Anti-endothelial cell antibodies are associated with apoptotic endothelial microparticles, endothelial sloughing and decrease in angiogenic progenitors in systemic sclerosis

Abstract

Introduction: Evidence has accumulated for the role of endothelial damage in systemic sclerosis (SSc) and the antiendothelial cell antibodies (AECAs) might underlie vascular injury. Aim: Since endothelial microparticles (EMPs) and circulating endothelial cells (CECs) reflect endothelial damage, we aimed to investigate their possible relationship with AECAs in SSc. We examined whether AECAs could affect endothelial repair based on the number of endothelial progenitor cells (EPCs). Material and methods: Forty-seven SSc patients were screened. The AECAs were identified in serum by indirect immunofluorescence. EPCs and CECs were isolated from the peripheral blood using anti-CD34-based immunomagnetic separation, whereas EMPs were analyzed in plasma. Flow cytometry was used to quantify EMPs, CECs and EPCs. Results: AECAs were found in 21 (44.7%) SSc patients and were significantly associated with higher levels of total as well as apoptotic (AnnV+ and CD51+) EMPs, whereas activated (CD62E+/AnnV-) EMPs did not differ between groups. Patients with AECAs had significantly elevated total CECs as well as activated CD105+ CECs. Total endothelial progenitors did not differ between patients with or without AECAs; however AECAs was negatively associated with the population of EPCs that express VEGFR2 or Tie2 receptors. Conclusions: We found an association between AECAs and the severity of endothelial damage in SSc based on higher levels of total EMPs and CECs. In our study, AECAs were associated with apoptosis of ECs rather than their activation. We also identified a possible role of AECAs in the impairment of vascular repair in SSc as evidenced by significantly fewer angiogenic EPCs.

Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

“…Since CECs and endothelial microparticles, i.e., microvesicles released from the cellular membrane during EC activation or apoptosis, both reflect the degree of endothelial injury, a recent study investigated their possible relationship with anti-EC antibodies (AECAs) and assessed if AECAs may contribute to endothelial damage by evaluating the number of EPCs [ 58 ]. In particular, the authors found that AECAs correlated with increased levels of total and apoptotic endothelial microparticles and that patients with AECAs were characterized by a higher number of CECs.…”

“…In particular, the authors found that AECAs correlated with increased levels of total and apoptotic endothelial microparticles and that patients with AECAs were characterized by a higher number of CECs. Moreover, as AECAs are negatively associated with angiogenic EPCs, these autoantibodies were suggested to play a role in the impairment of vascular repair [ 58 ].…”

Endothelial Dysfunction in Systemic Sclerosis

“…Levels of AECAs are correlated with the number of apoptotic endothelial microparticles. Impairment of vascular repair by having fewer endothelial cell progenitors is seen in subjects with AECAs [ 38 ]. Immune complexes (ICs) containing SSc specific antibodies (anti-centromere, anti-topoisomerase I, and anti- RNA polymerase) induce the endothelial cells to a pro-inflammatory and pro-fibrotic phenotype [ 39 ].…”

Endothelial Dysfunction in Systemic Lupus Erythematosus and Systemic Sclerosis: A Common Trigger for Different Microvascular Diseases

“…The anti-endothelial cell antibodies (AECAs) can be found in almost 50% of SSc patients and can react with various cell surface antigens on ECs leading them to apoptosis (102) through the antibody-dependent cell-mediated cytotoxicity mechanism (103)(104)(105). An association between circulating antibodies and vascular manifestations has been described for antibodies against cell surface receptors such as angiotensin II type 1 receptor and endothelin-1 type A receptor (106).…”