Leticia Fernandez, Gabriela Franco Salinas, Cecilia Rocha, Carla E Carvalho-Pinto, Nataliya Yeremenko, Laura Papon, Jan Paul Medema, Bernard Combe, Jacques Morel, Dominique Baeten, Michael Hahne
Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France.
Annals of the rheumatic diseases 2013 AugThe 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. To evaluate the role of APRIL on collagen-induced arthritis (CIA). 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. 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. 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.
Leticia Fernandez, Gabriela Franco Salinas, Cecilia Rocha, Carla E Carvalho-Pinto, Nataliya Yeremenko, Laura Papon, Jan Paul Medema, Bernard Combe, Jacques Morel, Dominique Baeten, Michael Hahne. The TNF family member APRIL dampens collagen-induced arthritis. Annals of the rheumatic diseases. 2013 Aug;72(8):1367-74
PMID: 23178293
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