Endogenous colony formation in mice with experimental pathology of the central nervous system

Models of endo- and exogenous clone formation were used to study colony formation in (CBA X C57B1)F1 mice in different periods after damage to the hypothalamic structures. The following dynamics of colony formation was revealed in the animals with hypothalamic damage in endogenous clone formation: intensified colony formation occurring 24 hours after injury to the brain structures was replaced by a tendency to decrease in 4 days, which was followed by marked inhibition of colony formation 8 days after injury to the hypothalamic structures. The effect of inhibition of colony formation was encountered in animals with damage to the posterior hypothalamic field. No essential changes were revealed in colony formation 4 and 8 hours after hypothalamic injury in exogenous clone formation. Comparison of the results of endo- and exogenous clone formation suggests that the inhibition of colony formation in late-term periods after injury to the posterior hypothalamic field may be due to inhibition of the migration of hematopoietic stem cells from the bone marrow.     

Protection by dehydroepiandrosterone in mice infected with viral encephalitis

Summary Dehydroepiandrosterone (DHEA) has a significant protective effect in mice infected with West Nile virus (WNV), Sindbis virus neurovirulent (SVNI) and Semliki Forest virus (SFV). Mice injected subcutaneously (SC) with a single injection of DHEA (1 g/kg) on the same day or one day pre or post infection with WNV resulted in 40–50% mortality as compared to 100% in control injected mice (p<0.05). The drug was effective following a single SC injection or serial intraperitoneal (IP) injections (5–20mg/kg) on days 0, 2, 4, and 6 following virus inoculation. Moreover, DHEA injection not only reduced viremia and death rate, but also significantly delayed the onset of the disease and mortality. The titers of antivirus antibodies in surviving mice were very high. However, DHEA had no effect on WNV growth in BHK or Vero cell cultures. In this study it was shown that DHEA protects mice against WNV, SVNI and SFV lethal infection. Though the mechanism of the protective effect of DHEA is still unknown, it seems that DHEA can modify the host resistance mechanisms rather than the virus itself.     

Pathogenic and physiological autoantibodies in the central nervous system

In this article, we review the current knowledge on pathological and physiological autoantibodies directed toward structures in the central nervous system (CNS) with an emphasis on their regulation and origin. Pathological autoantibodies in the CNS that are associated with autoimmunity often lead to severe neurological deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a marker for diagnostic purposes without contributing to the pathological process and/or disease progression. The existence of naturally occurring physiological autoantibodies has been known for a long time, and their role in maintaining homeostasis is well established. Within the brain, naturally occurring autoantibodies targeting aggregated proteins have been detected and might be promising candidates for new therapeutic approaches for neurodegenerative disorders. Further evidence has demonstrated the existence of naturally occurring antibodies targeting antigens on neurons and oligodendrocytes that promote axonal outgrowth and remyelination. The numerous actions of physiological autoantibodies as well as their regulation and origin are summarized in this review.     

Morphological features of Murray Valley encephalitis virus infection in the central nervous system of Swiss mice

We have examined the histological and ultrastructural features of CNS infection with Murray Valley encephalitis (MVE) virus in mice inoculated with a virulent parental strain (BH3479). Light microscopic examination revealed neuronal necrosis in the olfactory bulb and hippocampus of MVE-infected brains by 5 days post-infection (pi). Electron microscopy of these regions showed endoplasmic reticulum membrane proliferation, and tubular and spherical structures in the cisternae of the endoplasmic reticulum, Golgi complex and nuclear envelope. At seven to eight days pi, infected neurones exhibited chromatin condensation and extrusion, nuclear fragmentation, loss of segments of the nuclear envelope, reduced surface contact with adjacent cells and loss of cytoplasmic organelles. This cell injury was particularly noticeable in the proximal CA3 and distal CA1 regions of the hippocampus. The inflammatory cell profile consisted of macrophages, lymphocytes and especially neutrophils, and many of these inflammatory cells were apoptotic. High mortality rates in the BH3479-infected population of mice correlated with the intense polymorphonuclear and mononuclear leucocyte inflammatory infiltrate in the CNS.     

Early developing B cells undergo negative selection by central nervous system-specific antigens in the meninges

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Mortality following peripheral infection with Tick-borne encephalitis virus results from a combination of central nervous system pathology, systemic inflammatory and stress responses

Tick-borne encephalitis virus (TBEV) induces acute central nervous system (CNS) disease in humans. In this study, we investigate the pathogenetic mechanisms that correlate with fatal infection with TBEV in a mouse model. Following subcutaneous infection with high challenge doses (> 10⁷ PFU), mice started to die early (8 days) and mortality rates reached > 80%. These doses induced acute and widespread infection of the CNS. On the other hand, following subcutaneous infection with low challenge doses (10²-10⁶ PFU), mice started to die late (11 days) and approximately one half of the mice survived but exhibited degrees of encephalitis similar to dying mice. However, low dose dying mice exhibited severe systemic stress response, and increased levels of TNF-α compared with recovering mice. We therefore conclude that in addition to the development of CNS disease, systemic inflammatory and stress responses contribute to induce a fatal infection following subcutaneous infection of mice with TBEV.     

