COMBINED CLINICAL, VIRAL AND IMMUNOLOGICAL STUDIES IN NEUROMUSCULAR DISEASES

进行临床和实验室研究，以确定神经肌肉系统各种疾病的病因（感染，免疫和/或遗传学），并设计有效的治疗方法。目前的研究涉及患有多发性肌炎、皮肌炎、包涵体肌炎、运动神经元疾病（包括脊髓灰质炎后综合征）、脱髓鞘性多发性神经病、与HIV感染相关的神经肌肉疾病、代谢性肌病、低钾性周期性麻痹、某些营养不良和僵人综合征的患者。持续性或突变型脊髓灰质炎病毒在脊髓灰质炎后综合征和ALS患者中寻找。脊髓灰质炎后疲劳的机制，在许多患者中常见的和致残的症状，通过分析神经内分泌轴，磁共振波谱和睡眠研究。在炎性肌病中，研究了细胞因子TGF-β和IL-1以及金属蛋白酶MMP-2和MMP-9在促进淀粉样蛋白形成和持续性肌内膜炎症中的作用。通过检查T细胞受体谱和对CDR 3区进行测序，研究了炎性肌病和神经病患者肌内膜T细胞的抗原特异性和原位克隆扩增。检测肌纤维或雪旺细胞作为抗原呈递细胞并与T细胞上的配体CTLA-4和CD 28结合的能力。通过研究IAP样蛋白和mRNA表达，探讨了肌肉和T细胞中凋亡的缺乏。研究了抗逆转录病毒核苷类似物引起肌肉和神经中线粒体功能障碍和mDNA缺失的机制。研究了僵硬人综合征患者抗GAD抗体的细胞毒性基础，并在体内、体外以及治疗期间研究了抗体滴度的变化。目前正在研究两性霉素和GAD在这种疾病中的作用，以及其他影响突触传递的自身免疫性疾病。研究了与心肌病相关的远端肌病的原因，并在同一患者中发现了结蛋白基因突变。在转染的细胞系中研究了这些突变的功能作用。某些IgM相关的副蛋白血症性神经病作为抗原的糖脂类型也进行了检查。随机对照临床试验进行了高剂量静脉注射免疫球蛋白的患者多发性肌炎，皮肌炎，包涵体肌炎，某些自身免疫性脱髓鞘性多发性神经病和僵硬的人综合征。 在实验上，使用纤连蛋白肽基序作为实验疗法研究了TGF-β双敲除小鼠中肌内膜炎症反应的抑制。

Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various diseases of the neuromuscular system and design effective therapies. Current studies involve patients with polymyositis, dermatomyositis, inclusion body myositis, motor neuron diseases including post-polio syndrome, demyelinating polyneuropathies, neuromuscular diseases associated with HIV infection, metabolic myopathies, hypokalemic periodic paralysis, certain dystrophies, and stiff-person syndrome. Persistent or mutant poliovirus is sought in patients with post-polio syndrome and ALS. The mechanism of post-polio fatigue, a common and disabling symptom in many patients, is examined by analysis of the neuroendocrine axis, magnetic resonance spectroscopy and sleep studies. In inflammatory myopathies, the role of cytokines TGF-beta and IL-1 and metalloproteinases MMP-2 and MMP-9 in promoting amyloid formation and persistent endomysial inflammation were studied. The antigenic specificity and in situ clonal expansion of the endomysial T cells of patients with inflammatory myopathies and neuropathies was studied by examining the T cell receptor profile and sequencing the CDR3 region. The capacity of the muscle fiber or the Schwann cell to behave as antigen-presenting cells and bind to their ligands, CTLA-4 and CD28, on T cells was examined. The lack of apoptosis in muscle and T cells was explored by studying IAP-like proteins and mRNA expression. The mechanism by which anti-retroviral nucleoside analogs cause mitochondrial dysfunction and mDNA deletion in muscle and nerve was investigated. The cytotoxic basis of anti-GAD antibodies in patients with stiff-man syndrome was investigated and changes in the antibody titers were studied in vivo and in vitro as well as during therapy. The role of amphiphysin and GAD in this disease, as well as other autoimmune disorders affecting synaptic transmission, are being explored. The cause of distal myopathies associated with cardiomyopathies was examined and mutations in the desmin gene were discovered in the same patients. The functional role of these mutations was studied in transfected cell lines. The type of glucolipids recognized as antigens by certain IgM-associated paraproteinemic neuropathies was also examined.Randomized-controlled clinical trials were conducted with high-dose intravenous immunoglobulin in patients with polymyositis, dermatomyositis, inclusion body myositis, certain autoimmune demyelinating polyneuropathies and in the stiff-person syndrome. Experimentally, the suppression of the endomysial inflammatory response in TGF-beta double knock-out mice was studied using fibronectin peptide motifs as experimental therapies.