B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments

Abstract

Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell–T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell–T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.

Immunomodulatory Effects of Diet and Nutrients in Systemic Lupus Erythematosus (SLE): A Systematic Review

“…Parallel to this, a decline in CD8 + T cells and a higher proportion of naïve CD4 + and CD8 + T cells have been observed ( 25 ). This finding is of special importance as it shows the direct impact of calorie restriction on B-cell and T-cell compartments, key immunocompetent cell compartments involved directly in SLE pathogenesis ( 26 , 27 ). In another SLE-prone mouse model, when a 40% calorie-restricted diet was provided, B:T cell and CD4 + :CD8 + T-cell ratios were significantly lowered compared with the control group ( 28 ).…”

Flow Cytometric Methods for the Detection of Intracellular Signaling Proteins and Transcription Factors Reveal Heterogeneity in Differentiating Human B Cell Subsets

“…The regulation of TF expression through the intracellular signal transduction pathways activated by T FH -cell-provided CD40L, IL-21 and IL-4 is essential for the GC response and B cell differentiation. The ability to monitor both this signaling and transcriptional regulation is necessary to enable fundamental research on wanted B cell responses against pathogens and unwanted B cell responses, as observed in autoimmune diseases [37][38][39] or during allo-antibody formation after blood transfusion [40]. Additionally, transcriptional dysregulation and overactivated signaling pathways can lead to B cell malignancies [41,42].…”

A Comprehensive Review of Biological Agents for Lupus: Beyond Single Target

“…B cells are central to the pathogenesis of SLE. Dysregulation of transcription factors and cytokines in B cells and interaction between B-T cells can lead to abnormal maturation of B cells and the production of autoantibodies ( 4 , 5 ). Targeted blocking of B-cell-related cytokines has an obvious effect on down-regulating the overly strong immune response.…”