期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 138, 期 3, 页码 839-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.01.035
关键词
B-cell anergy; break of tolerance; T-cell help; CD45 phosphatase activity; systemic lupus erythematosus
资金
- Research Council of Norway through its Centres of Excellence funding scheme [179573/V40]
- South-Eastern Norway Regional Health Authority [2011018]
- UNIFOR funds by the University of Oslo
- Norwegian Rheumatism Association
- National Institutes of Health [DK080165]
Background: We recently identified a human B-cell population that is naturally autoreactive and tolerized by functional anergy (BND cells). Objective: We sought to identify the molecular mechanism of how anergic autoreactive BND cells escape functional anergy and whether this process is altered in patients with lupus. Methods: Isolated peripheral blood naive and B-ND cells were cultured with various stimuli, and their activation status was determined by using an intracellular Ca+2 mobilization assay. Lyn kinase and Syk activities were assessed by using phospho-flow analysis. CD45 phosphatase activity was determined by using a novel flow-based assay, which takes advantage of the fluorogenic properties of phosphorylated coumaryl amino propionic acid, an analog of phosphotyrosine, which can be incorporated into peptides. Real-time quantitative PCR was used to quantitate LYN, SYK, and CD45 mRNA. Results: T-helper signals reversed the state of anergy, allowing BND cells to fully respond to antigenic stimulation by restoring signaling through the B-cell receptor (BCR). The mechanism was dependent on increased activity of the tyrosine phosphatase CD45 and CD45-dependent activation of Lyn and Syk. CD45 phosphatase activity was increased by T-cell help both in B-ND and naive B cells. Furthermore, we found that B-ND cells obtained from patients with systemic lupus erythematosus exhibited increased CD45 activity and BCR-signaling capacity, thus being less tolerized than B-ND cells from healthy control subjects. Conclusion: Our findings suggest that CD45 is a key regulator of BCR-signaling thresholds mediated by T-cell help. This raises the possibility that B-ND cells could represent precursors of autoantibody-secreting plasma cells and suggests a role for these autoreactive B cells in contributing to autoimmunity if not properly controlled.
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