Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysfunction, production of autoantibodies directed toward cellular and nuclear components, and multiorgan damage caused by immune complex deposition and inflammation within affected tissues 1. much mainly because 60% of disease risk 2. Although rare monogenic causes do exist, heredity in SLE is definitely complex, with multiple common variants contributing to disease, with individuals having to accomplish a certain genetic threshold for disease risk. This genetic risk, in combination with environmental factors (exposure to Artemisinin ultraviolet sunlight, smoking, and infections including Epstein\Barr virus have all been implicated), leads to development of the disease 1. In this review, we summarize some of the B cell anomalies in SLE and incorporate evidence from studies in humans and mouse models, together with data from genetic association studies, to explain the mechanisms behind B cell dysregulation in SLE. The B cell phenotype in SLE Artemisinin The crucial role of B cells in SLE pathogenesis is well recognized, from producing autoantibodies to abnormal regulation of immune responses 3, 4. Various abnormalities have been noted in SLE B cells. First, there is an imbalance of B cell subtype numbers, with an increase in class\switched memory B cells relative to naive B cells 3. Second, B cells from SLE patients have exaggerated BCR responses, with receptor crosslinking leading to increased calcium influx and tyrosine phosphorylation of downstream signaling molecules 3. Increased memory B cell numbers confer significant disease risk as these have a lower activation threshold, allowing autoreactive B cells to thrive with minimal antigen contact, while enhanced receptor activation contributes to the steady\state active phenotype seen in SLE 3, 5. B cells contribute to disease mainly by producing autoantibodies targeting nuclear components including DNA (antiCdouble\stranded DNA [anti\dsDNA]), RNP particles (anti\Ro, anti\La, and anti\Sm), histones, and nonhistone chromatin proteins. These are present in 90% of patients and contribute to disease progression via immune complex formation Artemisinin 6. Titers of these autoantibodies (especially anti\dsDNA) correlate positively with increased disease activity, and serial measurements are used to monitor patients for disease flares 6. There is also evidence that autoantibodies cross\react with cellular components other than nuclear targets 7. For example, anti\dsDNA antibodies bind to major glycosaminoglycan components in the glomerular basement membrane, suggesting a possible direct role in nephritis 7. In mouse models, Artemisinin transfer of autoantibodies from diseased to unaffected animals leads to development of typical immune complexCmediated nephritis 8. Moreover, in MRL/mice (which develop lupus\like disease spontaneously), disease severity can be attenuated and mortality reduced by ~50% if antibody secretion is blocked, providing robust evidence that autoantibodies are more than spectators in disease etiology 9. A recent explosion in genome\wide association studies (GWAS) has identified 80 potential risk loci across multiple immunopathologic pathways 10. In this review, we discuss how genetic variants affect the development of B cells, allowing them to overcome several checkpoints to break self tolerance, and how they donate to the irregular active phenotype seen in SLE. We examine how these genes alter both early developmental pathways within the bone tissue marrow and past due maturation procedures to trigger B cell dysregulation. Central tolerance checkpoint of B cell advancement within the bone tissue marrow in SLE Regular B cell advancement starts within the bone tissue marrow, where in fact the 1st round of adverse collection of autoreactive B cells (termed central tolerance) happens. This process can HBEGF be summarized in Shape ?Shape1.1. Many potential abnormalities in central tolerance have already been implicated in SLE, including failing of adequate adverse collection of autoreactive B cells and insufficient receptor editing and enhancing (measures 6 and 3, respectively, in Shape ?Shape1),1), both which are critical measures in maintaining tolerance to personal 11. Open up in another window Shape 1 Central tolerance. 1, Common lymphocyte precursor commits to B cell lineage via manifestation of B cellCspecific transcription elements.