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Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Abstract

Inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both. Inflammatory neuropathies may be divided into three major disease categories: Guillain–Barré syndrome (particularly the acute inflammatory demyelinating polyradiculoneuropathy variant), chronic inflammatory demyelinating polyradiculoneuropathy and nonsystemic vasculitic neuropathy (or peripheral nerve vasculitis). Despite major advances in molecular biology, pathology and genetics, the pathogenesis of these disorders remains elusive. There is insufficient knowledge on the mechanisms of hematogenous leukocyte trafficking into the peripheral nervous system to guide the development of specific molecular therapies for immune-mediated inflammatory neuropathies compared to disorders such as psoriasis, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The recent isolation and characterization of human endoneurial endothelial cells that form the blood–nerve barrier provides an opportunity to elucidate leukocyte–endothelial cell interactions critical to the pathogenesis of inflammatory neuropathies at the interface between the systemic circulation and peripheral nerve endoneurium. This review discusses our current knowledge of the classic pathological features of inflammatory neuropathies, attempts at molecular classification and genetic determinants, the utilization of in vitro and in vivo animal models to determine pathogenic mechanisms at the interface between the systemic circulation and the peripheral nervous system relevant to these disorders and prospects for future potential molecular pathology biomarkers and targets for specific therapeutic intervention.

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Acknowledgments

Special thanks to past and current employees of the Shin J Oh Muscle and Nerve Histopathology Lab, the University of Alabama at Birmingham for generating histopathology slides from which digital photomicrographs are shown, and current and past members and collaborators of the Neuromuscular Immunopathology Research Laboratory (NIRL) for digital photomicrographs and videos depicting inflammation in murine models and in vitro leukocyte trafficking. Work in the NIRL is currently supported by National Institutes of Health Grants R21 NS078226 (2012-2015), R01 NS075212 (2012-2017) and a Creative and Novel Ideas in HIV Research subaward P30 AI27767 (2012-2015), as well as institutional support from the Department of Neurology, the University of Alabama at Birmingham (2013-). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

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Correspondence to Eroboghene E. Ubogu.

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Supplementary material 1 (MPG 22070 kb) Supplementary Video 1. Pathogenic leukocyte trafficking at the human BNB in vitro. Peripheral blood mononuclear leukocytes (200,000/mL) from an untreated AIDP patient were infused over a cytokine-treated monolayer of primary human endoneurial endothelial cells (that form the BNB) at a linear velocity of 1 mm/s, mimicking estimated capillary flow rates in vivo. The multi-step paradigm is demonstrated with leukocytes (phase bright) rolling on the endothelial monolayer surface, followed by arrest, firm adhesion and some transmigration (change from phase bright to phase dark) during this 20 min epoch (compressed to 10X normal frame rate). Clusters of leukocytes aggregate at sites of intercellular junctions, presumably at sites of high chemokine presentation by specific glycosaminoglycans, and migrate via the paracellular route in this model system. Frame size 650 μm × 870 μm

Supplementary material 1 (MPG 22070 kb) Supplementary Video 1. Pathogenic leukocyte trafficking at the human BNB in vitro. Peripheral blood mononuclear leukocytes (200,000/mL) from an untreated AIDP patient were infused over a cytokine-treated monolayer of primary human endoneurial endothelial cells (that form the BNB) at a linear velocity of 1 mm/s, mimicking estimated capillary flow rates in vivo. The multi-step paradigm is demonstrated with leukocytes (phase bright) rolling on the endothelial monolayer surface, followed by arrest, firm adhesion and some transmigration (change from phase bright to phase dark) during this 20 min epoch (compressed to 10X normal frame rate). Clusters of leukocytes aggregate at sites of intercellular junctions, presumably at sites of high chemokine presentation by specific glycosaminoglycans, and migrate via the paracellular route in this model system. Frame size 650 μm × 870 μm

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Ubogu, E.E. Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention. Acta Neuropathol 130, 445–468 (2015) doi:10.1007/s00401-015-1466-4

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Keywords

  • Blood–nerve barrier
  • Chronic inflammatory demyelinating polyradiculoneuropathy
  • Genetic polymorphisms
  • Guillain–Barré syndrome
  • Inflammation
  • Leukocyte trafficking
  • Mechanisms
  • Pathology
  • Peripheral nerves
  • Vasculitic neuropathies