Lethal encephalitis and non-lethal multifocal central nervous system demyelination in herpes simplex virus type 2 infections in mice.

Six-week-old Swiss-Webster mice were infected intracerebrally with a low dose of herpes simplex virus type 2 (HSV-2) and were studied by pathological, virological and immunological methods. One third of mice developed severe neurological disease and died during the first 31/2 weeks of infection, while the remaining two thirds survived this acute stage with relatively minor neurological signs. These survivors had multifocal demyelinative white-matter lesions in the CNS, and gray-matter lesions, if present, were few, small and usually minor. By contrast, groups of mice killed during the acute stage had a much greater proportion of gray-matter lesions, and these were frequently larger and more severe. Two subgroups could be identified in the acute stage. Mice with severe gray-matter disease, high virus titres, abundant viral antigen and later virus clearance had more severe neurological signs leading to death. By contrast, those destined to survive had pupillary signs alone, and pathologically had white-matter lesions of primary demyelination with minimal or no evidence of gray-matter involvement, low levels of detectable virus and earlier virus clearance. These results show that HSV-2 can produce non-lethal CNS disease in a high proportion of mice, even if infected by the intracerebral route, and that the lesions, which may be found throughout the CNS, are mainly in the white matter, and are demyelinative in type. Survivors of this infection may be useful in a search for evidence of herpes-virus persistence in the CNS, and for a role of this virus in chronic demyelinating disease.     

原发性中枢神经系统淋巴瘤临床病理及病因学分析

目的 探讨原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma, PCNSL)的临床病理特征、预后指标及病因学.方法 复习39例PCNSL患者的临床资料,同时进行免疫组化、原位杂交检测EBER及PCR检测bcl-2/JH基因重排,并对临床资料、免疫标志物与预后的关系进行分析.结果 34例PCNSL患者的3年生存率为46.4%,5年生存率为27.1%,年龄≥60岁及病变部位深对预后不利(P=0.009和P=0.027),bcl-6阳性表达者的生存率高于阴性表达者(P=0.044),但多因素Cox回归分析显示,进入回归方程的为年龄因素.CD10/bcl-6/MUM-1/CD138分型和治疗方法对预后的判断无显著性差异(P＞0.05).39例患者EBER原位杂交均为阴性,bcl-2/JH基因重排5例阳性(12.8%),其中3例为CD10阳性病例.结论 PCNSL是一种少见的高侵袭性结外非霍奇金淋巴瘤,年龄因素是判断预后的独立性指标,CD10/bcl-6/MUM-1/CD138分型未发现有预后意义,但显示PCNSL的同质性较高,可能是弥漫性大B细胞淋巴瘤的一种亚型.EB病毒感染与PCNSL的病因无相关性.     

A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord

We examined the role of tumor necrosis factor receptor 1 (TNFR1) in inflammation initiated by the adoptive transfer of central nervous system (CNS)-specific Th1 cells in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. This adoptive transfer paradigm eliminates the confounding effects of bacterial adjuvants in the analysis of inflammation. We found that although T cells could reach the meninges and perivascular space in the absence of TNFR1, recruitment of other inflammatory cells from the blood was dramatically reduced. The reduction in the recruitment of CD11b(hi) cells correlated with a dramatic reduction in the production of the chemokines CCL2 (MCP-1) and CXLC2 (MIP-2) in TNFR1-deficient hosts. Bone marrow chimera experiments demonstrated that TNF can be effectively supplied by either the hematopoietic system or the CNS, but the essential TNFR1-responsive cells reside in the CNS. Previous work has demonstrated that microglia produce CCL2, and here we demonstrate that astrocytes and endothelial cells produced CXCL2 in the early stages of inflammation. Therefore, productive inflammation results from a conversation, or mutually responding signals, between the initiating T cells and cells in the parenchyma of the spinal cord.     

Epidermoid cysts in the central nervous system of mice

Two epidermoid cysts are described in mice, one intracranial, in the fourth ventricle and the other in the thoracic spinal canal. They were lined by compressed squamous epithelium and contained keratinaceous squamae. These incidental findings suggest that such cysts might be detected more often if more extensive examinations of the CNS were carried out in group studies.     

