Abstract
The TNF family cytokines B‐cell activating factor (BAFF) and a proliferation‐inducing ligand (APRIL) support plasma cell survival. It is known that inhibitors of BAFF only (BAFFR‐Fc) or BAFF and APRIL (TACI‐Fc) administered early enough in an NZB/NZW F1 mouse model of systemic lupus erythematosus (SLE) ameliorate clinical outcomes, pointing to a pathogenic role of BAFF. In the present study, TACI‐Fc administrated at a later stage of disease, after onset of autoimmunity, decreased the number of bone marrow plasma cells and slowed down further formation of autoantibodies. TACI‐Fc prevented renal damage during a 12‐week treatment period regardless of autoantibody levels, while BAFFR‐Fc did not despite a similar BAFF‐blocking activity in vivo. TACI‐Fc also decreased established plasma cells in a T‐dependent hapten/carrier immunization system better than single inhibitors of BAFF or APRIL, and sometimes better than combined single inhibitors with at least equivalent BAFF and APRIL inhibitory activities. These results indicate that TACI‐Fc can prevent symptoms of renal damage in a mouse model of SLE when BAFFR‐Fc cannot, and point to a plasticity of plasma cells for survival factors. Targeting plasma cells with TACI‐Fc might be beneficial to prevent autoantibody‐mediated damages in SLE.
Highlights
The homotrimeric TNF family ligands BAFF (B cell-activating factor of the TNF family, known as B Lymphocyte stimulator) [1, 2] and a proliferation-inducing ligand (APRIL) (A proliferation-inducing ligand) [3] are important differentiation and survival cytokines for B cells
We report that in immunized, nonautoimmune mice, 2 weeks’ treatment with TACI-fragment crystallizable of an antibody · NP (Fc), but not with BAFF receptor · BCMA (BAFFR)-Fc, decreased both recently-generated and long-lived plasma cell · TACI (PC) in the bone marrow, but that the latter were not depleted by the combined action of single BAFF and APRIL inhibitors
Mice treated with Apry-1-1 were as affected as controls, and mice receiving mBAFFR-Fc only showed a nonsignificant trend to delayed onset of proteinuria (Fig. 1B)
Summary
The homotrimeric TNF family ligands BAFF (B cell-activating factor of the TNF family, known as B Lymphocyte stimulator) [1, 2] and APRIL (A proliferation-inducing ligand) [3] are important differentiation and survival cytokines for B cells. BAFF engages three specific receptors, BCMA (B cell maturation antigen) [7, 8], TACI (transmembrane activator and CAML interactor) [9] and BAFFR (BAFF receptor) [10], while APRIL binds to BCMA, TACI and, via another portion of its structure, to sulfated glycosidic chains of proteoglycans [11, 12]. BAFF-deficient mice have reduced numbers of peripheral B cells, showing that BAFF is required for mature B cell survival in vivo [13, 14]. TACI is required for T-independent antibody responses and to negatively regulate the B-cell pool [17, 18]
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