Background/Purpose:

Various citrullinated proteins and anti-citrullinated protein antibodies (ACPA) are increased in patients with rheumatoid arthritis (RA). ACPA have high specificity for RA, and are the predictive factor of joint radiographic progression. It is considered that citrullinated proteins and ACPA may contribute to the development and progression of RA. However, the relevance in the course of arthritis development remains uncertain. In this study, we explored the pathogenic relevance of citrullinated proteins and ACPA in peptide glucose-6-phosphate isomerase (pGPI)-induced arthritis (pGIA) mice.

Methods: 1) The titers of anti-pGPI antibodies and ACPA in sera from pGIA mice were analyzed by ELISA.

2) Citrullinated protein expressions in joints, skins and lungs were examined by immunohistochemistry. The protein expressions in sera were examined by Western blot analysis.

3) Cl-amidine, the inhibitor of protein arginine deiminase (PAD), was injected intraperitoneally to pGIA mice. Clinical score, the titers of ACPA, citrullinated protein expressions, T cell response and the level of proinflammatory cytokines in sera were assessed.

Results: 1) The titers of anti-pGPI antibodies and ACPA in sera from pGIA mice were elevated from day14, and were significantly higher than those from control mice.

2) In immunohistochemistry, citrullinated proteins were detected in joints on day 14 and in skins on day 7 from pGIA mice, whereas not detected from control mice. In joints, citrullinated proteins were expressed in areas of synovial hyperplasia. In skins, these proteins were expressed in infiltrating inflammatory cells surrounding injected areas in subcutaneous tissues. In lungs, citrullinated proteins were not detected from pGIA or control mice. In sera, citrullinated protein was detected at approximately 120 kD on day 14 from pGIA mice, and significantly increased than control mice.

3) Cl-amidine treatment significantly decreased clinical and synovitis score. The titers of anti-pGPI antibodies and ACPA in sera were not significantly different, but tended to lower by Cl-amidine treatment. Citrullinated proteins in joints, skins and sera from treated mice were clearly decreased. The level of IL-6 in sera on day 14 was significantly decreased in Cl-amidine injected mice as compared with control mice, but pGPI-specific CD4+ T cell response was not changed.

Conclusion:

Citrullinated proteins and ACPA were increased in pGIA mice. Additionally, the inhibition of PAD decreased the expression of citrullinated proteins and the production of proinflammatory cytokines, resulting in the suppression of arthritis. These results suggested that PAD was involved in the pathogenesis and maintenance of autoimmune arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/crucial-involvement-of-citrullinated-proteins-and-acpa-in-the-development-of-peptide-glucose-6-phosphate-isomerase-induced-arthritis/