Eye pathology associated with measles encephalitis in hamsters

Summary Measles encephalitis was produced in 41 hamsters by intracerebral injection of the hamster-neuroadapted Mantooth HBS viral strain. Group I (n=10) included 2-day old (newborn) hamsters, each inoculated with 0.02 ml of 1:20 diluted virus. This group was sacrificed 4 days postinoculation (DPI). Group II (n=31) included 25-day old hamsters, each inoculated with 0.03 ml of 1:10 diluted virus. This group was sacrificed 6, 13, 17, and 31 DPI. Clinical and histological evidence of measles encephalitis was present in all infected hamsters. Retinal lesions varied with the age of the animals at the time of inoculation. Retinal folds were observed in the 2-day old group and represented one form of retinal dysplasia. In the 25-day old group, however, earliest retinal involvement was in the form of hemorrhages, followed by focal retinitis in animals sacrificed 6–17 DPI. Measles keratitis was noted only in animals sacrificed 6 DPI. In 25-day old hamsters, measles keratitis and retinal hemorrhages represented the acute manifestations, whereas retinitis occurred later. However, ocular involvement did not correlate with the degree of severity of measles encephalitis.     

Emergence and re-emergence of viral diseases of the central nervous system

Neurologic disease is a major cause of disability in resource-poor countries and a substantial portion of this disease is due to infections of the CNS. A wide variety of emerging and re-emerging viruses contribute to this disease burden. New emerging infections are commonly due to RNA viruses that have expanded their geographic range, spread from animal reservoirs or acquired new neurovirulence properties. Mosquito-borne viruses with expanding ranges include West Nile virus, Japanese encephalitis virus and Chikungunya virus. Zoonotic viruses that have recently crossed into humans to cause neurologic disease include the bat henipaviruses Nipah and Hendra, as well as the primate-derived human immunodeficiency virus. Viruses adapt to new hosts, or to cause more severe disease, by changing their genomes through reassortment (e.g. influenza virus), mutation (essentially all RNA viruses) and recombination (e.g. vaccine strains of poliovirus). Viruses that appear to have recently become more neurovirulent include West Nile virus, enterovirus 71 and possibly Chikungunya virus. In addition to these newer challenges, rabies, polio and measles all remain important causes of neurologic disease despite good vaccines and global efforts toward control. Control of human rabies depends on elimination of rabies in domestic dogs through regular vaccination. Poliovirus eradication is challenged by the ability of the live attenuated vaccine strains to revert to virulence during the prolonged period of gastrointestinal replication. Measles elimination depends on delivery of two doses of live virus vaccine to a high enough proportion of the population to maintain herd immunity for this highly infectious virus.     

Exacerbated graft-versus-host disease in Pirb-/- mice

Immune responses are often regulated by opposing receptor pairs that recognize the same ligand but deliver either activating or inhibitory signals. Paired immunoglobulin-like receptors (PIRs) expressed on B cells and myeloid cells comprise a major histocompatibility complex class I recognition system that regulates the responsiveness of these cells. Here, activating PIR-A and inhibitory PIR-B bound various mouse major histocompatibility complex class I (H-2) molecules, and in vitro H-2 tetramer stimulation of PIR-B on B cells or PIR-A on macrophages induced intracellular phosphotyrosine signaling. After transfer of allogeneic splenocytes into PIR-B-deficient mice, the mice showed exacerbated graft-versus-host disease, which was due to augmented activation of recipient dendritic cells with concomitant upregulation of PIR-A and increased interferon-gamma production. PIR-A-induced dendritic cell activation also led to increased proliferation of donor cytotoxic T cells. Thus, PIR-A and PIR-B are counteracting receptors that are essential for successful tissue transplantation and may regulate irrelevant reaction to autologous tissues in a constitutive way in physiological conditions.     

Vaccination of mice with gonococcal TbpB expressed in vivo from Venezuelan equine encephalitis viral replicon particles

We investigated the immunogenicity of gonococcal transferrin binding protein B (TbpB) expressed with and without a eukaryotic secretion signal from a nonpropagating Venezuelan equine encephalitis virus replicon particle (VRP) delivery system. TbpB was successfully expressed in baby hamster kidney (BHK) cells, and the presence of the eukaryotic secretion signal not only apparently increased the protein's expression but also allowed for extracellular localization and glycosylation. Mice immunized with VRPs produced significant amounts of serum antibody although less than the amounts produced by mice immunized with recombinant protein. The response of mice immunized with VRPs encoding TbpB was consistently more Th1 biased than the response of mice immunized with recombinant protein alone. Boosting with recombinant protein following immunization with TbpB VRPs resulted in higher specific-antibody levels without altering the Th1/Th2 bias. Most of the immunization groups produced significant specific antibody binding to the intact surface of the homologous Neisseria gonorrhoeae strain. Immunization with TbpB VRPs without a eukaryotic secretion signal generated no measurable specific antibodies on the genital mucosal surface, but inclusion of a eukaryotic secretion signal or boosting with recombinant protein resulted in specific immunoglobulin G (IgG) and IgA in mucosal secretions after TbpB VRP immunization. The TbpB VRP system has potential for an N. gonorrhoeae vaccine.