Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies
ABSTRACT The blood-nerve barrier (BNB) is a dynamic and competent interface between the endoneurial microenvironment and the surrounding extracellular space or blood. It is localised at the innermost layer of the multilayered ensheathing perineurium and endoneurial microvessels, and is the key structure that controls the internal milieu of the peripheral nerve parenchyma. Since the endoneurial BNB is the point of entry for pathogenic T cells and various soluble factors, including cytokines, chemokines and immunoglobulins, understanding this structure is important to prevent and treat human immune mediated neuropathies such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome and a subset of diabetic neuropathy. However, compared with the blood-brain barrier, only limited knowledge has been accumulated regarding the function, cell biology and clinical significance of the BNB. This review describes the basic structure and functions of the endoneurial BNB, provides an update of the biology of the cells comprising the BNB, and highlights the pathology and pathomechanisms of BNB breakdown in immune mediated neuropathies. The human immortalised cell lines of BNB origin established in our laboratory will facilitate the future development of BNB research. Potential therapeutic strategies for immune mediated neuropathies manipulating the BNB are also discussed.
- SourceAvailable from: Satoshi Kuwabara
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- "These findings might not reflect the direct effects of VEGF alone, because multiple inflammatory cytokines such as interleukin-12, and tumor necrosis-a are simultaneously and markedly upregulated in the active phase of POEMS syndrome (Kanai et al., 2012), and it is possible such cytokines other than VEGF affect ion channel function, although this should be investigated in further studies. Nevertheless, increased vascular permeability mediated by VEGF presumably responsible for nerve edema, frequently found on pathological examination (Kanda, 2013). We initially expected membrane depolarization due to edema-induced compression ischemia in POEMS syndrome, and nerve edema detected by ultrasound partly correlated with axonal excitability. "
ABSTRACT: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating neuropathy with upregulation of vascular endothelial growth factor (VEGF). This study aimed to elucidate axonal excitability properties and their relation to VEGF levels and nerve edema in POEMS neuropathy. Axonal excitability measurement and nerve ultrasound were performed in the median nerve of 33 patients with POEMS syndrome. Serum VEGF levels were measured by ELISA. Compared with normal subjects (n=87), POEMS patients showed longer strength-duration time constant, fanning-out of threshold electrotonus curves, and greater threshold changes in a hyperpolarizing current-threshold relationship. Nerve ultrasound showed significant enlargement in POEMS patients. Serum VEGF levels and the extent of nerve edema partly correlated with nerve conduction slowing, as well as persistent sodium currents and inward rectification. In POEMS syndrome, patterns of changes in excitability properties could suggest increased persistent sodium currents, and impaired potassium and inward rectifying channels. The findings were not consistent with depolarization due to nerve edema and compression ischemia. In addition to demyelination, nerve edema induced by upregulated VEGF, and upregulated inflammatory cytokines could modulate profiles of POEMS neuropathy. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 02/2015; DOI:10.1016/j.clinph.2015.01.018 · 2.98 Impact Factor
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- "The BNB is made up of specialized endothelial cells within the endoneurium, along with the perineurial barrier. Under healthy conditions, the BNB acts as a selectively permeable barrier that creates an immunologically and biochemically privileged space for axons and supporting cells to function within . The importance of the BNB is further highlighted when we note that the endoneurial fluid has a different electrolyte composition than that of surrounding tissues and blood . "
ABSTRACT: The blood-nerve barrier (BNB) is a selectively permeable barrier that creates an immunologically and biochemically privileged space for peripheral axons and supporting cells. The breakdown of the BNB allows access of blood-borne (hematogenous) cells and molecules to the endoneurium to engage in the local inflammatory cascade. This process was examined in a mouse model of trauma associated neuropathic pain. The impact of nerve injury triggered-opening of the BNB in the development of chronic pain behavior was investigated. Partial ligation of the sciatic nerve led to a long-lasting disruption of the BNB distal to the site of injury. Vascular endothelial growth factor (VEGF) was expressed by resident macrophages after nerve injury. Intraneural injection of VEGF decreased mechanical thresholds while opening the BNB. Serum from nerve injured or LPS treated animals elicited mechanical allodynia in naive animals, when allowed to bypass the BNB by intraneural injection. Intraneural injection of fibrinogen, a clotting protein in plasma which was found to deposit in the nerve following nerve injury, also produced a decrease in mechanical thresholds when introduced into naive nerves. These results demonstrate that blood-borne molecules may play a role in the generation of neuropathic pain, suggesting that pain may be driven from infection or injury, at a distance from the nervous system. Furthermore, the breakdown of the BNB in neuropathic conditions was exploited to permit the entry of analgesic molecules that typically cannot pass the BNB, such as ProToxin-II, a BNB impermeable Nav1.7 inhibitor. Therapeutics utilizing this mechanism could have selective access to injured nerves over healthy tissues.Pain 02/2014; 155(5). DOI:10.1016/j.pain.2014.01.026 · 5.84 Impact Factor
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ABSTRACT: Diabetic encephalopathy is now accepted as an important complication of diabetes. The breakdown of the blood-brain barrier (BBB) is associated with dementia in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to identify the possible mechanisms responsible for the disruption of the BBB after exposure to advanced glycation end-products (AGEs). We investigated the effect of AGEs on the basement membrane and the barrier property of the BBB by Western blot analysis, using our newly established lines of human brain microvascular endothelial cell (BMEC), pericytes, and astrocytes. AGEs reduced the expression of claudin-5 in BMECs by increasing the autocrine signaling through vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) secreted by the BMECs themselves. Furthermore, AGEs increased the amount of fibronectin in the pericytes through a similar up-regulation of the autocrine transforming growth factor (TGF)-β released by pericytes. These results indicated that AGEs induce basement membrane hypertrophy of the BBB by increasing the degree of autocrine TGF-β signaling by pericytes, and thereby disrupt the BBB through the up-regulation of VEGF and MMP-2 in BMECs under diabetic conditions.Neurobiology of aging 02/2013; 34(7). DOI:10.1016/j.neurobiolaging.2013.01.012 · 4.85 Impact Factor