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Abstract
IntroductionAlthough the role of platelets in rheumatoid arthritis (RA) is relatively unexplored, recent studies point towards a contribution of platelets in arthritis. We set out to determine platelet phenotype in RA and studied whether this could be influenced by the presence of anti-citrullinated protein antibodies (ACPA).MethodsPlatelets from healthy controls were incubated in the presence of plasma of patients with RA or age- and sex-matched healthy controls and plasma from ACPAneg or ACPApos patients or in the presence of plate-bound ACPA. Characteristics of platelets isolated from patients with RA were correlated to disease activity.ResultsPlatelets isolated from healthy controls displayed markers of platelet activation in the presence of plasma derived from RA patients, as determined by P-selectin expression, formation of aggregates and secretion of soluble CD40 ligand (sCD40L). Furthermore, levels of P-selectin expression and sCD40L release correlated with high ACPA titres. In accordance with these findings, enhanced platelet activation was observed after incubation with ACPApos plasma versus ACPAneg plasma. Pre-incubation of platelets with blocking antibodies directed against low-affinity immunoglobulin G receptor (FcγRIIa) completely inhibited the ACPA-mediated activation. In addition, expression of P-selectin measured as number of platelets correlated with Disease Activity Score in 44 joints, C-reactive protein level, ACPA status and ACPA level.ConclusionsWe show for the first time that ACPA can mediate an FcγRIIa-dependent activation of platelets. As ACPA can be detected several years before RA disease onset and activated platelets contribute to vascular permeability, these data implicate a possible role for ACPA-mediated activation of platelets in arthritis onset.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0665-7) contains supplementary material, which is available to authorized users.
Highlights
The role of platelets in rheumatoid arthritis (RA) is relatively unexplored, recent studies point towards a contribution of platelets in arthritis
Because platelets express the low-affinity immunoglobulin G (IgG) receptor (FcγRIIa), and because of the importance of autoantibodies on the thrombotic risk in systemic lupus erythematosus, we propose a role for anti-citrullinated protein antibodies (ACPA) in the activation of platelets [22]
Linear regression analysis indicated that platelet characteristics such as P-selectin expression, aggregate formation and the production of soluble CD40 ligand (sCD40L) induced by a given plasma sample predicted group in the plasma donor (Table 2)
Summary
The role of platelets in rheumatoid arthritis (RA) is relatively unexplored, recent studies point towards a contribution of platelets in arthritis. Because platelets express the low-affinity immunoglobulin G (IgG) receptor (FcγRIIa), and because of the importance of autoantibodies on the thrombotic risk in systemic lupus erythematosus, we propose a role for anti-citrullinated protein antibodies (ACPA) in the activation of platelets [22]. These autoantibodies recognise a group of autoantigens which are post-translationally modified by peptidyl arginine deaminase (PAD) enzymes, leading to the conversion of an arginine to citrulline. Because of the prominent role of platelets during endothelial dysfunction and vascular permeability that may lead to enhanced vascular leakage in the joints, this interplay could potentially contribute to the increased cardiovascular risk and RA disease burden observed in ACPApos patients
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