Increased Levels of Circulating Microparticles in Primary Sjögren's Syndrome, Systemic Lupus Erythematosus and Rheumatoid Arthritis and Relation with Disease Activity

Jérémie Sellam; Valérie Proulle; Astrid Jüngel; Marc Ittah; Corinne Miceli Richard; Jacques-Eric Gottenberg; Florence Toti; Joelle Benessiano; Steffen Gay; Jean-Marie Freyssinet; Xavier Mariette

Disclosures

Arthritis Res Ther. 2009;11(5):R156 

In This Article

Abstract and Introduction

Abstract

Introduction Cell stimulation leads to the shedding of phosphatidylserine (PS)-rich microparticles (MPs). Because autoimmune diseases (AIDs) are characterized by cell activation, we investigated level of circulating MPs as a possible biomarker in primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Methods We measured plasma levels of total, platelet and leukocyte MPs by prothrombinase capture assay and flow cytometry in 43 patients with pSS, 20 with SLE and 24 with RA and in 44 healthy controls (HCs). Secretory phospholipase A2 (sPLA2) activity was assessed by fluorometry. Soluble CD40 ligand (sCD40L) and soluble P-selectin (sCD62P), reflecting platelet activation, were measured by ELISA.
Results Patients with pSS showed increased plasma level of total MPs (mean ± SEM 8.49 ± 1.14 nM PS equivalent (Eq), P < 0.0001), as did patients with RA (7.23 ± 1.05 n PS Eq, P = 0.004) and SLE (7.3 ± 1.25 nM PS Eq, P = 0.0004), as compared with HCs (4.13 ± 0.2 nM PS Eq). Patients with AIDs all showed increased level of platelet MPs (P < 0.0001), but only those with pSS showed increased level of leukocyte MPs (P < 0.0001). Results by capture assay and flow cytometry were correlated. In patients with high disease activity according to extra-glandular complications (pSS), DAS28 (RA) or SLEDAI (SLE) compared with low-activity patients, the MP level was only slightly increased in comparison with those having a low disease activity. Platelet MP level was inversely correlated with anti-DNA antibody level in SLE (r = −0.65; P = 0.003) and serum β2 microglobulin level in pSS (r = −0.37; P < 0.03). The levels of total and platelet MPs were inversely correlated with sPLA2 activity (r = −0.37, P = 0.0007; r = −0.36, P = 0.002, respectively). sCD40L and sCD62P concentrations were significantly higher in pSS than in HC (P ≤ 0.006).
Conclusions Plasma MP level is elevated in pSS, as well as in SLE and RA, and could be used as a biomarker reflecting systemic cell activation. Level of leukocyte-derived MPs is increased in pSS only. The MP level is low in case of more severe AID, probably because of high secretory phospholipase A2 (sPLA2) activity, which leads to consumption of MPs. Increase of platelet-derived MPs, sCD40L and sCD62P, highlights platelet activation in pSS.

Introduction

A general feature of activated cells is their ability to shed fragments from their plasma membrane. These fragments represent a heterogeneous population of small membrane-coated vesicles with diameter of 0.1 to 1 μm, termed microparticles (MPs).[1] MPs belong to the family of circulating vesicles, including apoptotic bodies and exosomes, and can be detected in all biological fluids, especially plasma. MPs have to be differentiated from exosomes and from apoptotic bodies. Exosomes are smaller than MPs and not generated from the plasma membrane but arise from the inside of cells in multivesicular bodies, and are mostly devoid of phosphatidylserine. Apoptotic bodies are formed during the final stages of programmed cell death and are generally larger in diameter and volume than MPs.[1] The outer layer of the bilayer membrane of MPs contains aminophospholipids, mainly anionic phosphatidylserine (PS), which is procoagulant and detectable by its binding to annexin V. MPs also contain protein markers specific to the parental cell types, which allows for the detection of the cellular origin of MPs.[2] These subcellular structures can transfer bioactive molecules from parental to target cells, thus allowing for regulation and amplification of several biological mechanisms such as apoptosis or cell activation (inflammatory or autoimmune responses, cell proliferation or coagulation). Hence, MPs could reflect parental cell stimulation and be involved in target cell stimulation.[2]

Because of these properties, MPs have been associated with systemic inflammation or excessive risk of thrombosis in various diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), vasculitis and antiphospholipid syndrome (APLS).

Similar to RA and SLE, primary Sjögren's syndrome (pSS) is an autoimmune disease (AID) characterized by leukocyte activation. Platelet activation has been reported in SLE and RA, but this feature, illustrated by increased level of plasma soluble CD40 ligand (sCD40L), has been noted only once in pSS.[3,4]

We aimed to assess the plasma level of annexin V-positive (e.g., PS-positive or total), leukocyte and platelet circulating MPs in pSS and other AIDs (SLE and RA) as a biomarker of cell activation.

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