Beta 2 glycoprotein I and neutrophil extracellular traps: Potential bridge between innate and adaptive immunity in anti-phospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activation is crucial in animal models and can be found also in patients. Furthermore, neutrophil extracellular traps (NETs) have been documented in arterial and venous thrombi with different etiology, including clots in APS models. Keeping in mind that β2GPI is a pleiotropic glycoprotein, acting as scavenger molecule for infectious agents and apoptotic/damaged body constituents and that self-molecules externalized through NETs formation may become immunogenic autoantigens, we demonstrated β2GPI on NETs, and its ability to stimulate CD4+β2GPI-specific T cells. The aim of this review is to elucidate the role of β2GPI in the cross-talk between the innate and adaptive immunity in APS.

The Role of Neutrophil Extracellular Traps (NETs) in the Pathogenesis of Systemic Lupus Erythematosus and Antiphospholipid Syndrome

“…Antiphospholipid syndrome is an autoimmune thrombophilia in which the development of thrombosis and obstetric pathology is due to circulating antiphospholipid antibodies [2]. There is increasing evidence that NETs are involved in the pathogenesis of APS [21,42,[117][118][119][120][121][122][123][124][125][126][127][128][129][130][131]. Antiphospholipid syndrome is an autoimmune thrombophilia in which the development of thrombosis and obstetric pathology is due to circulating antiphospholipid antibodies [2].…”

“…Antiphospholipid syndrome is an autoimmune thrombophilia in which the development of thrombosis and obstetric pathology is due to circulating antiphospholipid antibodies [2]. There is increasing evidence that NETs are involved in the pathogenesis of APS [21,42,[117][118][119][120][121][122][123][124][125][126][127][128][129][130][131].…”

“…As inthe study by Yalavarthi et al [21], NETosis was mediated via the activation of NADPH oxidase and TLR4. Grossi et al [119] showed that β2GPI binds to NETs from APS patients and the β2GPI/NET complex stimulates β2GPI-specific CD + T cells, leading to loss of tolerance, clonal expansion of β2GPI-specific B cells and aPL production. You et al [120] also found that the anti-β2GPI/β2GPI complex induced NET formation, whereas anti-β2GPI and β2GPI alone did not stimulate NETosis.…”