IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines.
IgG autoantibodies that bind human endothelial cells (AECA) were detected by ELISA in 30 of 42 samples of sera from patients with scleroderma. Pretreatment of human umbilical vein endothelial cells with AECA-positive scleroderma sera, or IgG purified from these sera, led to a dose- and time-dependent increase in the ability of the cells to bind human U937 monocytic cells. Threshold-active IgG concentrations were 1-10 micrograms/ml; effects were significant after 3 h and maximal after 6-12 h. IgG from AECA-negative sera or normal sera were without effect. Increased adhesion of U937 cells was accompanied by increased expression of endothelial intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Transfer of endothelial cell-conditioned media after pretreatment with AECA and immunodepletion of IgG demonstrated the presence of transferable activity that mimicked the effects of AECA. Treatment with neutralizing anticytokine antibodies indicated that IL-1, generated by the endothelial cells in response to AECA, was involved in the upregulation of adhesion molecules and U937 cell adhesion. We conclude that AECA can play a pathogenic role in scleroderma by activating endothelial cells, in part due to autocrine or paracrine actions of IL-1.
Carvalho
D
D
Vascular Biology Research Centre, King's College, Kensington, London, United Kingdom.
Savage
C O
CO
Black
C M
CM
Pearson
J D
JD
D019138:Antibodies, Blocking; D001323:Autoantibodies / Q000494:pharmacology*; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G / Q000494:pharmacology*; D007375:Interleukin-1 / Q000502:physiology; D009000:Monocytes / Q000166:cytology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014471:Umbilical Veins
D019138:Antibodies, Blocking; D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007375:Interleukin-1; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide