title: The TNF family member APRIL dampens collagen-induced arthritis.
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.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France.
authors.forename: Leticia
authors.initials: L
authors.lastname: Fernandez
authors.forename: Gabriela Franco
authors.initials: GF
authors.lastname: Salinas
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rocha
authors.forename: Carla E
authors.initials: CE
authors.lastname: Carvalho-Pinto
authors.forename: Nataliya
authors.initials: N
authors.lastname: Yeremenko
authors.forename: Laura
authors.initials: L
authors.lastname: Papon
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.forename: Bernard
authors.initials: B
authors.lastname: Combe
authors.forename: Jacques
authors.initials: J
authors.lastname: Morel
authors.forename: Dominique
authors.initials: D
authors.lastname: Baeten
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies; D015550:Cell Degranulation / Q000276:immunology; D018450:Disease Progression; D005786:Gene Expression Regulation; D006614:Hindlimb; D056724:Immunity, Humoral / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D013264:Stifle / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D007074:Immunoglobulin G; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13