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Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells.
Csomos, Krisztian; Ujhazi, Boglarka; Blazso, Peter; Herrera, Jose L; Tipton, Christopher M; Kawai, Tomoki; Gordon, Sumai; Ellison, Maryssa; Wu, Kevin; Stowell, Matthew; Haynes, Lauren; Cruz, Rachel; Zakota, Bence; Nguyen, Johnny; Altrich, Michelle; Geier, Christoph B; Sharapova, Svetlana; Dasso, Joseph F; Leiding, Jennifer W; Smith, Grace; Al-Herz, Waleed; de Barros Dorna, Mayra; Fadugba, Olajumoke; Fronkova, Eva; Kanderova, Veronika; Svaton, Michael; Henrickson, Sarah E; Hernandez, Joseph D; Kuijpers, Taco; Kandilarova, Snezhina Mihailova; Naumova, Elizaveta; Milota, Tomas; Sediva, Anna; Moshous, Despina; Neven, Benedicte; Saco, Tara; Sargur, Ravishankar; Savic, Sinisa; Sleasman, John; Sunkersett, Gauri; Ward, Brant R; Komatsu, Masanobu; Pittaluga, Stefania; Kumanovics, Attila; Butte, Manish J; Cancro, Michael P; Pillai, Shiv; Meffre, Eric; Notarangelo, Luigi D; Walter, Jolan E.
Affiliation
  • Csomos K; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA. kcsomos@usf.edu.
  • Ujhazi B; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Blazso P; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Herrera JL; Department of Pediatrics, University of Szeged, Szeged, Hungary.
  • Tipton CM; Cancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Kawai T; Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Gordon S; Department of Medicine, Division of Rheumatology, Emory University, Atlanta, GA, USA.
  • Ellison M; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
  • Wu K; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Stowell M; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Haynes L; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Cruz R; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Zakota B; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Nguyen J; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Altrich M; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Geier CB; Department of Pathology & Laboratory Medicine, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.
  • Sharapova S; Eurofins Viracor Laboratories, Lee Summit's, MO, USA.
  • Dasso JF; Immunology Outpatient Clinic, Vienna, Austria.
  • Leiding JW; Belarusian Research Center for Pediatric Oncology, Minsk, Belarus.
  • Smith G; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Al-Herz W; Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • de Barros Dorna M; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Fadugba O; Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
  • Fronkova E; Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil.
  • Kanderova V; Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
  • Svaton M; Childhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
  • Henrickson SE; Childhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
  • Hernandez JD; Childhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
  • Kuijpers T; Allergy Immunology Division, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Kandilarova SM; Institute for Immunology, the University of Pennsylvania, Philadelphia, PA, USA.
  • Naumova E; Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
  • Milota T; Deptartment of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, Netherlands.
  • Sediva A; Department of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria.
  • Moshous D; Department of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria.
  • Neven B; Department of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.
  • Saco T; Department of Immunology, Second Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.
  • Sargur R; Université de Paris, Paris, France.
  • Savic S; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Université Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Sleasman J; Laboratory of Genome Dynamics in the Immune System, INSERM UMR1163, Institut Imagine, Paris, France.
  • Sunkersett G; Université de Paris, Paris, France.
  • Ward BR; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Université Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • Komatsu M; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR1163, Institut Imagine, Paris, France.
  • Pittaluga S; Windom Allergy, Asthma and Sinus, Sarasota, FL, USA.
  • Kumanovics A; Department of Immunology and Allergy, Sheffield Teaching Hospitals, Sheffield, UK.
  • Butte MJ; Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, UK.
  • Cancro MP; 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.
  • Pillai S; Division of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC, USA.
  • Meffre E; Cancer and Blood Disorder Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • Notarangelo LD; Division of Allergy and Immunology, Children's Hospital of Richmond, Virginia Commonwealth University, Richmond, VA, USA.
  • Walter JE; Cancer and Blood Disorders Institute and Department of Surgery, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
Nat Immunol ; 23(8): 1256-1272, 2022 08.
Article in En | MEDLINE | ID: mdl-35902638
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Nuclear Proteins / B-Lymphocytes / Homeodomain Proteins / DNA-Binding Proteins Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2022 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Nuclear Proteins / B-Lymphocytes / Homeodomain Proteins / DNA-Binding Proteins Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2022 Document type: Article Affiliation country: United States