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01-11-2016 | Original Paper

The pathogenic relevance of α_M-integrin in Guillain–Barré syndrome

Authors: Chaoling Dong, Steven P. Palladino, Eric Scott Helton, Eroboghene E. Ubogu

Published in: Acta Neuropathologica | Issue 5/2016

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 α_M-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.

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Title: The pathogenic relevance of αM-integrin in Guillain–Barré syndrome
Authors: Chaoling Dong
Steven P. Palladino
Eric Scott Helton
Eroboghene E. Ubogu
Publication date: 01-11-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1599-0

At a glance: The STEP trials

Springer Medicine

The pathogenic relevance of α_M-integrin in Guillain–Barré syndrome

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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