Review
The role of B cells in lupus pathogenesis

https://doi.org/10.1016/j.biocel.2009.10.011Get rights and content

Abstract

Autoantibodies clearly contribute to tissue inflammation in systemic lupus erythematosus. In order to therapeutically target B cells making pathogenic autoantibodies, it is necessary to identify their phenotype. It is also important to understand the defects in B cell repertoire selection that permit pathogenic autoreactive B cells to enter the immunocompetent B cell repertoire. We present the data that both marginal zone and follicular B cells can produce pathogenic autoantibodies. Moreover, we discuss how B cell survival and maturation are regulated centrally prior to antigen activation and in the periphery after antigen activation to form the repertoire that generates the spectrum of circulating antibodies.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect any organ system. Pathogenic autoantibodies are a hallmark of this disease, and have been shown to play a necessary role in many of the manifestations of lupus. Although many molecular pathways can be abnormal in lupus and several cell types can become dysregulated, B cells have emerged as central players in this disease because autoantibodies are key to diagnosis and because autoantibodies arise years before there is any other evidence of immune dysregulation (Arbuckle et al., 2003). B cells are not only the cells that secrete autoantibodies; they also play crucial roles in antigen presentation and cytokine secretion.

In this review, we will examine the pathogenic role played by B cells in lupus, including a discussion of the importance of different B cell subsets in lupus development and flare. We will examine important pathways involved in the generation of autoreactive B cells, focusing on the role of B cell receptor (BCR) signaling in B cell escape from negative selection early in B cell development, and again in the censoring of autoreactive mature B cells that emerge from the germinal center (GC). We will examine how non-BCR mediated signaling in B cells can contribute to lupus. Because lupus is predominantly a disease of women, we will discuss the effect of estrogen on B cell tolerance. Lastly, we will briefly examine B cell-directed therapies in lupus.

Section snippets

Pathogenic role of B cells in lupus

B cells are important initiators and effectors of a normal immune response. In autoimmunity, B cells carry out those same roles, turning their arsenal towards self-antigens. Autoantibodies are a defining characteristic of lupus, and many antibodies make a clearly delineated contribution to disease pathogenesis, such as anti-DNA antibodies, which we will discuss in detail and which contribute to kidney and brain disease, anti-β2 glycoprotein I and anti-cardiolipin antibodies that predispose to

Contribution of different B cell subsets to lupus

Mature B cells are designated as either B1 or B2 cells, and the latter are further divided into follicular and marginal zone B cells. While all three subsets are able to secrete anti-DNA antibodies (Schiffer et al., 2002), a major focus has been on the role of follicular B cells, as these are the B cells that were known to participate in T-dependent immune responses that involve germinal center reactions, and early studies of murine lupus emphasized the role of the germinal center reaction.

The role of BCR signaling in predisposition to lupus

B cells pass through various developmental stages before they become mature cells that can be activated by encounter with antigen. Of central importance to this maturation is the process of negative selection, which eliminates immature B cells that react to self-antigen with high affinity. B cells form immunoglobulin by random rearrangements of a set of genes, which for the heavy chain include the V (variability), D (diversity) and J (joining) gene segments, and for the light chains include V

Tolerance induction in antigen-activated B cells

In recent years, a series of peripheral tolerance checkpoints have been identified in antigen-experienced B cells, both in humans and in mice. Single-cell studies showed that in humans, up to 20% of IgM+ naïve mature B cells express low-affinity self-reactive antibodies (Tsuiji et al., 2006). However, these self-reactive B cell clones are removed from the IgM+ memory compartment before the onset of somatic mutation. The exclusion from the memory compartment seems to be specific for

Non-BCR-mediated signaling in autoreactive B cells

Non-BCR pathways of note in lupus include the Toll-like receptor (TLR), FcγRIIb, and BAFF signaling pathways. Contributing to their ability to induce inflammation in lupus, B cells express of a number of Toll-like receptors, in particular TLR7 and TLR9, which recognize single-stranded RNA and DNA rich in unmethylated CpG, respectively. Both DNA and RNA are found in the apoptotic blebs that are thought to be important to lupus pathogenesis. B cells that express DNA-reactive BCRs can be activated

B cell-directed therapies

As this review emphasizes, B cells have been proven to play a critical role in both human lupus and in mouse models. Thus, the rationale clearly exists for therapies that target B cells. Rituximab, a monoclonal antibody against CD20, was initially developed to treat B cell lymphomas (Marwick, 1997), but its application has grown to the treatment of autoimmune disease. CD20 is expressed on immature and mature B cells, but is not expressed on plasma cells (Glennie et al., 2007). Rituximab has

Conclusion

The failure of B cell depletion to demonstrate an effect of a B cell targeted therapy in SLE crystallizes our need to better understand the role B cells are playing in this disease. B cells are clearly important in lupus, and a tremendous number of B cell abnormalities may precipitate this disease. For example, in some murine models of lupus, increased BCR-mediated signaling leads to autoimmunity, while in other cases, diminished BCR signaling does the same. In some cases, marginal zone B cells

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