B-cell biology and related therapies in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. The immunologic events triggering the onset and progression of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis has been brought to the fore in the last several years. The breakdown of B-cell tolerance is likely a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Antibody-dependent and -independent mechanisms of B cells are important in SLE. Thus, autoantibodies contribute to autoimmunity by multiple mechanisms including immune complex mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including interferon alpha, tumor necrosis factor, and interleukin 1. Recent data have highlighted the critical role of toll-like receptors as a link between the innate and adaptive immune system in SLE immunopathogenesis. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, there has been a therapeutic focus on developing interventions that target the B-cell compartment. Several different approaches to targeting B cells have been used, including B-cell depletion with monoclonal antibodies against B-cell-specific molecules, induction of negative signaling in B cells, and blocking B-cell survival and activation factors. Overall, therapies targeting B cells are beginning to show promise in the treatment of SLE and continue to elucidate the diverse roles of B cells in this complex disease.

Figure 1. A model for B cell development, selection, and function after B cell depletion therapy

The outcome of BCD is going to depend on how well established autoimmunity is eradicated and how the immune system reconstitutes. B cells are continually generated in the bone marrow, and once rituximab is cleared can develop through well recognized stages (T=transitional, FO=follicular naïve, FM=follicular mantle, MZ=marginal zone, GC=germinal center) with defined tolerance check points as shown. Autoreactive B cells (depicted in pink) are deleted in the BM immature subsets, and cells in the transitional subsets undergo further selection, the stringency of which is determined in part by available BAFF (BAFF excess due to overproduction, peripheral lymphopenia, or reduced BM output reduces selective stringency). A favorable reconstitution profile (denoted A) will be characterized by an abundance of newly emerging transitional B cells in an environment that favors stringent negative selection of autoreactivity (high numbers of transitional B cells relative to BAFF). A non-favorable reconstitution profile (B in red) will be characterized by a higher fraction of residual memory B cells induced by an environment of TLR activation (via DNA and RNA containing immune complex activation of plasmacytoid dendritic cells), yielding large quantities of interferon and inhibition of new BM B cell lymphopoiesis. The outcome of BCD will also depend on the balance between protective (regulatory, anti-inflammatory) B cells and pathogenic (effector, pro-inflammatory) B cells and their corresponding cytokines. We postulate that physiologically, transitional cells predominantly produce IL10 (or TGFB) which in a normal environment exerts anti-inflammatory actions. This situation would be altered in autoimmune disease. Finally, BCDT may restore the physiological balance between protective and pathogenic B cell functions by creating an environment dominated by transitional cells with anti-inflammatory and tolerogenic functions and Treg inducing activity.

Figure 2. The diverse role of B cells in SLE

B cells contribute to SLE disease pathogenesis by both antibody dependent and independent mechanisms. In addition to direct binding of autoantibodies to target antigens on cells which can lead to cellular cytotoxicity and complement activation, immune complexes can also activate complement and cause toll-like receptor (TLR) activation. Antibody independent functions for B cells include antigen presentation and co-stimulation to T cells, such that B cells can affect T cell function in diverse ways, contributing to T cell activation, polarization, and even recruitment of follicular T helper cells to the GC. Other antibody independent functions for B cells include pro-inflammatory and anti-inflammatory cytokine secretion and chemokine secretion- including LTα which affects lymphoid organogenesis.