Targeting B cells in immune-mediated inflammatory disease: A comprehensive review of mechanisms of action and identification of biomarkers

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Abstract

B cell-depletion therapy, particularly using anti-CD20 treatment, has provided proof of concept that targeting B cells and the humoral response may result in clinical improvements in immune-mediated inflammatory disease. In this review, the mechanisms of action of B cell-targeting drugs are investigated, and potential biomarkers associated with response to treatment in patients with autoimmune diseases are identified. Most available data relate to B cell depletion using anti-CD20 therapy (rituximab) in patients with rheumatoid arthritis (RA). Treatment leads to significant clinical benefit, but apparently fails to deplete long-lived plasma cells, and discontinuation is associated with relapse. Biomarkers commonly used in studies of B cell-targeted therapies include rheumatoid factor, anti-citrullinated peptide antibodies, and immunoglobulin (Ig) levels. More recently, there has been interest in markers such as B cell phenotype analysis, and B lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL), the latter particularly in studies of the IgG Fc–transmembrane activator and CAML interactor (TACI) fusion protein (atacicept) and anti-BLyS therapy (belimumab). Data from clinical trials of B cell-depleting agents in RA suggest that specific autoantibodies, BLyS, APRIL, and circulating and synovial B lineage cell levels may have potential as biomarkers predictive of response to treatment. Further trials validating these markers against clinical outcomes in RA are required. In patients with systemic lupus erythematosus, Fc receptors and levels of circulating immune cells (including B cells and natural killer cells) may be relevant markers.

Introduction

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) are complex inflammatory autoimmune diseases, and their treatment is often difficult and less than optimal. Tumor necrosis factor-alpha (TNF-α) is an important mediator of inflammatory processes (Tracey et al., 2008), and in the late 20th century there was a substantial leap forward in the treatment of RA with the introduction of TNF-α inhibitors. Clinical trials of these agents showed that they can be highly effective in treating the symptoms of inflammatory conditions, particularly RA (Weinblatt et al., 1999, Lipsky et al., 2000, Weinblatt et al., 2003). Subsequently, the essential role of B cells in maintaining autoimmune inflammation in these diseases came into focus, while it has been shown that targeting B cells can directly alter autoimmune responses (Hiepe & Radbruch, 2005). The increased appreciation of the role of B cells in disease pathogenesis arises from progress made in recent decades in understanding the immune system, including the mechanisms of lymphocyte activation and antigen processing, the principles of immune tolerance, B and T cell crosstalk, and the role of pro-inflammatory cytokines in autoimmunity (Mitchison & Wedderburn, 2000).

In RA, B cells can play a number of roles critical for the pathogenesis of the disease. B cells can function as antigen-presenting cells for T cells, which can then proliferate and exert pro-inflammatory activities (Takemura et al., 2001, Dörner and Burmester, 2003). The synovial membrane in patients with RA most likely contains rheumatoid factor (RF)-producing plasma cells, although formal proof is lacking. RF is associated with more aggressive articular disease, a higher frequency of extra-articular manifestations, and increased mortality and morbidity (van Zeben et al., 1992). It may also provide a self-perpetuating stimulus for B cells through activation and antigen presentation to T cells, which causes continuation of local inflammatory responses and could be responsible for further production of RF (Edwards et al., 1999). Additionally, RF-containing immune complexes bind to Fc receptors on macrophages in the synovial membrane, which induces the secretion of pro-inflammatory cytokines, including TNF-α (Edwards et al., 1999, Choy and Panayi, 2001).

There is also strong evidence to suggest that B cell abnormalities are involved in the development of SLE (Lipsky, 2001). Generally, B cells have been thought to contribute to the disease pathogenesis of SLE through the production of autoantibodies, with defective B cell tolerance the likely cause of the accumulation of large numbers of autoreactive B cells (Jacobi and Diamond, 2005, Yurasov et al., 2005). In particular, anti-double-stranded DNA (dsDNA) antibody levels have been associated with renal flares in patients with SLE (Linnik et al., 2005). Autoantibody-independent mechanisms involving B cells have also been shown to contribute to SLE. In a genetically engineered mouse strain that had B cells but lacked circulating autoantibodies, the mice developed nephritis and vasculitis, indicating that B cells themselves exerted a pathogenic role in this model of SLE (Chan et al., 1999). The involvement of B cells has also been supported by results in other murine models of SLE (Reininger et al., 1996, Sato et al., 2004). In humans, patients with SLE exhibit abnormalities of B cell homeostasis, including B cell lymphopenia (with naïve B cells more affected than memory B cells), and expansion of peripheral blood plasmablasts (Odendahl et al., 2000, Anolik et al., 2004).

