Autoimmune diseases of the peripheral nervous system

Autoimmune-mediated diseases targeting the peripheral nerve represent a group of disorders often associated with high clinical disability. At present, therapeutic options are limited. The application of innovative and cutting-edge technologies to the study of immune-mediated disorders of the peripheral nervous system (PNS) have generated a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. These insights may foster the development of specific and highly effective therapies for autoimmune diseases of the peripheral nerve. Of great interest in this context is the application of monoclonal antibodies, such as rituximab or alemtuzumab, which in small observational studies provided promising clinical results. But also other immunomodulatory or immunosuppressive drugs used in other indications currently find their way to PNS autoimmunity. Clearly, prospective controlled clinical trials are warranted before making firm conclusions on the feasibility of these innovative therapeutic approaches for treating immune-mediated disease of the peripheral nerve.     

Changes in the peripheral nervous system due to experimental fever

Summary Studies of the nervous apparatus of the large veins in animals with experimental fever caused by the injection of a culture ofBacillus mesentericus demonstrated reactive changes of the sensory apparatus in the walls of the superior vena cava and pulmonary veins with intact afferent innervation. Structural changes mainly in preterminal and terminal sections of the medullated fibers were as a rule detected in 3 hours after the injection of the stimulus, reached the maximum in 6–8 hours and disappeared in 24 hours. Neurons of the afferent innervation in walls of the g-nodosa and the spinal ganglions were not changed. The data obtained show that reactive changes caused by experimental fever first appear in the peripheral section of the neuron and are reversible.Presented by V. N. Chemigovsky. Active Member of the Academy of Medical Sciences, USSR     

Myelin synthesis in the peripheral nervous system

By imposing saltatory conduction on the nervous impulse, the principal role of the myelin sheath is to allow the faster propagation of action potentials along the axons which it surrounds. Peripheral nervous system (PNS) myelin is formed by the differentiation of the plasma membrane of Schwann cells. One of the biochemical characteristics that distinguishes myelin from other biological membranes is its high lipid-to-protein ratio. All the major lipid classes are represented in the myelin membrane, while several myelin-specific proteins have been identified. During development, the presence of axons is required for the initiation of myelination, but the nature of the axonal signal is still unknown. The only certainties are that this signal is synthesized by axons whose diameter is greater than 0.7 microm, and that the signal(s) include(s) a diffusible molecule. Morphological studies have provided us with information concerning the timing of myelination, the mechanism by which immature Schwann cells differentiate into a myelinating phenotype and lay down the myelin sheath around the axon, and the accumulation and the structure of the myelin membrane. The last 20 years have seen the identification and the cDNA and gene cloning of the major PNS myelin proteins, which signalled the beginning of the knock-out decade: transgenic null-mutant mice have been created for almost every protein gene. The study of these animals shows that the formation of myelin is considerably less sensitive to molecular alterations than the maintenance of myelin. During the same period, important data has been gathered concerning the synthesis and function of lipids in PNS myelin, although this field has received relatively little attention compared with that of their protein counterparts.     

Role of integrins in the peripheral nervous system

Integrins, a subgroup of adhesion receptors, are transmembrane glycoproteins that mediate interactions between cytoplasm and the extracellular environment. These interactions influence, among others, events such as cell migration, proliferation, and differentiation. Differential expression of integrins is developmentally regulated in the peripheral nervous system (PNS) and is associated with crucial events in both physiological and pathological processes. Preliminary studies suggest that integrin expression influences neural crest cell migration, axonal outgrowth, and Schwann cell differentiation. Similarly, the abnormal expression of integrins or their ligands, is associated with degenerative, inflammatory, and malignant disorders of the PNS. Finally, integrins participate in the complex interactions that promote repair of the PNS. A better comprehension of the role of integrins in the PNS, their protein interactions and transducing signals is being achieved by selected biochemical and genetic experiments. Here we review a large bias of evidence suggesting the key functions for integrins in the PNS.     

Preparation and analysis of the peripheral nervous system

This article is from a presentation at the 2010 STP/IFSTP Symposium on Neuropathology. The organization and basic structure of the peripheral nervous system is reviewed. Examples of toxicant-induced peripheral nerve injury such as neuronopathy, axonopathy, and myelinapathy are discussed, as are contemporary methods for examination of these tissues.     

Three-dimensional slice cultures from murine fetal gut for investigations of the enteric nervous system.

Three-dimensional intestinal cultures offer new possibilities for the examination of growth potential, analysis of time specific gene expression, and spatial cellular arrangement of enteric nervous system in an organotypical environment. We present an easy to produce in vitro model of the enteric nervous system for analysis and manipulation of cellular differentiation processes. Slice cultures of murine fetal colon were cultured on membrane inserts for up to 2 weeks without loss of autonomous contractility. After slice preparation, cultured tissue reorganized within the first days in vitro. Afterward, the culture possessed more than 35 cell layers, including high prismatic epithelial cells, smooth muscle cells, glial cells, and neurons analyzed by immunohistochemistry. The contraction frequency of intestinal slice culture could be modulated by the neurotransmitter serotonin and the sodium channel blocker tetrodotoxin. Coculture experiments with cultured neurospheres isolated from enhanced green fluorescent protein (eGFP) transgenic mice demonstrated that differentiating eGFP-positive neurons were integrated into the intestinal tissue culture. This slice culture model of enteric nervous system proved to be useful for studying cell-cell interactions, cellular signaling, and cell differentiation processes in a three-dimensional cell arrangement.     

