvard University, Cambridge, MA, USA.ORCID 0000-0002-9905-875X
Eric MeffreDepartment of Immunobiology, Yale University, New Haven, CT, USA.ORCID 0000-0003-4326-0171
Luigi D NotarangeloLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.ORCID 0000-0002-8335-0262
Jolan E WalterDivision of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA. jolanwalter@usf.edu.ORCID 0000-0002-6192-0703
Johns Hopkins University · USCharles University · CZHôpital Necker-Enfants Malades · FRNational Institute of Allergy and Infectious Diseases · USNational Institutes of Health · USUniversity of Pennsylvania · USAmsterdam UMC Location University of Amsterdam · NLBelarusian Research Center For Pediatric Oncology and Hematology · BYDuke University · USEmory University · USHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo · BRKuwait University · KWMayo Clinic in Arizona · USRagon Institute of MGH, MIT and Harvard · USSheffield Teaching Hospitals NHS Foundation Trust · GBStanford University · USSt James's University Hospital · GBSummit School · USUniversity City Science Center · USUniversity of California, Los Angeles · US
Funding
Regulation of IgA class switching in the intestinal mucosaP01AI061093 · NIAID · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI CASANOVA, JEAN-LAURENT · 2004 to 2021
$29.8MCharacterization of the cellular and molecular bases of inborn errors of immunityZIAAI001222 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2017 to 2025
$15.2MModeling and correcting human SCID using patient-derived iPS cellsR01AI100887 · NIAID · BOSTON CHILDREN'S HOSPITAL · PI MANIS, JOHN P · 2012 to 2020
$4.5MMechanisms driving extrafollicular polyreactive B cell lineages in partial RAG deficiencyR01AI153830 · NIAID · UNIVERSITY OF SOUTH FLORIDA · PI WALTER, JOLAN ESZTER · 2021 to 2025
$2.2MAutoimmunity in Rag Deficiency: A Nexus of Immunodeficiency and DysregulationK08AI103035 · NIAID · UNIVERSITY OF SOUTH FLORIDA · PI WALTER, JOLAN ESZTER · 2012 to 2016
$683kIntramural NIH HHS ZIA AI001222NIAID NIH HHS K08 AI103035NIAID NIH HHS P01 AI061093NIAID NIH HHS R01 AI100887NIAID NIH HHS R01 AI153830
Abstract
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
Indexed as
B-LymphocytesDNA-Binding ProteinsHomeodomain ProteinsNuclear ProteinsCell DifferentiationHumansImmune ToleranceLymphocyte CountDNA-Binding ProteinsHomeodomain ProteinsNuclear ProteinsRAG-1 proteinRAG2 protein, human
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