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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
K. Csomos, B. Ujhazi, P. Blazso, JL. Herrera, CM. Tipton, T. Kawai, S. Gordon, M. Ellison, K. Wu, M. Stowell, L. Haynes, R. Cruz, B. Zakota, J. Nguyen, M. Altrich, CB. Geier, S. Sharapova, JF. Dasso, JW. Leiding, G. Smith, W. Al-Herz, M. de...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural
Grantová podpora
R01 AI153830
NIAID NIH HHS - United States
K08 AI103035
NIAID NIH HHS - United States
ZIA AI001222
Intramural NIH HHS - United States
P01 AI061093
NIAID NIH HHS - United States
R01 AI100887
NIAID NIH HHS - United States
NLK
ProQuest Central
od 2000-07-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 2000-07-01 do Před 1 rokem
- MeSH
- B-lymfocyty * MeSH
- buněčná diferenciace MeSH
- DNA vazebné proteiny * nedostatek genetika MeSH
- homeodoménové proteiny * genetika MeSH
- imunologická tolerance MeSH
- jaderné proteiny * nedostatek MeSH
- lidé MeSH
- počet lymfocytů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
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.
Belarusian Research Center for Pediatric Oncology Minsk Belarus
Cancer and Blood Disorder Institute Johns Hopkins All Children's Hospital St Petersburg FL USA
Department of Clinical Immunology and Allergy St James's University Hospital Leeds UK
Department of Immunobiology Yale University New Haven CT USA
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 Perelman School of Medicine University of Pennsylvania Pennsylvania PA 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
Division of Allergy and Immunology Massachusetts General Hospital for Children Boston MA 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 Genome Dynamics in the Immune System INSERM UMR1163 Institut Imagine Paris France
Section of Rheumatology Allergy and Clinical Immunology Yale School of Medicine New Haven CT USA
Citace poskytuje Crossref.org
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