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The TNF family member APRIL dampens collagen-induced arthritis
  1. Leticia Fernandez1,2,3,
  2. Gabriela Franco Salinas4,
  3. Cecilia Rocha1,2,3,5,
  4. Carla E Carvalho-Pinto6,
  5. Nataliya Yeremenko4,
  6. Laura Papon1,2,3,
  7. Jan Paul Medema4,
  8. Bernard Combe1,2,7,
  9. Jacques Morel1,2,7,
  10. Dominique Baeten8,
  11. Michael Hahne1,2,3,4
  1. 1Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France
  2. 2Université Montpellier 1, Montpellier, France
  3. 3Université Montpellier 2, Montpellier, France
  4. 4Academic Medical Center, Division of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands
  5. 5Institut Curie CNRS, UMR 3306/INSERM, Orsay, France
  6. 6Departamento de Imunobiologia, Laboratorio de Patologia Experimental, Universidade Federal Fluminense, Rio de Janeiro, Brazil
  7. 7Service d'Immuno-Rhumatologie, CHU Lapeyronie, Montpellier, France
  8. 8Academic Medical Center, Division of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr Michael Hahne, Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, 1919 Route de Mende, Montpellier Cedex 5, 34293, France; michael.hahne{at}igmm.cnrs.fr

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.

  • Arthritis
  • B cells
  • Cytokines

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