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.

Highlights

  • Systemic lupus erythematosus (SLE) is an autoimmune disease with abnormal interplay between innate and adaptive immunity, breach of immune tolerance, production of autoantibodies, and immunological insult to multiple organ systems

  • Our preliminary results showed decreased miRNA-148a and increased BACH1, BACH2, and PAX5 expression in B cells from lupus nephritis (LN) patients receiving mycophenolate mofetil (MMF) maintenance treatment compared with B cells from AZA-treated patients [91,92]

  • Increasing understanding of B cell biology in SLE and LN has propelled the development of novel and more specific treatments

Read more

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease with abnormal interplay between innate and adaptive immunity, breach of immune tolerance, production of autoantibodies, and immunological insult to multiple organ systems. Abnormalities in lymphocytes, aberrant complement activation, autoantibody production, and perturbed cytokine milieu all contribute to the pathogenesis of SLE and LN [5,6,7]. In this context, abnormalities in B cells is a key player in SLE and LN pathogenesis as autoantibodies are important for diagnosis and the changes in autoantibodies level may show correlations with clinical disease activity [5,6,7,8,9,10]. The following discussion will highlight the B cell abnormalities which are relevant to SLE and LN pathogenesis and the effect of immunosuppressive medications on the B cell repertoire

Normal Development and Homeostasis of B Lymphocytes
Conventional Immunosuppressive Treatments for SLE and LN
Biologics and Emerging Therapies or SLE and LN
Future Directions and Concluding Remarks
Findings
77. Kidney Disease
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call