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

Habets KL, Trouw LA, Levarht EW, Korporaal SJ, Habets PA, de Groot P, Huizinga TW, Toes RE - Arthritis Res. Ther. (2015)

Bottom Line: Furthermore, levels of P-selectin expression and sCD40L release correlated with high ACPA titres.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. k.l.l.habets@lumc.nl.

ABSTRACT

Introduction: 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.

No MeSH data available.


Related in: MedlinePlus

Platelet phenotype correlates with disease activity. The expression of P-selectin (CD62P) was determined on isolated platelets from patients with rheumatoid arthritis (RA) and correlated with Disease Activity Score in 44 joints (DAS44) (a), C-reactive protein (CRP) levels (b) and anti-citrullinated protein antibodies (ACPA) (c). Platelet (PLT) numbers correlated with DAS44 score (d), CRP levels (e) and ACPA levels (f). IgG immunoglobulin G
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Fig4: Platelet phenotype correlates with disease activity. The expression of P-selectin (CD62P) was determined on isolated platelets from patients with rheumatoid arthritis (RA) and correlated with Disease Activity Score in 44 joints (DAS44) (a), C-reactive protein (CRP) levels (b) and anti-citrullinated protein antibodies (ACPA) (c). Platelet (PLT) numbers correlated with DAS44 score (d), CRP levels (e) and ACPA levels (f). IgG immunoglobulin G

Mentions: In addition to increased P-selectin expression and sCD40L release, platelets transform from a normal discoid shape into a more spherical shape with protrusions of pseudopods during activation. This is visualised as increased MPV and enhanced PDW. As plasma from patients with RA is capable of inducing platelet activation, we next compared freshly isolated platelets from patients with RA with those of healthy controls. We observed a higher basal activation status of platelets isolated from patients with RA, as indicated by increased MPV, PDW, platelet numbers and expression of P-selectin (Table 3). Because there is variation in total IgG levels between patients, we corrected for the presence of IgG by isolating ACPA and calculating the percentage of ACPA to total IgG. The expression of P-selectin on platelets from patients with RA correlated with DAS44 (Pearson’s r=0.4708, P<0.05), C-reactive protein (CRP) levels (Pearson’s r=0.4239, P<0.05) and the percentage of ACPA (Pearson’s r=0.5497, P<0.01) (Fig. 4a–c). In addition, the number of platelets also correlated with DAS44 (Pearson’s r=0.5150, P<0.01), CRP (Pearson’s r=0.4240, P<0.05) and percentage of ACPA (Pearson’s r=0.6183, P<0.001) (Fig. 4d–f). Together, these findings indicate enhanced platelet activation in patients with RA which correlates with disease activity and the presence of ACPA.Table 3


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

Habets KL, Trouw LA, Levarht EW, Korporaal SJ, Habets PA, de Groot P, Huizinga TW, Toes RE - Arthritis Res. Ther. (2015)

Platelet phenotype correlates with disease activity. The expression of P-selectin (CD62P) was determined on isolated platelets from patients with rheumatoid arthritis (RA) and correlated with Disease Activity Score in 44 joints (DAS44) (a), C-reactive protein (CRP) levels (b) and anti-citrullinated protein antibodies (ACPA) (c). Platelet (PLT) numbers correlated with DAS44 score (d), CRP levels (e) and ACPA levels (f). IgG immunoglobulin G
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4548712&req=5

Fig4: Platelet phenotype correlates with disease activity. The expression of P-selectin (CD62P) was determined on isolated platelets from patients with rheumatoid arthritis (RA) and correlated with Disease Activity Score in 44 joints (DAS44) (a), C-reactive protein (CRP) levels (b) and anti-citrullinated protein antibodies (ACPA) (c). Platelet (PLT) numbers correlated with DAS44 score (d), CRP levels (e) and ACPA levels (f). IgG immunoglobulin G
Mentions: In addition to increased P-selectin expression and sCD40L release, platelets transform from a normal discoid shape into a more spherical shape with protrusions of pseudopods during activation. This is visualised as increased MPV and enhanced PDW. As plasma from patients with RA is capable of inducing platelet activation, we next compared freshly isolated platelets from patients with RA with those of healthy controls. We observed a higher basal activation status of platelets isolated from patients with RA, as indicated by increased MPV, PDW, platelet numbers and expression of P-selectin (Table 3). Because there is variation in total IgG levels between patients, we corrected for the presence of IgG by isolating ACPA and calculating the percentage of ACPA to total IgG. The expression of P-selectin on platelets from patients with RA correlated with DAS44 (Pearson’s r=0.4708, P<0.05), C-reactive protein (CRP) levels (Pearson’s r=0.4239, P<0.05) and the percentage of ACPA (Pearson’s r=0.5497, P<0.01) (Fig. 4a–c). In addition, the number of platelets also correlated with DAS44 (Pearson’s r=0.5150, P<0.01), CRP (Pearson’s r=0.4240, P<0.05) and percentage of ACPA (Pearson’s r=0.6183, P<0.001) (Fig. 4d–f). Together, these findings indicate enhanced platelet activation in patients with RA which correlates with disease activity and the presence of ACPA.Table 3

Bottom Line: Furthermore, levels of P-selectin expression and sCD40L release correlated with high ACPA titres.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, Leiden University Medical Centre, C1-R, PO Box 9600, 2300, RC, Leiden, the Netherlands. k.l.l.habets@lumc.nl.

ABSTRACT

Introduction: 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.

No MeSH data available.


Related in: MedlinePlus