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Published on: June 23, 2014
Anticyclic citrullinated protein antibodies are implicated in the development of cardiovascular disease in rheumatoid
Nuria Barbarroja1, Carlos Pérez-Sanchez2, Patricia Ruiz-Limon2
1From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.). nuria.barbarroja.exts@juntadeandalucia.es.
Insights
Autoantibodies against cyclic citrullinated peptides (anti-CCPs) drive cardiovascular disease in rheumatoid arthritis (RA) by promoting inflammation and oxidative stress in immune cells. Targeting anti-CCPs may prevent cardiovascular complications in RA patients.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is linked to increased cardiovascular disease (CVD) risk.
- Anticyclic citrullinated protein (CCP) autoantibodies are hallmarks of RA, but their direct role in CVD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the specific role of anti-CCP autoantibodies in the pro-oxidative, inflammatory, and proatherogenic profile of leukocytes in RA patients.
- To determine the impact of anti-CCPs on atherosclerosis markers and immune cell function.
Main Methods:
- Analysis of inflammatory and procoagulant factors, leukocyte activation, and oxidative stress markers in 75 RA patients and 31 healthy controls.
- Evaluation of carotid intima media thickness as an atherosclerosis marker.
- In vitro treatment of healthy leukocytes with purified anti-CCPs.
Main Results:
- High anti-CCP titers correlated with altered inflammatory markers, oxidative stress, and atherosclerosis in RA patients.
- Lymphocytes, monocytes, and neutrophils exhibited distinct pathogenic roles (inflammatory, prothrombotic/atherogenic, pro-oxidative, respectively).
- In vitro anti-CCP treatment replicated the pro-oxidative, inflammatory, and proatherogenic profile in leukocytes.
Conclusions:
- Anti-CCPs are critical mediators of inflammation and atherosclerosis in RA.
- The effects of anti-CCPs are cell-specific, influencing monocytes, neutrophils, and lymphocytes distinctly.
- Targeting anti-CCPs presents a promising strategy for preventing cardiovascular disease in RA.
Objective:
Previous studies have suggested a relationship between anticyclic citrullinated protein (CCP) levels and development of cardiovascular disease in rheumatoid arthritis (RA). However, a limited number of studies have demonstrated an involvement of anti-CCPs in those processes. This study was aimed to define the specific role of these auto-antibodies in the pro-oxidative, inflammatory, and proatherogenic profile observed in leukocytes from RA patients.
Approach And Results:
Seventy-five RA patients and 31 healthy donors were enrolled. Carotid intima media thickness was evaluated as atherosclerosis marker. Several procoagulant and inflammatory factors, leukocyte activation, and oxidative stress markers were analyzed in plasma and leukocyte subsets. Anti-CCPs were purified from plasma of RA patients, and in vitro treatment of healthy leukocytes was conducted. High titers of anti-CCPs were associated to altered expression of prothrombotic and inflammatory markers, high oxidative stress, and pathological carotid intima media thickness in RA patients. Notably, gene expression analysis showed that lymphocytes were major players in altered inflammatory profile, monocytes were responsible for the protrombotic and atherogenic status, and neutrophils mainly displayed a pro-oxidative feature. In vitro treatment with purified anti-CCPs fully recapitulated that pathogenic profile, promoting the activation of leukocytes.
Conclusions:
Anti-CCPs are key players in the inflammatory and proatherogenic status of RA patients. The effects are specific of the immune cell targeted, promoting overexpression of thrombotic, inflammatory, and pro-oxidative markers in monocytes; pro-oxidative status in neutrophils; and proinflammatory profile in lymphocytes. Targeting these autoantibodies would be an excellent strategy to prevent the development of cardiovascular disease in RA.
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