Altered β2‐glycoprotein I expression on microparticles in the presence of antiphospholipid antibodies

Abstract

Essentials β2 glycoprotein-I (β GPI) is a scavenger molecule that binds to microparticles (MPs). β GPI expression on MPs was measured in systemic lupus erythematosus (SLE) patients and controls. β GPI positive MPs is depressed among SLE patients positive for antiphospholipid antibodies. Complex formation between β GPI on MPs and patients own anti-β GPI may disturb MP clearance. Click to hear an ISTH Academy presentation on antiphospholipid antibody syndrome by Drs de Laat and Bertolaccini SUMMARY: Background Antiphospholipid antibodies (aPLs) together with thrombosis and/or pregnancy morbidities characterize the antiphospholipid syndrome. β -Glycoprotein I (β GPI), the most important antigen for aPLs, is a scavenger molecule that specifically binds to phosphatidylserine (PS) expressed on microparticles (MPs). Objectives To evaluate β GPI-expressing MPs in patients with systemic lupus erythematosus (SLE) stratified for aPL status, and in healthy controls. Patients/Methods We investigated 18 aPL/anti-β GPI-positive and 22 aPL-negative patients from a large SLE cohort and 19 healthy controls. β GPI-positive MPs and IgG-positive MPs were detected by flow cytometry. We measured plasma levels of β GPI, and performed in vitro experiments to investigate the binding properties of β GPI on MPs. Results SLE patients had more MPs and IgG-positive MPs than controls. We observed fewer β GPI-positive MPs in aPL/anti-β GPI-positive patients than in aPL/anti-β GPI-negative patients and controls (approximately two-fold). β GPI levels in plasma did not differ with aPL/anti-β GPI status in patients; however, controls had slightly higher levels of β GPI than aPL/anti-β GPI-positive patients. In vitro experiments revealed that β GPI preferentially binds to PS-positive MPs. Conclusions Despite abundant total MPs and MPs in immune complexes, β GPI-positive MPs were depleted in SLE patients, and the levels were especially low in aPL/anti-β GPI-positive patients. We suggest that anti-β GPI antibodies bind to β GPI-PS complexes expressed on MPs. Consequent loss of β GPI-PS expression on MPs may impair scavenging and contribute to the accumulation of circulating PS-negative MPs, a possible source of autoantigens. Autoantibodies delaying MP clearance may thus constitute an important mechanism underlying autoimmunity.

COVID-19 Related Coagulopathy: A Distinct Entity?

“…The most important antigen for aPLs is b2-glycoprotein-I (b2GPI), a scavenger molecule, which has a specific binding site for the negatively-charged phospholipid phosphatidylserine (PS). Under physiological conditions, the binding to PS, b2-GPI facilitates clearance of particles and apoptotic bodies from the circulation enabling the maintenance of vascular homeostasis [119]. b2GPI in plasma is normally present as a circular protein; in the case of endothelial cell activation and subsequent remodeling, the exposure of PS at the outer leaflet of the plasma membrane induces conformational changes of b2GPI that "opens up" to a J shape, thus exposing neo epitopes and antibody-binding sites [119].…”

“…Under physiological conditions, the binding to PS, b2-GPI facilitates clearance of particles and apoptotic bodies from the circulation enabling the maintenance of vascular homeostasis [119]. b2GPI in plasma is normally present as a circular protein; in the case of endothelial cell activation and subsequent remodeling, the exposure of PS at the outer leaflet of the plasma membrane induces conformational changes of b2GPI that "opens up" to a J shape, thus exposing neo epitopes and antibody-binding sites [119]. Membrane remodeling could also contribute to the alteration of natural anticoagulant shield represented by Annexin V, a protein with high PS affinity.…”

Microparticles as autoantigens in systemic lupus erythematosus

“…Recent studies indicate that exposure of PS on MPs is not invariable and that, in fact, the majority of the MPs measured in SLE blood are PS negative . The binding of β 2 glycoprotein‐I (β 2 GPI), a scavenger protein which interacts with PS, or autoantibodies could interfere with FCM assays of MPs based on staining with annexin V or lactadherin as a criterion for MP . An alternative approach to identify particles takes advantage of the presence of nucleic acids by labelling with SYTO 13 dye …”

“…40,55 The binding of β 2 glycoprotein-I (β 2 GPI), a scavenger protein which interacts with PS, or autoantibodies could interfere with FCM assays of MPs based on staining with annexin V or lactadherin as a criterion for MP. 56 An alternative approach to identify particles takes advantage of the presence of nucleic acids by labelling with SYTO 13 dye. 21 Microparticles in the blood of SLE patients display IgG and IgM on their surface, indicating their role as immune complexes.…”

The antiphospholipid syndrome – often overlooked cause of vascular occlusions?

“…In vitro studies demonstrate that that endothelial MPs can be released after stimulation by anti-b 2 GPI antibodies [171]. We recently noted that the subset of SLE patients that are positive for aPL/anti-b 2 GPI antibodies had, despite high numbers of total circulating MPs, lower concentrations of b 2 GPIexpressing MPs as compared both to aPL negative SLE patients and healthy controls [172]. These results imply that PS-b 2 GPI complexes, known to be upregulated in SLE MPs [173], could be hidden from the immune system on MP surfaces by the binding anti-b 2 GPI.…”