Abstract
BACKGROUND: The tumour necrosis factor (TNF)-family members B cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) play important roles in B cell biology, and share binding to B cell maturation antigen and transmembrane activator and cyclophilin ligand interactor, both receptors of the TNF-family. However, while it is reported that BAFF can break B cell tolerance, the role of APRIL in autoimmunity remains elusive. OBJECTIVE: To evaluate the role of APRIL on collagen-induced arthritis (CIA). METHODS: CIA was induced in APRIL-transgenic (Tg) DBA/1 mice and littermates. Disease progression was evaluated by clinical and histological signs of arthritis. In another experimental setting mice were exposed to the collagen antibody-induced arthritis. In addition, we tested T cell dependent humoral responses in APRIL-Tg mice. RESULTS: We found that APRIL-Tg displayed a strongly reduced incidence and severity of CIA compared with littermates, with decreases in collagen-specific autoantibody titres, immune complex deposition and downstream mast cell activation in joints. Notably, ectopic APRIL-expression was also found to negatively regulate T cell dependent humoral responses. The lower autoantibody production in APRIL-Tg mice during CIA appears to be crucial, as arthritis induced by administration of anti-collagen antibodies developed similar in APRIL-Tg and control mice, thus demonstrating that the downstream effector pathways induced by anti-collagen antibodies remain intact in APRIL-Tg mice. This protective effect was specifically mediated by APRIL, as adenoviral delivery of APRIL decreased CIA in a therapeutic setting. CONCLUSIONS: Collectively, our data identify APRIL as a negative regulator of CIA by regulating autoantibody production. These findings are of important clinical relevance, as the therapeutic potential of transmembrane activator and cyclophilin ligand interactor-Fc (atacicept) is presently evaluated in clinical trials.