Lupus is a complex autoimmune rheumatic disease of unknown aetiology. The disease is associated with diverse features of immunological abnormality in which B-lymphocytes play a central role. However, the cause of atypical B-lymphocyte responses remains unclear. In this article, we provide a synopsis of current knowledge on intracellular signalling abnormalities in B-lymphocytes in lupus and their potential effects on the response of these cells in mouse models and in patients. There are numerous reported defects in the regulation of intracellular signalling proteins and pathways in B-lymphocytes in lupus that, potentially, affect critical biological responses. Most of the evidence for these defects comes from studies of disease models and genetically engineered mice. However, there is also increasing evidence from studying B-lymphocytes from patients and from genome-wide linkage analyses for parallel defects to those observed in mice. These studies provide molecular and genetic explanations for the key immunological abnormalities associated with lupus. Most of the new information appears to relate to defects in intracellular signalling that impact B-lymphocyte tolerance, cytokine production and responses to infections. Some of these abnormalities will be discussed within the context of disease pathogenesis.
B1 (B1a/B1b) cells represent a population distinct from conventional B2 cells, which predominates the coelomic cavities. In contrast to B2 cells, B1 cells are selected by self‐antigens, and are chronically active in an autonomous B cell receptor pathway. B1 cells produce circulating IgM natural antibodies that provide ‘innate‐like’ protection against pathogens, contribute to the elimination of apoptotic cells and prevent B1 cell expansion. Furthermore, B1 cells are effective both in presenting autoantigens to T cells, and in inducing T cell activation and differentiation. The vast majority of B1 cells express CD5 and the new findings suggest that part of the B1 cell properties, as well as the capacity of B1 cells to contribute to the development of autoimmune diseases and chronic lymphocytic leukaemia, is related to the expression of the CD5 molecule. Key Concepts: B1 cells are a subclass of B cells. B1 cells are involved in the innate protection. B1 cells are first produced in the foetus. B1 cells predominate in the coelomic cavities in adults. B1 cells overlap incompletely with CD5 + B cells in humans.
Background and Objectives The immunosuppressive function of regulatory B cells (Breg) is defective in B cells from systemic lupus erythematosus (SLE) patients. Since the Ca2+ pathway is also altered in SLE B cells, the aim of the study was to explore the contribution of the Ca2+ channel Orai1 and its regulator, the stromal interaction molecule 1 (STIM1), on regulatory B cell functions. Materials and Methods Thirty SLE patients and healthy controls (HC) were included in the study. Orai1 and STIM1 expressions were explored in CD40/CpG activated B cells, and in the stimulated (anti-CD3, anti-CD28 plus CpG-ODN 2006) T- and B- cell autologous co-culture Breg model. Transfection were used using either siRNAs to down-modulate STIM1 in SLE B cells, or either the cDNA STIM1 vector in HC B cells. Results After 3 days, in CD40/CpG activated HC B cells, and in HC B cells stimulated during co-cultures, acquisition of the Breg phenotype (IgD/CD38/CD24/CD5high) was associated with an over-expression of the Ca2+ regulator STIM1 (x10.8 and x7.1 fold increase respectively). At day 4 and even more at day 5, STIM1 expression declined in co-cultures and this down-regulation was accompanied with IL-10 and TGF-beta up-regulation in B cells, FoxP3+ regulatory T cell expansion, and a reduction of T cell proliferation. Expression of the Ca2+ channel Orai1 was stable. In SLE B cells, STIM1 expression was overexpressed at basal level when compared to HC B cells (x4.3 fold) and remains elevated in B cells during all the time of the autologous co-culture (x8.8 fold). Then we hypothesised that maintaining high levels of STIM1 was critic in the regulatory capacity of SLE B cells. Accordingly, we demonstrated that STIM1 downregulation in SLE B cells, using a specific siRNA, was effective to restore IL-10, but not TGF-beta, expression, FoxP3+ regulatory SLE T cell expansion, and SLE T cell inhibition. In HC B cells, forcing STIM1 expression, with a STIM1 vector, was effective to reproduce the abnormalities observed in SLE B cells. No association was observed between STIM1 expression at basal level and organ involvement, disease activity (SLEDAI), or serological parameters thus suggesting that STIM1 over-expression and Ca2+ dysregulations are primary events in SLE. Conclusions Altogether, this study reveals that acquisition of the Breg phenotype and Breg functions are tightly regulated by STIM1. Furthermore, this observation could provide innovative B-cell based treatment to convert B cells into immunosuppressive cells with applications in human autoimmunity and in SLE. Key words lupus, regulatory B cells, calcium, STIM1, IL-10
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.