神经免疫系统对学习、记忆的影响

神经系统和免疫系统是维持机体内平衡的两个主要控制系统,具有双向调节作用。神经系统通过神经、内分泌途径,释放各种细胞因子、递质及神经肽调节机体的免疫反应过程;而免疫系统产生的免疫调节物或神经活性物质又可以调节神经系统的功能。神经-免疫系统的交互作用对促进神经系统正常功能的维持和发育具有重要作用。我们就大脑内部的免疫细胞即小胶质细胞、炎症细胞因子即白细胞介素（IL）-1β（IL-1β）、IL-6 和肿瘤坏死因子、Toll 样受体以及外周免疫系统在学习记忆以及调节突触传递、神经发生等功能方面的研究进行综述。     

哺乳动物视网膜节细胞中神经营养因子的主要生物学作用

哺乳动物视网膜节细胞的存活和再生受许多神经营养因子的调节。本文综述了神经营养素家族、细胞因子家族及玻璃体内移植外周神经节段等因素促进视网膜节细胞存活的作用 ;同时也分析了它们对视网膜节细胞的轴突生长和再生的影响 ,并提出这些神经营养因子可能通过升高cAMP水平起作用。     

microRNA调控树突状细胞分化与成熟的机制

树突状细胞(DC)含有不同的异质性亚群,在获得性免疫的启动、定向激活及调节中发挥重要作用.DC的自身发育分化及功能性成熟受细胞因子及转录因子构成的复杂网络调控.近期研究发现,microRNA (miRNA)通过抑制蛋白翻译或降解mRNA转录本来调控基因表达,调节包括免疫系统在内的多种生物学过程.许多miRNA在B、T淋巴细胞、DC、巨噬细胞及其他类型免疫细胞的发育、分化、存活及功能成熟起到重要作用,部分DC相关的miRNA如miR-155和miR-146a同时参与其他免疫细胞的调节.本文综述了DC亚群的功能,靶向不同DC亚群的免疫后果及细胞表面受体的种类;同时也总结了miRNA在DC由髓系前体细胞发育并分化为特异性亚群过程以及其在DC特异性功能中所发挥的重要作用.     

骨髓造血细胞粘附研究进展

在骨髓微环境中，造血过程受一系列复杂因素调节，细胞间粘附作用不仅调节干细胞归巢、未成熟细胞在微环境中定位、细胞成熟过程及细胞迁移和释放至外周血，还调节造血因子分泌与受体表达。细胞间粘附在造血生理与病理中起着重要作用。     

神经生长因子与造血

神经生长因子（Nerve Growth Factor，NGF）是最早发现的神经营养因子（Neurotrophic Factors，NTFs），对神经元的发育、营养、保护、突起生长具有重要的促进作用。随着研究的深入，越来越多的证据表明，与其它多种细胞因子一样，NGF也是一种多功能的细胞生长和调节因子，对免疫、生殖、细胞凋亡、内分泌等具有广泛的作用。本就NGF与造血及造血系统的关系作一综述。     

bHLH转录因子与大脑皮质祖细胞分化

在大脑新皮质发育过程中 ,bHLH转录调控因子 (basichelix loop helixtranscripitionfactor)参与调节大脑皮质多能祖细胞的分化。前神经bHLH因子 (Mash1,Neurogenin1,andNeurogenin2 )活性增强和Hes、Id因子的活性相应的减弱引起皮质多能祖细胞由增殖状态向神经生成转变。神经元形成后 ,Hes因子的激活促进星形胶质细胞的分化 ,而前神经bHLH因子Ngn抑制星形胶质细胞的分化。bHLH因子Olig1和Olig2活性的增加和Id活性的减弱启动了少突胶质细胞的形成。     

微环境与树突状细胞的发育

树突状细胞(DC)是专职的抗原递呈细胞(APC),体内的CD均来源于造血干细胞,在其分化成熟过程中各种微环境因素都起着不可忽视的作用。以往的研究曾报道过诸如TNF-α、GM-CSF、IL-4等细胞因子对(DC)生成的影响,最近又发现IL-10,IL-21和IL-15对DC的发育成熟也发挥巨大作用。除了细胞因子,胞间接触对DC的发育也有着深远的意义。探讨各种因素对DC的调控作用可以使我们更清楚的了解DC的发育过程并实现利用DC治疗各种自身免疫性疾病和肿瘤性疾病的目的。     

NK细胞趋化因子和细胞因子的分泌与调节

NK细胞是固有免疫系统中一个非常重要的成员，能够杀死病毒、细菌、寄生虫感染的细胞以及肿瘤细胞。同时，NK细胞也可以分泌一些细胞因子和趋化因子来调节免疫应答以及炎症反应，然而，这种分泌功能与NK细胞的成熟状态相关，同时也受到一些调控因子的调节，比如P1108，深入研究这些因子的功能和调控过程，对NK细胞参与免疫应答以及炎症反应具有重要意义。     

神经轴突导向分子Slit3功能研究进展

 神经轴突导向分子Slit3是近年发现的分泌型细胞外基质蛋白,基因功能研究表明,Slit3对神经元的发育并非必要,但对非神经细胞相关发育过程却是必须的。目前研究认为Slit3也是一个新的血管生成因子,对细胞迁移、血管生成、器官发育、生殖调节以及肿瘤和精神疾病的发生等多种生命活动具有重要作用。     

Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma.

Neurofibromas, the hallmark of neurofibromatosis 1, are composed mainly of Schwann cells and fibroblasts. Inactivation of both NF1 alleles is the cause of these benign tumors, but it is unknown which cell type is the progenitor. In this study, we selectively cultured Schwann cells from an NF1-associated neurofibroma. Fibroblasts were also obtained by culturing the tumor cells under standard conditions. Using four intragenic markers, we genotyped the NF1 locus in the original tumor and in the derived Schwann cells and fibroblasts. Loss of heterozygosity for two informative markers, which indicates loss of one NF1 allele, was found in Schwann cells but not in fibroblasts. This result suggests that genetic alterations of the NF1 gene in Schwann cells are responsible for the development of neurofibromas.     

Evidence for a Notch1‐mediated transition during olfactory ensheathing cell development

Olfactory ensheathing cells (OECs) are a unique glial population found in both the peripheral and central nervous system: they ensheath bundles of unmyelinated olfactory axons from their peripheral origin in the olfactory epithelium to their central synaptic targets in the glomerular layer of the olfactory bulb. Like all other peripheral glia (Schwann cells, satellite glia, enteric glia), OECs are derived from the embryonic neural crest. However, in contrast to Schwann cells, whose development has been extensively characterised, relatively little is known about their normal development in vivo. In the Schwann cell lineage, the transition from multipotent Schwann cell precursor to immature Schwann cell is promoted by canonical Notch signalling. Here, in situ hybridisation and immunohistochemistry data from chicken, mouse and human embryos are presented that suggest a canonical Notch‐mediated transition also occurs during OEC development.     

Specific expression of an HNK-1 carbohydrate epitope and NCAM on femoral nerve Schwann cells in mice

Schwann cells are glial cells of the peripheral nervous system. There are two known subtypes of Schwann cells: those that are myelin-forming; and those that are non-myelin-forming. In this study, we looked at the expression of cell adhesion molecules in Schwann cells to determine whether other subtypes might exist. We used immunohistological analysis of femoral nerve segments containing sensory and motor fascicles, stained with anti-HNK-1, M6749 and anti-neural cell adhesion molecule (NCAM) monoclonal antibodies. Anti-HNK-1 and M6749 were positive in the motor fascicle, while anti-NCAM was positive in the sensory fascicle. Immunoblot analysis with the anti-HNK-1 and M6749 antibodies showed stronger immunoreactivity in the motor fraction than in the sensory fraction in the 100 kDa band. With the anti-NCAM antibody, the 140 and 120 kDa bands were seen in the sensory fascicle fraction, but not in the motor fascicle fraction. HNK-1-positive-cells were seen in motor fascicles 7 days after transection. However, the level of immunoreactivity diminished at 14 days, and no immunoreactivity was seen at 21 days. NCAM-positive cells were not observed 3 days after transection. In development, HNK-1-positive-cells and NCAM-positive cells were seen after P-21. These results suggest that the Schwann cells from the motor and the sensory fascicles have different subtypes. The motor and sensory Schwann cells may play different roles and function in a different way during peripheral nerve regeneration. In addition, there could be more stages of Schwann cell differentiation than previously thought; it is possible that myelin-forming Schwann cells differentiate into HNK-1-positive-cells (motor myelin-forming Schwann cells) and HNK-1-negative-cells (sensory myelin-forming Schwann cells), and non-myelin-forming Schwann cells differentiate into NCAM-positive cells (sensory non-myelin-forming Schwann cells) and NCAM-negative cells (autonomic non-myelin-forming Schwann cells).     

