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 Ca2+ 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-kappaB. 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+) were identified, as were CD8+ and 32 gamma delta+ 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.