Short Analytical ReviewB cell depletion therapy in systemic rheumatic diseases: Different strokes for different folks?
Introduction
It has long been appreciated that many disease states are associated with circulating autoantibodies. In several of them (e.g., myasthenia gravis, Graves' disease, Goodpasture's syndrome), the autoantibodies are unequivocally pathogenic. However, as our global understanding of autoimmune diseases expands, it has become increasingly clear that not all autoantibodies are created equal. Although the presence of a circulating autoantibody characteristic of a given disorder may indicate pathogenicity of that autoantibody, the presence of a circulating autoantibody does not ipso facto prove the autoantibody's pathogenicity. A striking example of this is rheumatoid factor (RF). Whereas circulating RFs were widely felt 40 years ago to be central to development of rheumatoid arthritis (RA), it subsequently became as widely felt that RFs were strictly epiphenomena (albeit useful clinical markers) with essentially no direct role in disease pathogenesis. Of note, interest in a pathogenic role for RFs in RA is again waxing, but pathogenic potential may have more to do with membrane RF on the B cell surface than with circulating RFs [1], [2], [3].
The focus on autoantibodies and their pathogenic potential led investigators to B cells, the producers of “good” antibodies and “bad” autoantibodies. In the context of autoantibody-associated diseases, B cells were not viewed as an independent entity from a pathogenetic perspective—they simply were the machines that cranked out the deleterious autoantibodies. Indeed, until the past 10–15 years, B cell function was virtually synonymous with antibody production. The raison d'être of B cells was to produce antibodies—period. The fact that the overwhelming majority of B cells were not producing antibodies at any single point in time did not sway “conventional wisdom” from this view of monolithic B cell function. Even if a B cell was presently not actively producing antibody, it was, nevertheless, “waiting” to produce antibody. It was the autoantibody products of “forbidden” B cell clones that drove autoantibody-associated diseases. If one would rid the host of autoantibodies, one would invariably cure the disease.
We are now far more sophisticated in our understanding of B cells. We now appreciate that B cells, in addition to serving as antibody-secreting cells, serve also as antigen-presenting cells, as cytokine-producing cells, and as effector and regulatory cells [4]. In the context of autoimmunity, the autoantibody-independent role for B cells was most clearly highlighted by the seminal work of Shlomchik and colleagues [5], [6] in the MRL-lpr/lpr murine systemic lupus erythematosus (SLE) model. MRL-lpr/lpr mice genetically rendered deficient in B cells displayed neither the activated T cell phenotype nor the end-organ pathology observed in intact MRL-lpr/lpr mice. However, MRL-lpr/lpr.mIgM/JHD mice, which harbored B cells in normal numbers and with a normal subset distribution but remained incapable of secreting Ig (including autoantibodies), did undergo T cell activation similar to that observed in wild-type MRL-lpr/lpr mice and did develop disease (albeit with a lesser severity than that observed in wild-type mice) [7]. Thus, B cells are indisputably needed for development of SLE (at least in the MRL-lpr/lpr model), and this indispensability contains an element that is independent of autoantibody production.
The pendulum has now swung, and B cells themselves are viewed as appropriate and, in some cases, preferred targets of therapeutic interventions. In this review, we will focus on two distinct approaches of depleting B cells: one employing a direct-kill approach (by engagement of a B cell surface molecule), and the other employing an indirect starvation approach (by neutralization of a B cell survival factor). The underlying biology of the former approach is relatively straightforward, and considerable clinical experience has accrued to date with this therapeutic modality. In contrast, the underlying biology of the latter approach is highly complex, and the clinical experience to date in humans with this modality is very limited. We will focus on two systemic immune-based rheumatic disorders, SLE and RA, as paradigms of B-cell-dependent autoimmune diseases in which the B cells (likely) contribute to disease via pathways other than (just) circulating autoantibodies.
Section snippets
CD20
CD20 is a 33- to 37-kDa non-glycosylated tetraspan (spans the surface membrane four times) phosphoprotein whose natural ligand and physiologic function remain unknown [8]. CD20 expression is limited to B cells, begins in humans at the early pre-B cell stage, and persists until the B cells undergo terminal plasma cell differentiation. Of great clinical relevance, CD20 is expressed neither by T cells nor by (antibody-producing) plasma cells.
Notwithstanding our ignorance of fundamental
General biology and preclinical observations
BLyS (also known as BAFF, TALL-1, THANK, TNFSF13B, and zTNF4) is a 285-amino acid member of the TNF ligand superfamily [27], [28], [29], [30], [31], [32]. It is expressed as a type II transmembrane protein that is cleaved at the cell surface by a furin protease, resulting in release of a soluble, biologically active 17-kDa molecule [29], [33]. Expression of BLyS systemically is largely (but not exclusively) restricted to myeloid lineage cells [27], [28], [29], [31], [33], [34] and by bone
Concluding remarks
B-cell-targeted therapy is here to stay. It is unrealistic to believe that all RA and/or SLE patients would benefit from such treatment, but it is already established that many RA patients do benefit, and it is highly likely that clinical benefit will be formally proven for many SLE patients as well. It remains to be determined whether a CD20-based approach or a BLyS-based approach (or some other approach) will be the better one. Ongoing and future basic and clinical investigations should help
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