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Neuroimmune Diseases pp 235–302Cite as

Structural and Functional Characteristics of the Human Blood-Nerve Barrier with Translational Implications to Peripheral Nerve Autoimmune Disorders

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Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

Peripheral nerves and nerve roots comprise of three structural compartments: the outer epineurium consisting of longitudinal arrays of collagen fibers responsible for structural integrity and the inner perineurium consisting of multiple concentric layers of specialized epithelioid myofibroblasts that surround the innermost endoneurium which consists of myelinated and unmyelinated axons embedded in a looser mesh of collagen fibers. Axons are responsible for signal transduction to and from the central nervous system required for normal physiological processes and are targeted by the immune system in autoimmune disorders. A highly regulated endoneurial microenvironment is required for normal axonal function. This is achieved by tight junction-forming endoneurial microvessels that control ion, solute, water, nutrient, macromolecule and leukocyte influx and efflux between the bloodstream and endoneurium, and the innermost layers of the perineurium that control interstitial fluid component flux between the epineurium and endoneurium. Endoneurial microvascular endothelium is considered the blood-nerve barrier (BNB) due to direct communication with circulating blood. The mammalian BNB is considered the second most restrictive vascular system after the blood-brain barrier (BBB). Guided by human in vitro studies using primary and immortalized endoneurial endothelial cells that form the BNB, in situ studies in normal and pathologic human peripheral nerves, and representative animal models of peripheral nerve autoimmune disorders, knowledge is emerging on human BNB molecular and functional characteristics, including its array of cytokines/cytokine receptors, selectins, and cellular adhesion and junctional complex molecules that may be employed during normal immune surveillance and altered in autoimmune diseases, providing potential targets of efficacious immunotherapy.

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Abbreviations

BBB:

Blood-brain barrier

BNB:

Blood-nerve barrier

CIDP:

Chronic inflammatory demyelinating polyradiculoneuropathy

DSP:

Distal sensory polyneuropathy

EAN:

Experimental autoimmune neuritis

FITC:

Fluorescein isothiocyanate

GBS:

Guillain-Barré syndrome

GDNF:

Glial-derived neurotrophic factor

HIFs:

Hypoxia-inducing factors

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

ICAM-1:

Intercellular adhesion molecule-1

IFN-γ:

Interferon-γ

IL-1β:

Interleukin-1β

IL-2:

Interleukin-2

MAPK:

Mitogen-activated protein kinase

RET:

“rearranged upon transformation”

RNA:

Ribonucleic acid

SAPP:

Spontaneous autoimmune peripheral polyneuropathy

TEER:

Transendothelial electrical resistance

TGF-β:

Transforming growth factor-β

VCAM-1:

Vascular cell adhesion molecule-1

VEGF:

Vascular endothelial cell growth factor

ZO:

Zonula occludens

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Acknowledgments and Funding

Special thanks to past and current employees of the Shin J Oh Muscle and Nerve Histopathology Laboratory, the University of Alabama at Birmingham, for processing human tissue and 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 ultramicrographs of human cells and tissues and mouse tissues. Work described from the NIRL was supported by National Institutes of Health Grants R21 NS073702 (2011–2014), R21 NS078226 (2012–2015), R01 NS075212 (2012–2018), 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. 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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  1. Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

    Eroboghene E. Ubogu

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  1. Medical Education Promotion Center, Tokyo Medical University, Tokyo, Japan

    Hiroshi Mitoma

  2. Department of Neurology, CHU-Charleroi, Charleroi, Belgium, Department of Neurosciences, University of Mons, Mons, Belgium

    Mario Manto

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Ubogu, E.E. (2019). Structural and Functional Characteristics of the Human Blood-Nerve Barrier with Translational Implications to Peripheral Nerve Autoimmune Disorders. In: Mitoma, H., Manto, M. (eds) Neuroimmune Diseases. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-030-19515-1_8

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