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Immunology - Rheumatology

Enhanced Th17-Cell Responses Render CCR2-Deficient Mice More Susceptible for Autoimmune Arthritis
Published: Tuesday, October 04, 2011
Author: Rishi R. Rampersad et al.

by Rishi R. Rampersad, Teresa K. Tarrant, Christopher T. Vallanat, Tatiana Quintero-Matthews, Michael F. Weeks, Denise A. Esserman, Jennifer Clark, Franco Di Padova, Dhavalkumar D. Patel, Alan M. Fong, Peng Liu

CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2-/- mice compared to WT controls (p?=?0.017), whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1ß were approximately 2–6-fold elevated in the serum and 22–28-fold increased in the arthritic joints in CCR2-/- mice compared to WT mice (p?=?0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1ß, respectively, in the serum and p?=?0.009, 0.02, and 0.02 in the joints). Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2-/- mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2-/- mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2-/- mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.