Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The TNF-Ligand APRIL Can Control CIA by Regulating Antibody-Production and Stimulating Anti-Inflammatory IL-10 Producing B Cells.
Fernandez5, Leticia, Rocha5, Cecilia, Carvalho-Pinto6, Carla, Medema2, Jan Paul, Combe3, Bernard G., Baeten1, Dominique, Morel4, Jacques
Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Academic Medical Center, University of Amsterdam
Hopital Lapeyronie, Montpellier, France
Institut de Génétique Moléculaire de Montpellier
Universidade Federal Fluminense/UFF Niteroi
TNF family members are frequently implicated in inflammation and autoimmunity. Increased levels of the TNF-ligand APRIL (A Proliferation Inducing Ligand) were found in synovial fluid and serum of patients with inflammatory arthritis pointing to a pro-inflammatory role of APRIL. APRIL can bind to BCMA and TACI, two receptors of the TNF family, which can also bind the B cell activating factor (BAFF). In the collagen-induced arthritis (CIA), administration of TACI-Ig was found to prevent disease progression and to lower disease scores, compared with controls. As TACI binds both APRIL and BAFF, it remained to be determined, whether this effect was due to the capacity of TACI to block just one or both ligands.
CIA was induced in APRIL-transgenic (Tg) DBA/1 mice and littermates. Severity of disease was scored for each paw using a scale 04. In addition, mice were analyzed for histological signs of arthritis. Anti-collagen antibody titers were determined by ELISA. Lymphocyte populations in draining lymph nodes, spleen and peritoneum were analyzed by FACS. In another experimental setting mice were exposed to the collagen antibodies induced arthritis (CAIA). In addition, we employed the contact hypersensitivity model (CHS). For this, APRIL Tg and control mice were sensitized and challenged at the ear with oxazolone. Ear swelling and histological alterations were monitored.
APRIL Tg (n=14) mice displayed in contrast to littermates (n=16) a lower disease score (maximal score at day 38 after first immunization: 4.9+/-0.9 versus 1.0+/-0.5), a lower incidence of arthritis (p<0.01), and also produced less collagen specific antibodies (p<0.001, at day 41 after first immunization). Joints of littermates had higher IgG levels. One of the main effector mechanisms of anti-collagen antibodies in arthritis is the activiation of mast cells by immune-complexes. Indeed we detected decreased number of degranulating, thus activated, mast cells in the joints of Tg mice. To confirm that the decreased IgG levels developed in the CIA model in APRIL Tg mice are directly linked to the less severe disease development, we employed the model of CAIA. In fact, disease development in CAIA was similar in APRIL Tg and control mice. In addition, we detected a significantly increased IL-10 production of peritoneal B cells in APRIL Tg mice in the CIA model (n=8 for each group, p<0.05). Evidence is accumulating that IL-10 producing B cells can regulate autoimmune diseases including arthritis. The regulatory role of APRIL by modulating activity of mast cells and IL-10-producing B was confirmed in the CHS model.
Our results show that APRIL can control inflammation in two disease models, i.e. arthritis and CHS. This suggests a therapeutic potential of APRIL agonists to down-regulate inflammatory diseases such as rheumatoid arthritis.
To cite this abstract, please use the following information:
Fernandez, Leticia, Rocha, Cecilia, Carvalho-Pinto, Carla, Medema, Jan Paul, Combe, Bernard G., Baeten, Dominique, et al; The TNF-Ligand APRIL Can Control CIA by Regulating Antibody-Production and Stimulating Anti-Inflammatory IL-10 Producing B Cells. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1732