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.

Allergy Immunology Division Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia PA USA

Belarusian Research Center for Pediatric Oncology Minsk Belarus

Cancer and Blood Disorder Institute Johns Hopkins All Children's Hospital St Petersburg FL USA

Cancer and Blood Disorders Institute and Department of Surgery Johns Hopkins All Children's Hospital St Petersburg FL USA

Childhood Leukemia Investigation Prague Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Clinical Immunology and Allergy St James's University Hospital Leeds UK

Department of Clinical Immunology University Hospital Alexandrovska Medical University Sofia Bulgaria

Department of Immunobiology Yale University New Haven CT USA

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Immunology and Allergy Sheffield Teaching Hospitals Sheffield UK

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medicine Division of Rheumatology Emory University Atlanta GA USA

Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Baltimore MD USA

Department of Pathology and Laboratory Medicine Johns Hopkins All Children's Hospital St Petersburg FL USA

Department of Pathology Perelman School of Medicine University of Pennsylvania Pennsylvania PA USA

Department of Pediatrics Division of Allergy Immunology and Rheumatology Stanford University Stanford CA USA

Department of Pediatrics Faculdade de Medicina da Universidade de São Paulo São Paulo Brasil

Department of Pediatrics Faculty of Medicine Kuwait University Kuwait City Kuwait

Department of Pediatrics University of Szeged Szeged Hungary

Deptartment of Pediatric Immunology Rheumatology and Infectious Diseases Emma Children's Hospital Academic Medical Center Amsterdam Netherlands

Division of Allergy and Immunology Children's Hospital of Richmond Virginia Commonwealth University Richmond VA USA

Division of Allergy and Immunology Massachusetts General Hospital for Children Boston MA USA

Division of Allergy Immunology and Pulmonary Medicine Duke University School of Medicine Durham NC USA

Division of Immunology Allergy and Rheumatology Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center University of California Los Angeles Los Angeles CA USA

Division of Pediatric Allergy Immunology University of South Florida at Johns Hopkins All Children's Hospital St Petersburg FL USA

Division of Pulmonary Allergy and Critical Care Perelman School of Medicine University of Pennsylvania Pennsylvania PA USA

Eurofins Viracor Laboratories Lee Summit's MO USA

Immunology Outpatient Clinic Vienna Austria

Institute for Immunology the University of Pennsylvania Philadelphia PA USA

Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases NIH Bethesda MD USA

Laboratory of Genome Dynamics in the Immune System INSERM UMR1163 Institut Imagine Paris France

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases INSERM UMR1163 Institut Imagine Paris France

Laboratory of Pathology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA

National Institute for Health Research Leeds Musculoskeletal Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine St James's University Hospital Leeds UK

Pediatric Hematology Immunology and Rheumatology Unit Necker Enfants Malades Université Hospital Assistance Publique Hôpitaux de Paris Paris France

Ragon Institute of Massachusetts General Hospital Massachusetts Institute of technology and Harvard University Cambridge MA USA

Section of Rheumatology Allergy and Clinical Immunology Yale School of Medicine New Haven CT USA

Université de Paris Paris France

Windom Allergy Asthma and Sinus Sarasota FL USA

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