T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.

Multiple sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral encephalomyelitis and because of the presence in the blood of multiple sclerosis patients of in vivo-activated T cells reactive to myelin basic protein. Immune involvement in multiple sclerosis has been further suggested by the association with the major histocompatibility complex class II phenotype DR2, DQw1. To define the T-cell specificity toward myelin basic protein, 15,824 short-term T-cell lines were established from multiple sclerosis subjects, subjects with other neurological diseases, and normal controls. Here we report a higher frequency of T-cell lines reactive with a DR2-associated region of myelin basic protein between residues 84-102 in patients with multiple sclerosis compared with controls. A second region, identified between residues 143-168, was recognized equally in multiple sclerosis patients and controls and was associated with the DRw11 phenotype. These DR2 and DRw11 associations were also observed among T-cell lines generated from family members of a multiple sclerosis patient. The immunodominant 84-102 peptide from myelin basic protein was both DR2- and DQw1-restricted among different T-cell lines. These results raise the possibility that this immunodominant region may be encephalitogenic in some DR2+ individuals.     

Cannabinoids control spasticity and tremor in a multiple sclerosis model

Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future.     

Paramyxovirus SV5 and multiple sclerosis

Multiple sclerosis is commonly associated with a local humoral immune response within the central nervous system. A hallmark of this intrathecal response is the presence of electrophoretically demonstrable oligoclonal bands of IgG in the cerebrospinal fluid (CSF) of up to 95% of patients. Observations indicating that a major part of the CSF IgG in some patients may represent antibodies to SV5, a simian virus closely related to human parainfluenza type 2 virus, were recently reported by Goswami et al. We have studied thirty patients with multiple sclerosis, but although we find intrathecal synthesis of IgG antibodies reacting with SV5 in seven of these, the antibodies were not associated with oligoclonal CSF IgG bands and could in each case be explained as potentially cross-reacting antibodies to other paramyxoviruses known to be human pathogens. We have therefore been unable to confirm that SV5 may be a major intrathecal immunogen in multiple sclerosis.     

Treatment of severe autoimmune disease by stem-cell transplantation

Transplantation of haematopoietic stem cells--cells capable of self renewing and reconstituting all types of blood cell--can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.     

Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets

Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.     

Inflammation and therapeutic vaccination in CNS diseases

The spectrum of inflammatory diseases of the central nervous system has been steadily expanding from classical autoimmune disorders such as multiple sclerosis to far more diverse diseases. Evidence now suggests that syndromes such as Alzheimer's disease and stroke have important inflammatory and immune components and may be amenable to treatment by anti-inflammatory and immunotherapeutic approaches. The notion of 'vaccinating' individuals against a neurodegenerative disorder such as Alzheimer's disease is a marked departure from classical thinking about mechanism and treatment, and yet therapeutic vaccines for both Alzheimer's disease and multiple sclerosis have been validated in animal models and are in the clinic. Such approaches, however, have the potential to induce unwanted inflammatory responses as well as to provide benefit.     

Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement

Oligodendrocytes synthesize myelin in the central nervous system and maintain it in lamellar sheaths around axons. Techniques for studying oligodendrocyte development in vitro can be used, indirectly, to investigate the myelin injury that occurs in human and experimental demyelinating disease. Cell-mediated immune mechanisms are necessary but not sufficient to induce myelin damage in vivo; more recently complement has also been implicated in the pathogenesis both of multiple sclerosis and experimental allergic encephalomyelitis. Previously we have demonstrated that antibody-independent complement activation occurs in vitro at the oligodendrocyte surface. Here we show that the ensuing oligodendrocyte injury is reversible, and that recovery involves the release of membrane-attack complex-enriched vesicles from the surface of viable cells. The demonstration of morphologically and immunochemically identical vesicles in the cerebrospinal fluid of patients with multiple sclerosis suggests that reversible complement-mediated injury contributes to myelin damage in vivo.     

