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



  • 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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