Anti-citrullinated protein antibodies contribute to platelet activation in rheumatoid arthritis.
BACKGROUND
Although 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).


METHODS
Platelets from healthy controls were incubated in the presence of plasma of patients with RA or age- and sex-matched healthy controls and plasma from ACPA(neg) or ACPA(pos) patients or in the presence of plate-bound ACPA. Characteristics of platelets isolated from patients with RA were correlated to disease activity.


RESULTS
Platelets 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 ACPA(pos) plasma versus ACPA(neg) 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.


CONCLUSIONS
We 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.
Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. k.l.l.habets@lumc.nl.
Kim L L
KL
Habets
Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. l.a.trouw@lumc.nl.
Leendert A
LA
Trouw
Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. e.w.n.levarht@lumc.nl.
E W Nivine
EW
Levarht
Department of Clinical Chemistry and Haematology, University Medical Centre, Utrecht, the Netherlands. j.a.korporaal@umcutrecht.nl.|Division of Biopharmaceutics, Leiden Amsterdam Centre for Drug Research, University of Leiden, Leiden, the Netherlands. j.a.korporaal@umcutrecht.nl.
Suzanne J A
SJ
Korporaal
Knowledge Centre Forensic Psychiatric Care, Rekem Psychiatric Hospital, Rekem, Belgium. petra.habets@opzcrekem.be.
Petra A M
PA
Habets
Department of Clinical Chemistry and Haematology, University Medical Centre, Utrecht, the Netherlands. ph.g.degroot@umcutrecht.nl.
Philip
P
de Groot
Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. t.w.j.huizinga@lumc.nl.
Tom W J
TW
Huizinga
Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. r.e.m.toes@lumc.nl.
René E M
RE
Toes
D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood / Q000276:immunology / Q000378:metabolism; D002956:Citrulline / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood / Q000276:immunology / Q000378:metabolism; D010456:Peptides, Cyclic / Q000276:immunology*; D015539:Platelet Activation / Q000276:immunology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D019007:P-Selectin; D010456:Peptides, Cyclic; D023201:CD40 Ligand; D002956:Citrulline