B cells as therapeutic targets in SLE

Abstract

The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.

Conflict of interest statement

Competing interests

I. Sanz declares associations with the following companies: Genentech, GlaxoSmithKline and Biogen. See the article online for full details of the relationships. F. E.-H. Lee and the Journal Editor J. Buckland declare no competing interests. The CME questions author D. Lie has served as a nonproduct speaker for “Topics in Health” for Merck Speaker Services.

Figures

Figure 1

The Janus nature of B cells. B cells carry out multiple functions, through the production of antibodies (either protective natural autoantibodies or pathogenic IgG autoantibodies), and in an antibody-independent fashion. Pathogenic antibody-independent functions include the formation of ectopic lymphoid tissue (through lymphotoxin β receptor signaling) and lymphotoxin-independent functions, including the promotion of multiple effector CD4+ and CD8+ T-cell subsets, T-cell memory, DC recruitment and inhibition of TREG cells. Many of these functions are mediated by B-cell production of proinflammatory cytokines and chemokines. However, B cells also carry out essential protective functions that might prevent or suppress autoimmunity, including induction of T-cell anergy, suppression of effector TH cells, inhibition of DCs and expansion of TREG cells. Whether these functions are carried out by specialized, irreversibly committed B-cell populations (or by more plastic cells), their role in disease manifestations and progression, and their impact on treatment outcome, remain to be fully understood. Abbreviations: DC, dendritic cell; IFN, interferon; IL, interleukin; TFH, T follicular helper cell; TH, helper T cell; TREG cell, regulatory T cell; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor. Reprinted by permission from Macmillan Publishers Ltd: Journal of Investigative Dermatology129, 278–288 © 2008.

Figure 2

Strategies for B-cell targeting in SLE. B cells can be targeted at various stages of their development. Targeting surface antigens with depleting antibodies will provide differential breadth of depletion. Inhibition of B-cell co-stimulation and/or survival can also be therapeutically desirable and could be achieved by targeting surface receptors (both in the early phases of activation [1] and GC development and in later GC phases [2]). GC formation is dependent on the LTβR, and its structure and survival can also be influenced by targeting organizing chemokines and BAFF, respectively (3)., Chemokine blockade could also influence plasma cell homing or survival (or both) in different locales. The retention of GC B cells and autoantibody output can be powerfully influenced by IL-17 (4). Blockade of other critical co-stimulatory and survival/differentiation factors could be therapeutically beneficial (indicated in Table 1). The bars at the top indicate the phases and types of B-cell response preferentially affected by blockade of the corresponding factor. A more-comprehensive listing of the molecules involved is provided in Supplementary Figure 1 online. Abbreviations: APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; CB, centroblast; CC, centrocyte; CXCR, CXC-chemokine receptor; FDC, follicular dendritic cell; GC, germinal center; IL-17, interleukin-17; LTβR, lymphotoxin β receptor; TFH, T follicular helper cell; TH, helper T cell.

Figure 3

Phases of B-cell depletion: a working model. This model assumes that disease is balanced by protective and pathogenic B-cell functions with active disease characterized by a pathogenic B-cell environment with dominance of effector B cells and/or autoantibodies (owing to expansion of pathogenic cells or deficit of regulatory cells). The benefit of early B-cell depletion would depend on: the extent of initial B-cell killing and early re-expansion; the relative impact of depletion on protective versus pathogenic B cells; the relative importance of effector versus regulatory B-cell functions at the time of treatment; and the pathogenic contribution of short-lived autoantibodies. Long-term outcome would depend on: the relative numerical and functional balance between pathogenic and regulatory B cells; and the pathogenic contribution of long-lived autoantibodies, which would continue to be produced by long-lived plasma cells unless they are directly targeted by other agents or eventually decreased by chronic B-cell depletion. Long-term remission could be achieved if immunological tolerance is restored during the reconstitution period owing to the confluence of factors discussed elsewhere., This model provides a template for understanding the phases and underpinnings of B-cell depletion, how to design combination therapies either for induction or maintenance, and how to evaluate the success or failure of B-cell targeted therapies. Abbreviation: TREG cell, regulatory T cell. Permission obtained from Drug Discovery Today: Therapeutic Strategies6, Sanz, I. Indications of rituximab in autoimmune diseases, 13–19 © (2009) Elsevier Ltd, with permission from Elsevier.

Figure 4

Variable B-cell homeostasis in human SLE. The challenge of tailoring specific B-cell therapies for a heterogeneous B-cell disease is illustrated by the high variability of B-cell profiles displayed by individual SLE patients. This variability applies to both populations with regulatory potential (transitional and marginal zone-like cells) and pathogenic potential (memory, effector and plasma cells). This figure represents a heat map showing B-cell profiles for normal individuals and patients with SLE. Each column represents an individual and each row corresponds to a B-cell subset (specified on the right according to previously published classifications). Both individuals and cell populations are hierarchically clustered and reordered accordingly. Color maps correspond to the log of the percentage of the cell subset with respect to the CD19+ subset (except for the 9G4+ group, which are expressed relative to their immediate parent population). The healthy and SLE groups were clustered separately, each using correlation as the distance measure and complete linkage. There were 25 healthy individuals and 49 patients with SLE. This type of data visualization clearly demonstrates both high interindividual variability as well as clustering of patient subsets, and should help design and evaluate B-cell therapies in SLE. Abbreviations: CXCR, CXC-chemokine receptor; SLE, systemic lupus erythematosus.