Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Csomos, K; Ujhazi, B; Blazso, P; Herrera, JL; Tipton, CM; Kawai, T; Gordon, S; Ellison, M; Wu, K; Stowell, M; Haynes, L; Cruz, R; Zakota, B; Nguyen, J; Altrich, M; Geier, CB; Sharapova, S; Dasso, JF; Leiding, JW; Smith, G; Al-Herz, W; de Barros Dorna, M; Fadugba, O; Fronkova, E; Kanderova, V; Svaton, M; Henrickson, SE; Hernandez, JD; Kuijpers, T; Kandilarova, SM; Naumova, E; Milota, T; Sediva, A; Moshous, D; Neven, B; Saco, T; Sargur, R; Savic, S; Sleasman, J; Sunkersett, G; Ward, BR; Komatsu, M; Pittaluga, S; Kumanovics, A; Butte, MJ; Cancro, MP; Pillai, S; Meffre, E; Notarangelo, LD; Walter, JE

Published Date

  • August 2022

Published In

Volume / Issue

  • 23 / 8

Start / End Page

  • 1256 - 1272

PubMed ID

  • 35902638

Pubmed Central ID

  • PMC9355881

Electronic International Standard Serial Number (EISSN)

  • 1529-2916

Digital Object Identifier (DOI)

  • 10.1038/s41590-022-01271-6


  • eng

Conference Location

  • United States