In:
Nature Immunology, Springer Science and Business Media LLC, Vol. 23, No. 8 ( 2022-08), p. 1256-1272
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.
Type of Medium:
Online Resource
ISSN:
1529-2908
,
1529-2916
DOI:
10.1038/s41590-022-01271-6
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
2026412-4
