Therapeutic CD154 antibody for lupus: promise for the future?

Abstract

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by the production of pathogenic autoantibodies. A new study demonstrates that passive antibody specific for the TNF family member, CD154, ameliorates disease by reducing levels of self-reactive antibody in the serum. This study demonstrates a substantial potential for anti-CD154 antibody in the treatment of humoral autoimmunity.

Figure 1

Potential cellular targets for passive CD154 antibody to interrupt thymus-dependent GC and antibody responses. Antigen-specific T and B lymphocytes meet at the interface of T and B cell zones (follicles) in secondary lymphoid tissues (I). CD40-CD154 interaction results in the local proliferation of both lymphocyte types. Following clonal expansion, a fraction of activated T and B cells, prompted by CD40-CD154 signaling, migrate into the follicle to initiate the GC reaction (II). In GCs, B cells proliferate and activate AID-dependent SHM and CSR. Other clonally related B lymphocytes are retained in extra-follicular sites and differentiate into antibody-forming cells (AFCs), or plasmacytes (III). These transient AFCs do not express AID and do not support CSR and SHM. In GCs, centroblasts proliferate in the DZ, migrate to the LZ as centrocytes, present antigen to LZ T cells, and receive signals that direct either their exit from the GC or return to the DZ (IV). Centrocytes that do not receive survival signals die by apoptosis. Active GCs require continuous CD40-CD154 signaling; these signals may represent homotypic interaction between CD40⁺CD154⁺ centroblasts or heterotypic signals between CD40⁺ centrocytes and CD154⁺CD4 T cells. Selected B cells exit the GC (V) to enter the memory or long-lived plasmacyte compartments. Grammer et al. (17) observe that passive anti-CD154 reduces the numbers of IgD⁺CD38⁺ GC precursors (I and II) and CD38^bright plasmacytes (III and V) but has little effect on circulating GC (IgD^–CD38⁺) cells (IV). The primary effect(s) of CD154 antibody in SLE patients may be to interrupt the early initiation (I) and/or migrations steps (II) of the GC reaction.