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。目前的研究涉及的患者有：a)炎症性肌病，重点是包涵体肌炎（IBM）；B)中间纤维相关疾病，重点是与末梢相关的神经肌肉疾病；C)脱髓鞘性多发性神经病；d)僵硬人综合症（SPS）。在炎性肌病中，我们检测了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，IBM的T细胞是由特定抗原驱动的。为了寻找假定的抗原，从肌内膜T细胞浸润中建立了T细胞克隆；目前正在使用组合肽库探索驱动T细胞反应并作为自身抗原的候选免疫优势肽。研究发现，在IBM中，趋化因子和共刺激分子如ICOS和ICOS- l上调，肌纤维可能具有抗原提呈细胞的功能。由于细胞因子与阿尔茨海默样β - app淀粉样蛋白沉积物具有共同的抗原决定因子，一项正在进行的研究探索了淀粉样蛋白在引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，设计了一项治疗性和研究性临床试验，使用CAMPATH，一种人源化单克隆抗体，诱导成熟T细胞持续耗竭，允许耐受性T细胞反应。

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).