Background/Purpose:

Anti-cyclic citrulinated protein antibodies (anti-CCP) are the most specific autoantibody markers in rheumatoid arthritis (RA) patients. However no previous studies have evaluated their role in the atherogenic process and cardiovascular (CV) risk in RA. The aim of this study was to investigate the role of anti-CCP antibodies in the induction of a pro-oxidative and inflammatory status in white blood cells, and their relationship with chronic inflammation and early atherogenesis in RA.

Methods:

Fifty three RA patients and 31 healthy donors were included. Tissue factor (TF), protease activated receptors (PARs) expression, peroxides and peroxinitrites levels, and mitochondrial membrane potential (MMP), were analyzed by flow cytometry in white blood cells; glutathione peroxidase activity (GPx) was evaluated in cell lysates. Atherosclerosis/CV risk markers were also evaluated. RT-PCR was performed to elucidate the cellular origin of plasma inflammatory molecules. The carotid-intimate media thickness (CIMT) was measured as a surrogate marker of atherosclerosis. In parallel in vitro studies, isolated monocytes, lymphocytes, or neutrophils were incubated with non-specific human IgG or with purified anti-CCP antibodies.

Results:

Increased expression of TF and PAR2 was found in neutrophils from RA patients, with higher plasma levels of VEGF, tPA, MCP1, MIP1α, TNFα , IL-2, -6, -8, -17A and -23. RA monocytes and neutrophils had higher peroxides and peroxynitrite levels, more depolarised mitochondria and lower GPx activity. Significantly higher levels of mRNA MCP-1, IL-1ß, -6, -8, and TF were found in monocytes, pointing to the main cell sources of inflammatory molecules in RA. Notably, augmented titres of anti-CCPs were not only directly related to increased expression of protrombotic, pro-inflammatory and oxidative stress markers, but also to increased CIMT. Moreover, in vitro treatment of with anti-CCP increased peroxide production in monocytes and neutrophils, as well as on the percentage of cells with increased MMP. Anti-CCP treatment in monocytes induced elevated cell surface TF expression and increased mRNA levels of MCP-1, IL-1ß, -6, and -8 while in lymphocytes provoked increased IL-1ß, -2, -6, -8, TNFα, and VEGF mRNA expression levels. No changes in cytokine mRNAs were found in neutrophils.

Conclusion:

1) Anti-CCP antibodies directly induce inflammation and oxidative stress in RA patients. 2) Monocytes and lymphocytes are key mediators of the anti-CCP-induced inflammatory state by expressing particular cytokines, which may constitute promising therapeutical targets for the prevention of atherosclerosis and CVD in RA patients. Support: JA0246/2009, P08-CVI-04234, PS09/01809, Spanish Foundation of Rheumatology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-cyclic-citrullinated-protein-antibodies-induce-inflammation-and-oxidative-stress-in-white-blood-cells-of-rheumatoid-arthritis-patients/