NF1 loss disrupts Schwann cell–axonal interactions: a novel role for semaphorin 4F

Neurofibromatosis type 1 (NF1) patients develop neurofibromas, tumors of Schwann cell origin, as a result of loss of the Ras-GAP neurofibromin. In normal nerves, Schwann cells are found tightly associated with axons, while loss of axonal contact is a frequent and important early event in neurofibroma development. However, the molecular basis of this physical interaction or how it is disrupted in cancer remains unclear. Here we show that loss of neurofibromin in Schwann cells is sufficient to disrupt Schwann cell/axonal interactions via up-regulation of the Ras/Raf/ERK signaling pathway. Importantly, we identify down-regulation of semaphorin 4F (Sema4F) as the molecular mechanism responsible for the Ras-mediated loss of interactions. In heterotypic cocultures, Sema4F knockdown induced Schwann cell proliferation by relieving axonal contact-inhibitory signals, providing a mechanism through which loss of axonal contact contributes to tumorigenesis. Importantly, Sema4F levels were strongly reduced in a panel of human neurofibromas, confirming the relevance of these findings to the human disease. This work identifies a novel role for the guidance-molecules semaphorins in the mediation of Schwann cell/axonal interactions, and provides a molecular mechanism by which heterotypic cell–cell contacts control cell proliferation and suppress tumorigenesis. Finally, it provides a new approach for the development of therapies for NF1.     

Schwann cell proliferation following lysolecithin-induced demyelination

Summary Schwann cell division, meticulously regulated throughout development, occurs at an extremely low level in normal adult nerves. Loss of the myelin sheath in disease results in active proliferation of Schwann cells. The dividing cells are usually thought to be the Schwann cells of the demylinated fibres and their daughters. In this study we asked if other populations of Schwann cells might also divide following focal monophasic demyelination, and if the proliferating Schwann cells would be found only in the foci of demyelination. [³H]thymidine incorporation was examined by autoradiography at intervals after topical application of lysolecithin (lysophosphatidyl choline) to rat sciatic nerves. The postlabelling intervals were set to identify premitotic cells, cells shortly after mitosis (perimitotic cells) and postmitotic cells, as well as to provide cumulative labelling over 3 days. The affected nerves had three distinct zones. The first was a zone of nearly complete demyelination immediately beneath the perineurium. The subjacent zone was normal morphologically except for numerous supernumerary Schwann cells, displacement of some Schwann cell perikarya, ultrastructural changes in a few myelinated fibres, and rare demyelinated and remyelinated fibres. The third zone, beneath the first two, was normal.In the focus of demyelination there were large numbers of Schwann cells in S phase on days 4 and 6. These cells included premyelinating Schwann cells that were contacting or ensheathing demyelinated axons or collateral axonal sprouts. The subjacent region also contained dividing Schwann cells, most of which were Schwann cells of unmyelinated Remak fibres. In addition, occasional Schwann cells of thickly myelinated fibres (fibres that had not previously undergone demyelination) were labelled by the premitotic schedule; most of these fibres had morphological abnormalities in the Schwann cell perikaryon or myelin sheath. In many, the perikaryon of the Schwann cell was beginning to separate from the rest of the Schwann cell cytoplasm and the myelin sheath. These changes suggested that these fibres were destined to undergo subsequent demyelination, a hypothesis supported by the absence of any normal myelinated fibres with labelled Schwann cell nuclei in nerves removed 1 week after labelling. Thus, this model provided no evidence for division by Schwann cells that continued to maintain myelin sheaths.Taken together, these results suggest that there is a surround of Schwann cell proliferation around foci of demyelination; in this surround multiple populations of Schwann cells are recruited to proliferate, including Schwann cells of intact unmyelinated fibres. Structurally normal unmyelinated fibres appear to provide an unexpected source of new Schwann cells in nerve disease.     

Changes in Schwann cells and vessels in lead neuropathy.