In addition, there is accumulating evidence for the role of B lymphocyte stimulator (BLyS) and B cells (Mackay et al., 2007, Youinou et al., 2007) in SS; an excess of BLyS may corrupt B cell tolerance, allowing self-reactive B cells to present antigens to T cells, while BLyS may also stimulate T cell-independent activation of B cells via Toll-like receptors.

With knowledge of the role of B cells in autoimmune diseases, numerous rational targets for therapeutic intervention have been investigated, including factors involved in B cell differentiation and survival, and autoantibody and immunoglobulin (Ig) production. Initial strategies used direct targeting of B cells with monoclonal antibodies (mAbs) directed against B cell surface markers (e.g., CD20) expressed at various stages of B cell development (Dörner & Burmester, 2008). More recently, indirect strategies have been developed that aim to block the cytokine actions responsible for autoimmune activation, therefore providing more specificity for particular B cell functions than is possible by direct depletion of B cells (Dörner & Burmester, 2008).

The successful use of B cell-targeting therapies in the treatment of autoimmune diseases, e.g., rituximab in RA (Cohen et al., 2006, Emery et al., 2006), has raised questions regarding their mechanism of action. For example, rituximab directly depletes specific B cell populations, but also indirectly affects autoantibody production. Consequently, novel biomarkers may be identified through greater knowledge of the mechanism of action of such agents. In particular, deeper insight into the identification of biomarkers of response is important in light of the observation that a subgroup of patients with RA does not respond to B cell-targeted therapies, with the lack of response perhaps independent of complete B cell depletion (Cohen et al., 2006, Emery et al., 2006, Thurlings et al., 2008a, Thurlings et al., 2008c).

Section snippets

Targeting B cells

Development of mature B cells involves numerous stages, each of which sees changes in expression of a wide range of cell surface markers (Fig. 1). Thus, there are several potential candidates on which B cell-depleting therapies can act directly or indirectly.

Direct B cell-targeting therapies

Clinical trials of rituximab have shown that it is effective in treating the symptoms of RA (Edwards et al., 2004, Cohen et al., 2006, Emery et al., 2006). An observational study in patients with RA with an inadequate response to TNF-α inhibitors has suggested that rituximab treatment may be more effective than switching to an alternative TNF-α inhibitor (Finckh et al., 2010). Furthermore, a retrospective analysis of rituximab treatment in patients with RA has shown that it is also effective in

Biologic markers

In order to effectively utilize biologic therapies and available resources it is necessary to target treatments towards patients with the highest likelihood of response. In this context, a number of biologic markers have been suggested as suitable and necessary for evaluation of the efficacy of such treatments. These include ‘traditional’ markers, such as levels of Ig, RF, and anti-citrullinated peptide antibody (ACPA), as well as markers related specifically to mechanisms of action, such as

Summary and conclusions

B cell-depletion therapy, particularly using anti-CD20 treatment, has provided proof of concept that targeting B cells and the humoral response may result in clinical improvements in immune-mediated inflammatory disease. The data described here from studies of biomarkers in patients with autoimmune diseases receiving B cell-targeting therapies clearly support the role of B cells in driving inflammatory processes in autoimmune disorders.

Results from studies of patients with RA confirm the

Acknowledgments

Editorial support was funded by Merck Serono S.A. – Geneva, an affiliate of Merck KGaA, Darmstadt, Germany.

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  • Cited by (0)

    Prof. Dörner has been principal investigator of a phase IIa study of epratuzumab in SLE sponsored by Immunomedics, and has served as a consultant to Roche, Genentech, GlaxoSmithKline, and UCB. Dr Kinnman is an employee and shareholder of Merck Serono S.A. – Geneva, an affiliate of Merck KGaA, Darmstadt, Germany. Prof. Tak has participated in trials sponsored by Biogen Idec, Genentech, Immunomedics, Merck Serono, and Roche, and has served as a consultant to Genentech, Genmab, Merck Serono, Roche, and Wyeth.

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