Journal
IMMUNOLOGICAL REVIEWS
Volume 292, Issue 1, Pages 120-138Publisher
WILEY
DOI: 10.1111/imr.12815
Keywords
autoantibodies; autoimmunity; BXD2; follicular T-helper cells; germinal center B cells; IFN beta; IL-17; IL-21; lupus; lymphotoxin beta; marginal zone macrophages; marginal zone-precursor B cells; plasmacytoid dendritic cells; regulator of G-protein signaling; SLE; transitional stage 1 B cells; type I IFNs
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Funding
- U.S. Department of Veterans Affairs [I01BX004049]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30-AR-048311]
- Lupus Foundation of America
- National Institute of Allergy and Infectious Diseases [2T32AI007051-39, P30-AI-027767, R01 AI134023, R01-AI-071110]
- Lupus Research Alliance
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The current concepts for development of autoreactive B cells in SLE (systemic lupus erythematosus) focus on extrinsic stimuli and factors that provoke B cells into tolerance loss. Traditionally, major tolerance loss pathways are thought to be regulated by factors outside the B cell including autoantigen engagement of the B-cell receptor (BCR) with simultaneous type I interferon (IFN) produced by dendritic cells, especially plasmacytoid dendritic cells (pDCs). Later, in autoreactive follicles, B-cells encounter T-follicular helper cells (Tfh) that produce interleukin (IL)-21, IL-4 and pathogenic cytokines, IL-17 and IFN gamma (IFN gamma). This review discusses these mechanisms and also highlights recent advances pointing to the peripheral transitional B-cell stage as a major juncture where transient autocrine IFN beta expression by developing B-cells imprints a heightened susceptibility to external factors favoring differentiation into autoantibody-producing plasmablasts. Recent studies highlight transitional B-cell heterogeneity as a determinant of intrinsic resistance or susceptibility to tolerance loss through the shaping of B-cell responsiveness to cytokines and other environment factors.
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