Transmission electron microscopy (TEM) of peripheral nerve in rats receiving 6% lead carbonate for 4-10 weeks provided evidence of a specific Schwann cell injury, associated with demyelination. Intranuclear inclusions in Schwann cells appeared within 2 weeks of administration of a lead-containing diet. Swelling of Schwann cells and disintegration of their cytoplasm was evident at 4 weeks. Distinctive electron-dense inclusions appeared in both Schwann and endothelial cells during the period of intoxication and were ultrastructurally identical to pathognomonic inclusions of lead poisoning seen in renal tubular epithelial cells. Scanning microscopy (SEM) with electron-probe microanalysis was used to identify the lead-containing deposits. In addition to Schwann cell changes, vessels revealed endothelial cell injury and alteread permeability to macromolecules. Since morphologic changes of Schwann cells precede the development of altered vascular permeability and endoneurial edema, it appears that lead gains access to the endoneurium prior to the development of altered vascular permeability, suggesting that edema and altered endoneurial fluid pressure are epiphenomena that supervene after demyelination occurs. Remyelination, Schwann cell proliferation and formation of onion bulbs are manifestations of persistent toxic injury to myelin-sustaining cells, resulting in chronic demyelination.     

Myelinated, but not unmyelinated axons, reversibly down-regulate N-CAM in Schwann cells

Summary There is evidence from chicks and mice that N-CAM expression in Schwann cells is subject to significant regulation during development and following injury. In the present work, rat sciatic nerve and immunohistochemical methods have been used to study developmental and injury-related modulation of N-CAM in Schwann cells, using cell type specific markers to identify different Schwann cell populations, and cell counting to quantify their size. The study has sought to determine unambiguously whether immature Schwann cells in developing nerves and denervated Schwann cells in injured adult nerves express surface N-CAM, and has investigated the temporal relationship between the gradual loss of surface N-CAM and the differentiation of myelin-forming Schwann cells, monitored by the sequential appearance of the glycolipid galactocerebroside and the myelin-specific protein P₀. Further points examined are whether this down-regulation of N-CAM is rapidly reversible following loss of axonal contact, and whether N-CAM reappearance in Schwann cells depends on protein synthesis.In nerves from 17- to 18-day embryos, 90% of the Schwann cells, identified with Ran-1 antibodies, expressed surface N-CAM. In nerves from newborn rats many cells are in the early stage of myelin synthesis and therefore express galactocerebroside, although they have not yet acquired P₀. Suspension staining of dissociated cells from this nerve showed that 92% of the galactocerebroside-positive cells were also N-CAM positive. In suspension staining of nerves from 5-day, 10-day and adult rats, P₀-positive cells were essentially N-CAM negative. If, however, cells from 10-day nerves were placed in culture and immunostained after, 3, 6, 9 and 24 h, N-CAM appeared in the P₀-positive cells that had formed myelinin vivo. The percentage of P₀-positive cells that also expressed N-CAM at these time points was 10, 28, 56 and 92%, respectively. Cell division was not a prerequisite for N-CAM reappearance which was, however, blocked by cycloheximide, an inhibitor of protein synthesis. Schwann cells in transected adult sciatic nerves in which regeneration was prevented, expressed surface N-CAM 2 months after injury, indicating that in the absence of axonal contact Schwann cells express N-CAM indefinitely.The results indicate that in myelin-forming Schwann cells N-CAM synthesis is continuously suppressed by ongoing axonal signals. Thus axon-Schwann cell signals are involved not only in up-regulation but also in reversible down-regulation of Schwann cell molecules.     

Development of meissner corpuscle of mouse toe pad

The cytologic development of Meissner corpuscles of the mouse toe pad has been studied using light and electron microscopy, and correlated with silver impregnations of frozen sections. By 18 days of gestation, neurites are seen near the epidermis, but intraepidermal neurites are few. One day after birth, the number of intraepidermal neurites increases, and some accompanying Schwann cells extend their cytoplasmic processes penetrating the basal lamina of the epidermis. Four days after birth, Schwann cells invade the epidermis further, extending many cytoplasmic processes which are intimately associated with basal cells of epidermis. These specialized Schwann cells which contact the epidermis proper also begin to develop cytoplasmic lamellae and thus denote the onset of lamellar cell development. By eight days after birth, the developing lamellar cells become more elaborated, and their cytoplasmic processes contain caveolae and filaments, characteristic features of lamellar cells. This developmental sequence supports the concept that lamellar cells are derived from Schwann cells. Through all stages of development, neurites and Schwann cells interact closely with epidermal cells. Epidermal cells may be essential for corpuscle formation. By 20 to 25 days after birth, mouse toe pad Meissner corpuscles are cytologically mature.