title: The pathogenic relevance of αM-integrin in Guillain-Barré syndrome.
abstract: The molecular determinants and mechanisms involved in leukocyte trafficking across the blood-nerve barrier (BNB) in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) variant of Guillain-Barré syndrome are incompletely understood. Prior work using a flow-dependent in vitro human BNB model demonstrated a crucial role for αM-integrin (CD11b)-intercellular adhesion molecule-1 interactions in AIDP patient leukocyte trafficking. The aim of this study is to directly investigate the biological relevance of CD11b in AIDP pathogenesis. Immunohistochemistry was performed on three AIDP patient sural nerve biopsies to evaluate endoneurial leukocyte CD11b expression. A severe murine experimental autoimmune neuritis (sm-EAN) model was utilized to determine the functional role of CD11b in leukocyte trafficking in vivo and determine its effect on neurobehavioral measures of disease severity, electrophysiological assessments of axonal integrity and myelination and histopathological measures of peripheral nerve inflammatory demyelination. Time-lapse video microscopy and electron microscopy were employed to observe structural alterations at the BNB during AIDP patient leukocyte trafficking in vitro and in situ, respectively. Large clusters of endoneurial CD11b+ leukocytes associated with demyelinating axons were observed in AIDP patient sural nerves. Leukocyte CD11b expression was upregulated during sm-EAN. 5 mg/kg of a function-neutralizing monoclonal rat anti-mouse CD11b antibody administered after sm-EAN disease onset significantly ameliorated disease severity, as well as electrophysiological and histopathological parameters of inflammatory demyelination compared to vehicle- and isotype antibody-treated mice. Consistent with in vitro observations of leukocyte trafficking at the BNB, electron micrographs of AIDP patient sural nerves demonstrated intact electron-dense endoneurial microvascular intercellular junctions during paracellular mononuclear leukocyte transmigration. Our data support a crucial pathogenic role of CD11b in AIDP leukocyte trafficking, providing a potential therapeutic target for demyelinating variants of Guillain-Barré syndrome.
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, Sparks Center 200, Birmingham, AL, 35294-0017, USA.
authors.forename: Chaoling
authors.initials: C
authors.lastname: Dong
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, Sparks Center 200, Birmingham, AL, 35294-0017, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Palladino
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, Sparks Center 200, Birmingham, AL, 35294-0017, USA.
authors.forename: Eric Scott
authors.initials: ES
authors.lastname: Helton
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, 1720 7th Avenue South, Sparks Center 200, Birmingham, AL, 35294-0017, USA. eeubogu@uabmc.edu.
authors.forename: Eroboghene E
authors.identifier: 0000-0002-8307-9994
authors.initials: EE
authors.lastname: Ubogu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D058948:Cell Tracking; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D020275:Guillain-Barre Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009431:Neural Conduction; D016900:Neurofilament Proteins / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000503:physiopathology; D018709:Statistics, Nonparametric
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D016756:Immunoglobulins, Intravenous; D016900:Neurofilament Proteins; D064568:S100 Calcium Binding Protein beta Subunit; C036763:monocyte-macrophage differentiation antigen; C051774:neurofilament protein H
keywords: Acute inflammatory demyelinating polyradiculoneuropathy; Blood–nerve barrier; CD11b; Experimental autoimmune neuritis; Guillain–Barré syndrome; Integrin