A shared antigenic determinant between natural killer cells and nervous tissue

Considerable evidence for shared antigenic determinants between nervous elements and lymphocytes has accumulated. It has also been suggested that this cross-recognition may be involved in the pathogenesis of human neurological diseases such as myasthenia gravis and multiple sclerosis. We report here evidence that a marker for natural killer (NK) cells, anti-Leu-7 (HNK-1), specifically binds to components of human and rodent central nervous tissue as well as peripheral nervous tissue, especially to myelin sheaths. In contrast, another NK-cell marker (VEP13) did not react with nervous tissue. Since NK-cell function is impaired in a population of multiple sclerosis patients, the observed cross-reactivity indicates that autosensitization against myelin may simultaneously cause a defect of NK-cell function. Furthermore, the shared antigenic determinant may help to identify a hitherto undefined nervous tissue antigen and simultaneously increase the knowledge about the nature of NK-cell antigens.     

Antibodies against the paramyxovirus SV5 in the cerebrospinal fluids of some multiple sclerosis patients

Multiple sclerosis is a demyelinating disease of the central nervous system and although there is little doubt that an infectious agent (or agents) is involved it has not been possible to demonstrate this unequivocally by any direct relationship to a given agent. Here we show that a significant proportion of patients with multiple sclerosis have antibodies against the paramyxovirus SV5 (simian virus 5) in their cerebrospinal fluid and in some of these such antibodies form a major proportion of the total immunoglobulin content. Further, we have been able to demonstrate that the oligoclonal bands displayed on electrophoresis of the cerebrospinal fluid of these patients can be removed by prior absorption with SV5 virus antigen.     

Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory condition of the central nervous system with similarities to multiple sclerosis. In both diseases, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis. We sought to identify the adhesion receptors that mediate the attachment of circulating leukocytes to inflamed brain endothelium in EAE, because this interaction is the first step in leukocyte entry into the central nervous system. Using an in vitro adhesion assay on tissue sections, we found that lymphocytes and monocytes bound selectively to inflamed EAE brain vessels. Binding was inhibited by antibodies against the integrin molecule alpha 4 beta 1, but not by antibodies against numerous other adhesion receptors. When tested in vivo, anti-alpha 4 integrin effectively prevented the accumulation of leukocytes in the central nervous system and the development of EAE. Thus, therapies designed to interfere with alpha 4 beta 1 integrin may be useful in treating inflammatory diseases of the central nervous system, such as multiple sclerosis.     

Absence of expression of OKT8 antigen on cultured human, calf and rat oligodendrocytes

Monoclonal antibodies which recognize human suppressor T cells (OKT8) have been reported by Oger and co-workers to bind to cultured sheep oligodendrocytes. These authors speculated that an immune response directed at determinants shared by suppressor lymphocytes and oligodendrocytes could explain the decrease in both circulating blood suppressor T cells and oligodendrocytes in patients with multiple sclerosis. In view of the vital issue of potential cross-reactivity between oligodendrocytes and lymphocytes, we studied the binding of viable cultured calf, rat and human oligodendrocytes using monoclonal antibodies to human T cells and monocytes. We report here that we were unable to confirm the presence of shared determinants among oligodendrocytes and any leukocytes, including human T cells or monocytes. As the reported observations of lymphocyte-oligodendrocyte shared determinants could not be identified in three other species, including man, we found no evidence to support the hypothesis that such shared determinants are of importance in the pathogenesis of multiple sclerosis.     

针对多发性硬化症病人的综合步态分析

 设计了一个针对多发性硬化症患者的三维步态分析实验,利用三维光学捕捉系统对实验被试身体不同部位标记点的三维坐标进行追踪和记录,成功发现了多个步态参数发生的变化,这些变化不仅能反映实验被试细微的步态功能上的变化,而且还与接受治疗的时间密切相关。此套基于步态数据的量化评估体系能够弥补目前广泛应用的评估方法主观和不够准确的缺点,为临床医生改进治疗方案以及制定更加有效的治疗方法提供帮助。     

多发性硬化误诊分析

多发性硬化是一种青壮年起病的中枢神经系统炎性脱髓鞘病 ,发病病因至今未明。其特点为病灶多发 ,病程中常有缓解与复发 ,由于病灶不定 ,临床表现不尽相同。在疾病早期或初次发病时易误诊为椎基底动脉供血不足 ,颈椎病 ,脑梗塞 ,散发性脑炎。其他多神经损害的内科疾病也易误诊为该疾病。文章中提出了一系列措施可防止误诊发生     

Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis

Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. We established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis--experimental autoimmune encephalomyelitis (EAE) in the mouse--either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.     

