Combined Clinical, Viral And Immunological Studies In Ne

进行临床、实验室和治疗研究，以确定各种神经肌肉疾病的病因（自身免疫、神经毒性、遗传学），并设计或应用有效的治疗方法。目前的研究涉及以下患者：a）炎性肌病，重点是包涵体肌炎（IBM）; B）中间丝相关疾病，重点是结蛋白相关神经肌肉疾病; c）脱髓鞘性多神经病;和d）僵硬人综合征（SPS）。在炎性肌病中，检测了T细胞受体的特异性和肌内膜T细胞的原位克隆扩增。研究表明，在IBM中，T细胞由特定抗原驱动。为了寻找推定的抗原，已经从肌内膜T细胞浸润中建立了T细胞克隆;目前使用组合肽文库探索了驱动T细胞应答并用作自身抗原的候选免疫显性肽。已经发现，在IBM中，趋化因子和共刺激分子如ICOS和ICOS-L被上调，并且肌纤维可以起到抗原呈递细胞的作用。由于细胞因子与阿尔茨海默病样β-APP淀粉样蛋白沉积物具有共同的抗原决定簇，一项正在进行的研究探讨了淀粉样蛋白在触发肌内膜炎症中的作用。这些信息将有助于寻求抗淀粉样蛋白策略作为IBM的潜在治疗方法。为了抑制T细胞的肌细胞毒性作用及其在增强β-APP形成中的假定作用，设计了使用CAMPATH的治疗性和研究性临床试验，CAMPATH是一种人源化单克隆抗体，其诱导成熟T细胞的持续消耗，从而允许耐受原性T细胞应答。 在与自身抗体相关的脱髓鞘神经病中，一项新的对照治疗研究已经开始使用针对B细胞克隆的人源化单克隆抗体。为了鉴定引起神经病变的周围神经抗原，该研究将临床反应与IgM对髓鞘上各种糖缀合物的结合亲和力相关联。 在僵直人综合征（SPS）患者中，鞘内合成抗GAD特异性IgG抗体的记录与临床病理学相关。抗GAD抗体似乎抑制GABA的体内合成，支持GABA水平降低与患者症状有因果关系的观点。由于GABA介导的抑制性中间神经元功能障碍而导致的僵硬和敏感性提高的表现已经通过发现脑干中间神经元回路的过度兴奋性而得到电生理学支持。用MRS光谱学研究脑中的GABA水平，并且正在检查治疗对GABA水平的影响。在努力寻找SPS患者中负责的自身抗原中，从CSF建立T细胞克隆;探索GAD以及作为抗原的其他肽的作用。 在调查IBM患者的过程中，确定了两组不同的遗传性远端肌病。一组与GNE基因突变有关，导致肌肉蛋白异常糖基化。另一组通常与心肌病有关，是由结蛋白基因的致病突变引起的。在转染细胞系中研究了突变的功能作用，并探索了突变结蛋白丝的溶解性。突变结蛋白患者的表型/基因型相关性现已完成。这些研究表明结蛋白肌病是一种影响中间丝的独特疾病（肌纤维肌病）。

Clinical, laboratory and therapeutic studies are conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Current studies involve patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) intermediate filament related disorders with emphasis on desmin-related neuromuscular disorders; c) demyelinating polyneuropathies; and d) the stiff-person syndrome(SPS). In inflammatory myopathies, the specificity of the T cell Receptors and the in situ clonal expansion of the endomysial T cells were examined. The studies have shown that in IBM the T cells are driven by specific antigens. To search for putative antigen(s), T cell clones have been established from the endomysial T cell infiltrates; candidate immunodominant peptides that drive the T cell responses and serve as autoantigens are currently explored using combinatorial peptide libraries. It has been found that in IBM chemokines and costimulatory molecules such as ICOS and ICOS-L are upregulated and the muscle fiber may function as Antigen Presenting cells. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an ongoing study explores the role of amyloid in triggering endomysial inflammation. The information will be useful in pursuing anti-amyloid strategies as potential therapy for IBM. To suppress the myocytotoxic effect of T cells and their putative role in enhancing the formation of beta-APP, a therapeutic and investigational clinical trial was designed using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. In demyelinating neuropathies associated with autoantibodies,a new controlled therapeutic study has started using a humanized monoclonal antibody against B cell clones. In an effort to identify peripheral nerve antigens responsible for the neuropathy, the study correlates clinical responses with the binding affinity of IgM to various glycoconjugates on the myelin sheath. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented and correlated with the clinical symptomatology. The anti-GAD antibodies appear to suppress the synthesis of GABA in vivo supporting the view that reduced GABA level is causatively related to the patients' symptoms. The manifestation of stiffness and heightened sensitivity as a result of dysfunction of the GABA-mediated inhibitory interneurons has been supported electrophysiologically by finding hyperexcitability of the brainstem interneuronal circuits. The GABA level in the brain was studied with MRS spectroscopy and the effect of therapies on GABA level is being examined. In an effort to find the responsible autoantigen in SPS patients, T cell clones were established from the CSF; the role of GAD as well as other peptides serving as antigens is explored. During the investigation of patients with IBM, two groups of distinct hereditary distal myopathies were identified. One group was related to mutations in the GNE gene resulting in abnormal glycosylation of muscle proteins. The other group, often associated with cardiomyopathy, was caused by pathogenic mutations in the desmin gene. The functional role of the mutations was studied in transfected cell lines and the solubility of mutant desmin filaments was explored. A phenotype/genotype correlation has now been completed in patients with mutant desmin. These studies have shown that desmin myopathy is a distinct disease affecting intermediate filaments (filamentopathy).