title: 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 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.
authors: Division of Clinical Immunology, Karolinska University Hospital at Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors: Carolina
authors: C
authors: Holmén
authors: Elzafir
authors: E
authors: Elsheikh
authors: Marta
authors: M
authors: Christensson
authors: Jining
authors: J
authors: Liu
authors: Anne-Sofie
authors: AS
authors: Johansson
authors: Abdul Rashid
authors: AR
authors: Qureshi
authors: Sirpa
authors: S
authors: Jalkanen
authors: Suchitra
authors: S
authors: Sumitran-Holgersson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D000941:Antigens / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053146:Myeloblastin / Q000172:deficiency; D015854:Up-Regulation
chemical_list: D000941:Antigens; D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D018925:Chemokines; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; C099187:MHC class I-related chain A; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D053146:Myeloblastin