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.     

女子篮球运动员气质类型分析

女子篮球运动员气质类型分析李颂（呼和浩特市交通学校，呼和浩特，０１００２０）中图分类号Ｇ８４１，Ｇ８０４．８５气质是决定人的个性心理特征因素之一，一般分为胆汁质、多血质、粘液质、抑郁质４种类型以及它们之间的多种混合型．笔者对运动员心理选材的内容及个性...     

他汀类药物与免疫调节

目的:综述他汀类药物的作用及应用前景.方法:回顾学习他汀类药物研究的文献.结果:他汀类药物通过竞争性的抑制HMG-CoA还原酶而减少胆固醇的生物合成,作为降脂药由于它的安全有效性已广泛应用于临床.他汀类对自身免疫疾病如多发性硬化、动脉粥样硬化、器官移植排斥反应及糖尿病等有较好的治疗效果.结论:他汀类具有抗炎免疫调节作用,应用前景好.     

骨纤维异常增殖症的临床分型及其影像学诊断

目的提高对骨纤维异常增殖症的临床分型认识以及影像学诊断水平。方法结合文献，对经病理证实的27例骨纤维异常增殖症的临床、x线平片、CT和MR资料进行观察分析。根据病变的范围和临床表现进行分型，探讨其各自影像学表现。结果27例骨纤维异常增殖症中，单骨局灶型病变4例，均发生于股骨上段，表现为边界清楚、形态规则且伴有硬化边的囊状病变，病灶内密度高于肌肉，可见斑片状、条絮状钙质样高密度影；单骨广泛型和多骨广泛型病变分别为6例和14例，均表现为囊状膨胀性骨质破坏，毛玻璃样密度，累及范围广泛，边界不清，无硬化边，在MRI上T1WI以等信号为主，脂肪抑制T2WI以稍高信号为主，增强扫描后不均匀较明显强化；多骨广泛型病变合并皮肤色素沉着、性早熟等临床表现即Albright综合症3例。结论不同类型的骨纤维异常增殖症，其临床和影像学表现有所不同，但均以病灶内出现条絮状骨化呈毛玻璃样密度为影像学诊断的共同特征。     

Increased levels of myelin basic protein transcripts in virus-induced demyelination

In multiple sclerosis, a demyelinating disease of young adults, there is a paucity of myelin repair in the central nervous system (CNS) which is necessary for the restoration of fast saltatory conduction in axons. Consequently, this relapsing disease often causes marked disability. In similar diseases of small rodents, however, remyelination can be quite extensive, as in the demyelinating disease caused by the A59 strain of mouse hepatitis virus (MHV-A59), a coronavirus of mice. To investigate when and where oligodendrocytes are first triggered to repair CNS myelin in such disease, we have used a complementary DNA probe specific for one major myelin protein gene, myelin basic protein (MBP), which hybridizes with the four forms of MBP messenger RNA in rodents. Using Northern blot and in situ hybridization techniques, we previously found that MBP mRNA is first detected at about 5 days after birth, peaks at 18 days and progressively decreases to 25% of the peak levels in the adult. We now report that in spinal cord sections of adult animals with active demyelination and inflammatory cells, in situ hybridization reveals a dramatic increase in probe binding to MBP-specific mRNA at 2-3 weeks after virus inoculation and before remyelination can be detected by morphological methods. This increase of MBP-specific mRNA is found at the edge of the demyelinating area and extends into surrounding areas of normal-appearing white matter. Thus, in situ hybridization with myelin-specific probes appears to be a useful method for detecting the timing, intensity and location of myelin protein gene reactivation preceding remyelination. This method could be used to elucidate whether such a reactivation occurs in multiple sclerosis brain tissue. Our results suggest that in mice, glial cells react to a demyelinating process with widespread MBP mRNA synthesis which may be triggered by a diffusible factor released in the demyelinated areas.