Targeted drug delivery to the peripheral nervous system using gene therapy

Gene transfer to target delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathy, or of inhibitory neurotransmitters for relief of chronic pain, offers the possibility of a highly selective targeted release of bioactive molecules within the nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in reducing-pain related behaviors in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer, and in preventing progression of sensory neuropathy caused by toxins, chemotherapeutic drugs or resulting from diabetes. Successful completion of the first phase 1 clinical trial of HSV-mediated gene transfer in patients with intractable pain from cancer has set the stage for further clinical trials of this approach.     

中枢神经系统与周围神经系统对骨痂构建的影响

[摘要] 神经系统在骨痂构建过程中具有重要作用。本研究通过网络检索维普数据库、中国万方数据库、PubMed数据库（1960-03/2013-02）关于神经系统和骨痂构建的文献。回顾性分析了不同神经系统对骨痂构建的影响，及其作用机制。经分析后发现：骨痂构建是一个复杂的骨生长过程，存在复杂的生物学调节机制，受到机体内部环境的作用，中枢神经系统与周围神经系统对骨痂的构建的具有不同的调节作用。     

The role of macrophages in immune-mediated damage to the peripheral nervous system

Macrophage-mediated segmental demyelination is the pathological hallmark of autoimmune demyelinating polyneuropathies, including the demyelinating form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. Macrophages serve a multitude of functions throughout the entire pathogenetic process of autoimmune neuropathy. Resident endoneurial macrophages are likely to act as local antigen-presenting cells by their capability to express major histocompatibility complex antigens and costimulatory B7-molecules, and may thus be critical in triggering the autoimmune process. Hematogenous infiltrating macrophages then find their way into the peripheral nerve together with T-cells by the concerted action of adhesion molecules, matrix metalloproteases and chemotactic signals. Within the nerve, macrophages regulate inflammation by secreting several pro-inflammatory cytokines including IL-1, IL-6, IL-12 and TNF-alpha. Autoantibodies are likely to guide macrophages towards their myelin or primarily axonal targets, which then attack in a complement-dependent and receptor-mediated manner. In addition, non-specific tissue damage occurs through the secretion of toxic mediators and cytokines. Later, macrophages contribute to the termination of inflammation by promoting T-cell apoptosis and expressing anti-inflammatory cytokines including TGF-beta1 and IL-10. During recovery, they are tightly involved in allowing Schwann cell proliferation, remyelination and axonal regeneration to proceed. Macrophages, thus, play dual roles in autoimmune neuropathy, being detrimental in attacking nervous tissue but also salutary, when aiding in the termination of the inflammatory process and the promotion of recovery.     

Fast optical signals in the peripheral nervous system

We present a study of the near-infrared optical response to electrical stimulation of peripheral nerves. The sural nerve of six healthy subjects between the ages of 22 and 41 was stimulated with transcutaneous electrical pulses in a region located approximately 10 cm above the ankle. A two-wavelength (690 and 830 nm) tissue spectrometer was used to probe the same sural nerve below the ankle. We measured optical changes that peaked 60 to 160 ms after the electrical stimulus. On the basis of the strong wavelength dependence of these fast optical signals, we argue that their origin is mostly from absorption rather than scattering. From these absorption changes, we obtain oxy- and deoxy-hemoglobin concentration changes that describe a rapid hemodynamic response to electrical nerve activation. In five out of six subjects, this hemodynamic response is an increase in total (oxy+deoxy) hemoglobin concentration, consistent with a fast vasodilation. Our findings support the hypothesis that the peripheral nervous system undergoes neurovascular coupling, even though more data is needed to prove such hypothesis.     

Morphological diagnosis of peripheral nervous system diseases

Peripheral neuropathies are among the most common neurological diseases. Various tissues are available for morphological investigation, depending on the purpose of diagnosis. The sural nerve is most frequently used for nerve biopsy. The nomenclature of neuropathies is described together with prerequisites and techniques for nerve biopsy. Morphologically, a distinction can be made between parenchymatous and interstitial lesions. An account is given of the most important morphological patterns, such as axonal and neuronal degeneration and regeneration, including Waller's degeneration, segmental demyelinisation and remyelinisation as well as hypertrophic alterations. Brief reference is made to conjunctival, dermal, and rectal biopsies.     

Expression of complement components in the peripheral nervous system

We have generated a SAGE (serial analysis of gene expression) library of normal sciatic nerve and found tags encoding for mRNAs of the complement system highly represented. RNA (RT-PCR and northern blot hybridization) and protein (western blot analysis and immunohistochemistry) studies confirmed these findings. High expression of classical pathway components, alternative pathway components and inhibitory components was observed in specific regions of the sciatic nerve. The first components of complement were found in axons, whereas the inhibitory components were detected in the perineurium, thereby protecting the nerve from a complement attack. Immunoreactivity towards activated complement factors was noted in post traumatic neuromas and after acute crush injury, which exemplify nerve regeneration and degeneration. We propose that local production of complement in the peripheral nervous system participates in the protection of healthy nerve and is needed for efficient clearance of myelin after injury: a prerequisite for normal regeneration and remyelination of the peripheral nerve.