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: 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
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 72 Issue 8 Pg. 1367-74 (Aug 2013) ISSN: 1468-2060 [Electronic] England
• PMID: 23178293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigen-Antibody Complex
• Autoantibodies
• Immunoglobulin G
• Tnfsf13 protein, mouse
• Tumor Necrosis Factor Ligand Superfamily Member 13

Topics

• Animals
• Antigen-Antibody Complex (metabolism)
• Arthritis, Experimental (genetics, immunology, pathology)
• Autoantibodies
• Cell Degranulation (immunology)
• Disease Progression
• Gene Expression Regulation
• Hindlimb
• Immunity, Humoral (genetics, immunology)
• Immunoglobulin G (blood)
• Mast Cells (immunology, pathology)
• Mice
• Mice, Inbred DBA
• Mice, Transgenic
• Stifle (immunology, metabolism, pathology)
• T-Lymphocytes (immunology, metabolism)
• Tumor Necrosis Factor Ligand Superfamily Member 13 (genetics, metabolism)