Mechanisms of Cellular Activation in the Antiphospholipid Syndrome

Abstract

It is long known that antiphospholipid antibodies (aPL) induce proinflammatory and procoagulant cellular responses. The underlying signal transduction has been a major focus of research and is the topic of this review. An amazingly heterogeneous panel of signaling pathways has been described and it turns out that at least some of this heterogeneity can be explained by effects of distinct aPL species. On the one hand, there are antibodies against β2-glycoprotein I (β2GPI) which appear to exert their cellular effects only as a complex of β2GPI/anti-β2GPI. Their major targets are low-density lipoprotein-receptor related protein 8 (LRP8), annexin A2 (ANXA2), toll-like receptor 4 (TLR4), and possibly TLR2. The other relevant aPL species are antibodies against cardiolipin which are internalized into endosomes and induce cellular responses via activation of endosomal NADPH-oxidase. Their cell surface target is still unknown. Another important issue relates to the role of complement. It has been shown in vivo that certain pathogenic effects of aPL depend on complement activation, but the exact interplay with the signaling pathways described earlier needs to be elucidated. Thus, while there has been tremendous progress over the past decade, many open questions remain to be answered.

Antiphospholipid antibody‐induced cellular responses depend on epitope specificity : implications for treatment of antiphospholipid syndrome

“…However, this observation is in line with previous work on this topic showing that gene induction by anti‐β 2 GPI in monocytes is not immediate . Our data confirm a role of TLR2 and TLR4 in signal transduction of anti‐β 2 GPI . However, signal intensity was only reduced, and not abolished, by these two TLRs.…”

“…As TLR2 and TLR4 have been implicated in signaling of aPLs , we analyzed monocytes from TLR2 −/− and TLR4 −/− mice (Fig. G–I).…”

“…Currently, the induction of cellular inflammatory and procoagulant responses is considered to be a major pathogenic action of aPLs. Several such cellular responses can be elicited by aPLs, and important insights into the underlying signaling processes have been obtained in recent years . These data suggest that different aPL subtypes may induce specific signaling cascades.…”

Antiphospholipid syndrome: an update for clinicians and scientists

“…The mechanistic schema is that anti-β 2 GPI antibodies potentiate thrombosis by engaging β 2 GPI protein that has been recruited to cell surfaces—and thereby promote cell activation [24–26]. The mechanisms by which anti-β 2 GPI antibodies activate cells have been recently reviewed [27], with roles especially suggested for the cell surface proteins annexin A2, apolipoprotein E receptor 2 (ApoER2), Toll-like receptor 2 (TLR2), and TLR4 [27]. …”

Recent Developments in Antiphospholipid Antibodies and the Antiphospholipid Syndrome

“…Furthermore, Muller-Calleja and Lackner provide an overview of the current insights in the way target cells are activated by aPL and discuss the data that support the role for the various cellular receptors that have been implicated in the pathophysiology of the syndrome. 18 Our knowledge on extracellular vesicles, including microvesicles and exosomes, is ever increasing. They have been reported to transport ribonucleic acid (RNA) to other cells and to contain information about the cells they originate from.…”