학술논문
Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells
Document Type
Original Paper
Author
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.
Source
Nature Immunology. 23(8):1256-1272
Subject
Language
English
ISSN
1529-2908
1529-2916
1529-2916
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.
Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet+ B cells revealing how RAG impacts stringency of tolerance and B cell fate in the periphery.
Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet