Shedding of soluble glycoprotein VI is neither affected by animal-derived antibeta-2-glycoprotein 1 antibodies nor IgG fractions from patients with systemic lupus erythematosus.

: Antibeta-2-glycoprotein 1 (antiß2GP1) antibodies are associated with increased risk of thrombosis in patients with systemic lupus erythematosus (SLE). The specific effect(s) of antiß2GP1 antibodies on platelets are unclear. Platelet activation in response to antiplatelet antibodies has been shown to induce shedding of the ectodomain of the platelet collagen receptor, glycoprotein VI (GPVI), releasing soluble GPVI (sGPVI). The aim of this study was to therefore determine whether antiß2GP1 antibodies, and/or purified IgG fractions, from patients with SLE shed sGPVI from platelets. We determined sGPVI levels in platelet poor plasma from SLE patients with/without antiß2GP1 antibodies (n = 37), as well as in platelet-rich plasma from healthy donors treated with either SLE-derived IgG fractions containing antiß2GP1, animal-derived antiß2GP1, or isotype control antibodies. Levels of sGPVI were higher in three SLE-derived platelet poor plasma with antiß2GP1 antibodies (103.52 ±â€Š12.32 ng/ml) compared with those without (28.11 ±â€Š12.73 ng/ml). Neither SLE-derived IgG fractions containing antiß2GP1 antibodies, nor animal-derived antiß2GP1 antibodies induced significant shedding of sGPVI from healthy donor platelets compared with isotype controls. These results suggest that antiß2GP1 antibodies do not affect shedding of sGPVI, and therefore collagen-mediated platelet signalling pathways. The shedding activity in SLE patients may be due to factors other than antiß2GP1 antibodies, for example, metalloproteinases.

Further Investigations of the Effects of Anti-ß2GP1 Antibodies on Collagen-Induced Platelet Aggregation.

Anti-beta-2-glycoprotein 1 (anti-ß2GP1) antibodies are associated with increased thrombotic risk in patients with autoimmune disease. There is conflicting evidence on the effects of anti-ß2GP1 antibodies on platelets, with both enhanced and inhibited aggregation previously reported. However, previous studies did not include isotype antibodies to ensure the observed effects were due to anti-ß2GP1 antibodies. The aims of this study were to (1) investigate the effects of anti-ß2GP1 antibodies on collagen-induced platelet aggregation in parallel with negative control (buffer normal saline) and isotype control antibodies and (2) determine the lupus anticoagulant (LA) activity of anti-ß2GP1 antibodies used. Three animal-derived anti-human-ß2GP1 antibodies (1.25, 2.5, and 5 µg/mL) incubated with healthy platelet-rich plasma were activated by collagen (2.5 µg/mL). Each anti-ß2GP1 antibody demonstrated the inhibition of aggregation compared to negative control, but not to isotype control. No anti-ß2GP1 antibody demonstrated LA activity, suggesting they were probably nonpathological. This study highlights both negative and isotype control markers are important to validate the effects of anti-ß2GP1 antibodies. Assays to measure anti-domain I-ß2GP1 antibodies are recommended to be used in conjunction with functional measures to further investigate the effects of anti-ß2GP1 antibodies.

ß2GP1, Anti-ß2GP1 Antibodies and Platelets: Key Players in the Antiphospholipid Syndrome.

Anti-beta 2 glycoprotein 1 (anti-ß2GP1) antibodies are commonly found in patients with autoimmune diseases such as the antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Their presence is highly associated with increased risk of vascular thrombosis and/or recurrent pregnancy-related complications. Although they are a subtype of anti-phospholipid (APL) antibody, anti-ß2GP1 antibodies form complexes with ß2GP1 before binding to different receptors associated with anionic phospholipids on structures such as platelets and endothelial cells. ß2GP1 consists of five short consensus repeat termed "sushi" domains. It has three interchangeable conformations with a cryptic epitope at domain 1 within the molecule. Anti-ß2GP1 antibodies against this cryptic epitope are referred to as 'type A' antibodies, and have been suggested to be more strongly associated with both vascular and obstetric complications. In contrast, 'type B' antibodies, directed against other domains of ß2GP1, are more likely to be benign antibodies found in asymptomatic patients and healthy individuals. Although the interactions between anti-ß2GP1 antibodies, ß2GP1, and platelets have been investigated, the actual targeted metabolic pathway(s) and/or receptor(s) involved remain to be clearly elucidated. This review will discuss the current understanding of the interaction between anti-ß2GP1 antibodies and ß2GP1, with platelet receptors and associated signalling pathways.