The TNF superfamily member a proliferation-inducing ligand (APRIL) “suppresses rather than promotes immune-mediated inflammatory diseases,” write Michael Hahne and colleagues in Annals of the Rheumatic Diseases. This finding comes as a surprise, as elevated levels of APRIL have been previously detected in patients with inflammatory autoimmune diseases such as rheumatoid arthritis, and the agents belimumab (targeting BAFF, a cytokine closely related to APRIL) and atacicept (targeting both BAFF and APRIL) are in clinical trials in patients with autoimmune diseases. “APRIL's role in B-cell malignancies is established, but its role in autoimmunity is less clear and rather controversial,” says Hahne.
The researchers induced collagen-induced arthritis (CIA) in APRIL transgenic (APRIL-Tg) mice backcrossed with DBA/1 mice and in littermate controls. Postmortem histological analyses of joint sections showed that overall incidence and severity of disease was lower in APRIL-Tg mice compared with controls. In addition, titres of anti-collagen type II (anti-CII) IgG antibodies were significantly lower in the former, as were numbers of mast cells in the joints. In a collagen antibody-induced model of arthritis, APRIL-Tg mice developed disease similarly to control mice following injection with a cocktail of anti-CII antibodies. These data suggest that APRIL negatively regulates anti-CII antibody production, but is not involved in the downstream effector mechanisms. In addition, T-cell-dependent humoral responses were reduced in APRIL-Tg mice and this reduction was associated with lower percentages of antigen-specific memory B cells in these mice. Furthermore, adenoviral delivery of APRIL into CII-immunized DBA/1 mice led to reduced severity of CIA compared with control mice.
Altogether, these findings indicate that “APRIL dampens CIA by controlling the generation of anti-collagen antibodies,” comments Hahne. “Our findings suggest a therapeutic potential for APRIL agonists in inflammatory diseases,” he concludes.
ORIGINAL RESEARCH PAPER
Fernandez, L. et al. The TNF family member APRIL dampens collagen-induced arthritis. Ann. Rheum. Dis. doi:10.1136/annrheumdis-2012-202382
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Ozerlat, I. APRIL suppresses CIA in mice. Nat Rev Rheumatol 9, 4 (2013). https://doi.org/10.1038/nrrheum.2012.220
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DOI: https://doi.org/10.1038/nrrheum.2012.220