Are autoantibodies the targets of B-cell-directed therapy?

Abstract

B-cell-directed therapy-the use of agents that eliminate B cells or block cytokines important for B-cell function-is emerging as a promising approach to the treatment of rheumatic disease. Target diseases, including systemic lupus erythematosus (SLE), display diverse patterns of autoantibody production and aberrant activation of B cells. Despite the success of this general approach, the mechanisms by which B-cell-directed therapy ameliorates disease, and the role of autoantibodies as biomarkers of clinical response remain unclear. Importantly, although B-cell-directed therapy can reduce the production of some autoantibodies, the effects can be variable and heterogeneous, probably reflecting the critical (but ill-defined) roles of different B-cell and plasma cell populations in autoantibody production. Future studies during clinical trials of these agents are needed to define which B-cell and autoantibody populations are affected (or ought to be), and to discover informative biomarkers of clinical response that can be used to advance this therapeutic approach.

Potential Utility of Rituximab for Graves' Orbitopathy

“…More studies are needed to explain the effects of B-cell depletion therapy in humans. B cells are likely to contribute more during early disease whereas T-cell activation and autoantibody production occurs later independently, during disease progression (7,28,30). The data on RTX therapy in GO herein reviewed suggest that pursuing Bcell depletion shortly after diagnosis, and not only as a therapeutic option when standard immunosuppression has failed, may represent a novel strategy for GO.…”

“…RTX has been used off-label in various autoimmune disorders, but it is approved for clinical use in non-Hodgkin's lymphoma and in moderate-to-severe rheumatoid arthritis (RA) when patients are not unresponsive to standard immunosuppression and TNF inhibitors. It is not clear whether in human autoimmune disease RTX is effective due to its direct B-cell-depleting action or by indirectly affecting autoantibody production (30). In this context, studies also in autoimmune thyroid disease should address why response does not always correlate with B-cell depletion, as has been reported in some patients with RA (31,32).…”

Fueling autoimmunity: type I interferon in autoimmune diseases

“…However, even high-dose methylprednisolone pulse therapy, an aggressive immunosuppressive approach, fails to induce the desired apoptosis of pDCs due to their ongoing TLR activation by ICs [94]. With the encouragement from the approval of Belimumab (anti-BAFF mAb), major drug development effort directly targets B cells – the leukocyte secreting autoreactive antibodies with pathological consequences (recently reviewed in [95,96]). Given the central role played by type I IFN pathway in propelling lupus in human and in experimental models, strategies to interfere with the key steps by which this central mediator influences the development of autoimmunity represent a rational design for the next generation of therapeutic remedies for lupus and beyond.…”

Autoreactive helper T cells alleviate the need for intrinsic TLR signaling in autoreactive B cell activation

“…For example, in MRL.Fas lpr mice in which B cells lack MHC class II, and hence are unable to present antigen to CD4 T cells, the most affected autoAb was anti-Sm (13). In both patients and lupus-prone mice, RNA-related autoAbs were not affected by B cell depletion (42,43). Such treatment does not deplete long-lived plasma cells, which derive from GC cells, suggesting that B cells with RNA-related specificities derive from GC cells (44).…”