Anti–Endothelial Cell Autoantibodies Selectively Activate SAPK/JNK Signalling in Wegener’s Granulomatosis

Abstract

The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca 2ϩ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-B. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D ϩ ) were identified, as were CD8 ϩ and 32 ␥␦ ϩ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis.

Endothelial Response to Glucocorticoids in Inflammatory Diseases

“…Stimulation of human kidney endothelial cells with AECA upregulated vascular adhesion protein-1 (VAP-1), CCL2 (MCP-1), MHC class I-related antigen A (MICA), and CXCL6 (GCP-2) expression. AECA also activated c-Jun, ATF2, and NF- κ B (204). IgA anti-endothelial cell antibodies present in sera from children with active Henoch–Schönlein purpura induce ERK phosphorylation and CXCL8 (IL-8) expression in HUVECs (205).…”

Antibodies to kidney endothelial cells contribute to a “leaky” glomerular barrier in patients with chronic kidney diseases

“…Accordingly, EC-binding antibodies have been shown to activate cultured EC, as manifested by the expression of adhesion molecules (27). Perry et al (36) found that AECA levels were associated with histological evidence of active renal damage on biopsy specimens, while George et al (24) reported that the presence of AECA could contribute to future EC dysfunction with a resultant prothrombotic tendency.…”

Semicarbazide-sensitive amine oxidase and kidney disease

“…After in vitro stimulation with antiendothelial cell auto-antibodies from patients with Wegener's granulomatosis, human renal microvascular endothelial cells acquired a proinflammatory phenotype with upregulation of the expression of chemokines and VAP-1. While the proinflammatory effects of anti-endothelial antibodies may be blocked by specific inhibitors of the signaling cascade (such as SAPK/ JNK), VAP-1 overexpression cannot (32).…”