BAFF blockade mediates profound effects on B cells in mice. Within 1–2 weeks of administration of TACI-Ig or BAFF-R-Ig to normal mice, the spleen and lymph nodes decrease in size and the B cell frequency decreases by 50%. The decrease in T2, marginal-zone and follicular B cells is relatively greater than the decrease in T1 cells, but B1 cells are unaffected ([28
] and M Ramanujam, unpublished data). Germinal center formation is impaired [25
], as is the generation of memory responses [11
]. However, established memory cells can survive a short period of BAFF blockade [26
]. One study has reported a decrease in the frequency of antigen-specific bone marrow plasma cells after TACI-Ig treatment [13
]. Recovery of B cells takes several months after the cessation of treatment.
We have found that in normal mice TACI-Ig induces a reversible decrease in the serum levels of IgM and IgG1 and impairs primary IgM immune responses to a T-dependent antigen, but BAFF-R-Ig has little effect on serum immunoglobulin levels. In SLE-prone NZB/W mice, which have a marked polyclonal increase in serum IgM, TACI-Ig, but not BAFF-R-Ig, normalizes serum IgM levels for months after a short treatment course. Nevertheless, both agents delay disease onset. BAFF blockade has little effect on total serum IgG in NZB/W mice. In the NZB/W SLE model, both fusion proteins have only modest effects on the emergence of IgG anti-double-stranded DNA antibodies but they induce B cell depletion and a marked delay in the expansion of activated and memory T cells. The addition of a short course of cytotoxic T lymphocyte-associated antigen 4 (CTLA4)Ig to TACI-Ig results in a decrease in the serum levels of IgG and of autoantibodies, perhaps because T cell-derived cytokines augment the effect of BAFF on plasma cell survival [12
]. Despite some differences in the immunologic effects of TACI-Ig and BAFF-R-Ig, both reagents delay disease onset and death by 4–5 months when given before the emergence of nephritis in NZB/W F1
mice, and the combination of TACI-Ig and CTLA4Ig can even reverse established nephritis in this model ([26
] and M Ramanujam and A Davidson, unpublished data). In the collagen-induced arthritis model, TACI-Ig given just before disease onset inhibits both anti-collagen antibodies and T cell proliferative and cytokine responses to collagen and markedly attenuates disease [29
The effect of a 4-week course of anti-BLyS in primates is similar to that of BAFF-R-Ig, with a decrease in B cells in secondary lymphoid organs but no effect on serum Ig [38
]. A Phase 1 study of anti-BLyS in patients with SLE showed that the agent has a half-life of 13–17 days, that it reduces the number of circulating B cells and that, in some patients, serum levels of anti-DNA antibodies decreased after treatment [41
The extensive information available about BAFF and APRIL allows us to make several predictions about the effects of BAFF blockade in autoimmune disease. The first is that BAFF blockade will deplete B2 cells but not B1 cells. B2 cells are bone marrow-derived B cells that differentiate into either marginal-zone or follicular cells in a BAFF-dependent manner. B1 cells might constitute a separate self-renewing lineage that derives from the fetal liver, is located predominantly in the peritoneal cavity and does not seem to depend on BAFF for survival [42
] (Fig. ). Thus, autoimmune diseases in which B1 cells have a dominant role might be resistant to BAFF blockade. Second, diseases in which BCMA-expressing plasma cells produce pathogenic antibodies might be more sensitive to blockade with TACI-Ig than with selective BAFF blockers because APRIL can support the survival of these cells. TACI-Ig might also be more effective for diseases in which short-lived extrafollicular plasma cells produce IgM autoantibodies. In contrast, if autoantibody-producing plasmablasts are continuously newly formed from memory cells or naive cells that predominantly express BAFF-R, blockade of BAFF alone should be effective. Third, the immunoglobulin repertoire of newly emerging B cells may be altered by BAFF blockade because the survival of transitional B cells will be decreased and because of possible alterations in the strength of the BCR signal, but the repertoire of established memory cells is unlikely to be altered. Fourth, depletion of B cells by blockade of BAFF should have indirect effects on other cell types and on inflammatory mediators, some of which might improve disease activity independently of effects on autoantibody production. These include decreased antigen presentation to T cells, decreased epitope spreading, decreased cytokine secretion, decreased immune complex formation and decreased infiltration of target organs. Finally, BAFF blockade might synergize with agents that block T cell activation (Fig. ). It is important to explore these hypotheses in autoimmune individuals and in rodent auto-immunity models because intrinsic B cell hyperreactivity, the provision of excessive T cell help and the presence of inflammatory mediators might alter the normal dependence of B cells on BAFF or APRIL and thus the response to blockade.
Figure 3 BAFF forms part of an amplification loop that is activated by inflammation. Immune complexes induce interferon-α (IFN-α) secretion from plasmacytoid dendritic cells (DCs) that in turn stimulates myeloid dendritic cells to further activate (more ...)