Autor(es)Yosef Nejla,Ubogu Eroboghene E

ResumoThe mechanisms of hematogenous leukocyte trafficking at the human blood-nerve barrier (BNB) are largely unknown. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in the pathogenesis of Guillain-Barré syndrome (GBS). We developed a cytokine-activated human in vitro BNB model using primary endoneurial endothelial cells. Endothelial treatment with 10 U/ml tissue necrosis factor-? and 20 U/ml interferon-? resulted in de novo expression of pro-inflammatory chemokines CCL2, CXCL9, CXCL11, and CCL20, with increased expression of CXCL2-3, CXCL8, and CXCL10 relative to basal levels. Cytokine treatment induced/enhanced ICAM-1, E- and P-selectin, vascular cell adhesion molecule-1 and the alternatively spliced pro-adhesive fibronectin variant, fibronectin connecting segment-1 expression in a time-dependent manner, without alterations in junctional adhesion molecule-A expression. Lymphocytes and monocytes from untreated GBS patients express ICAM-1 counterligands, ?(M)- and ?(L)-integrin, with differential regulation of ?(M) -integrin expression compared to healthy controls. Under flow conditions that mimic capillary hemodynamics in vivo, there was a >3-fold increase in total GBS patient and healthy control mononuclear leukocyte adhesion/migration at the BNB following cytokine treatment relative to the untreated state. Function neutralizing monoclonal antibodies against human ?(M)-integrin (CD11b) and ICAM-1 reduced untreated GBS patient mononuclear leukocyte trafficking at the BNB by 59% and 64.2%, respectively. Monoclonal antibodies against ?(L)-integrin (CD11a) and human intravenous immunoglobulin reduced total leukocyte adhesion/migration by 22.8% and 17.6%, respectively. This study demonstrates differential regulation of ?(M)-integrin on circulating mononuclear cells in GBS, as well as an important role for ?(M)-integrin-ICAM-1 interactions in pathogenic GBS patient leukocyte trafficking at the human BNB in vitro.

ImprentaJournal of Cellular Physiology, v. 227, n. 12, p. 3857-3875, 2012

DescritoresGuillain-Barre Syndrome - Biosynthesis ; Guillain-Barre Syndrome - Cell ; Guillain-Barre Syndrome - Pathogenesis ; Guillain-Barre Syndrome - Proteins ; Guillain-Barre Syndrome - Antibodies ; Guillain-Barre Syndrome - Cytokines ; Guillain-Barre Syndrome - Immunopathology

Data de Publicação:2012