Peptidylarginine Deiminase 4 Contributes to Tumor Necrosis Factor alpha-Induced Inflammatory Arthritis ARTHRITIS & RHEUMATOLOGY Shelef, M. A., Sokolove, J., Lahey, L. J., Wagner, C. A., Sackmann, E. K., Warner, T. F., Wang, Y., Beebe, D. J., Robinson, W. H., Huttenlocher, A. 2014; 66 (6): 1482-1491


Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor a (TNFa), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Further, in other settings, TNFa has been shown to induce PAD4 activity and modulate antibody formation. We undertook this study to investigate whether TNFa and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis.To determine whether TNFa and PAD4 augment autoantibody production and inflammatory arthritis, we first used a multiplex assay to determine whether mice with chronic inflammatory arthritis due to overexpression of TNFa develop autoantibodies against native and citrullinated antigens. With TNF(+) PAD4(+/+) and TNF(+) PAD4(-/-) mice, we then compared serum autoantibody levels by multiplex array, lymphocyte activation by flow cytometry, total serum IgG levels by enzyme-linked immunosorbent assay, arthritis by clinical and histologic scoring, and systemic inflammation using microfluidic devices.TNFa-overexpressing mice had increased levels of autoantibodies reactive against native and citrullinated antigens. PAD4(-/-) mice with TNFa-induced arthritis had lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to PAD4(+/+) TNFa-overexpressing mice.PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNFa.

View details for DOI 10.1002/art.38393

View details for Web of Science ID 000337366200010

View details for PubMedCentralID PMC4148484