Combined Clinical, Viral And Immunological Studies In Ne

临床和实验室研究是为了确定各种神经肌肉疾病的病因(感染、免疫和/或遗传学)并设计有效的治疗方法。目前的研究涉及炎症性肌病(多发性肌炎、皮肌炎、包涵体肌炎)、以脊髓灰质炎后综合征为重点的运动神经元疾病、脱髓鞘多神经病、低钾性周期性瘫痪、以结蛋白和结蛋白相关的肌病为重点的营养不良症，以及僵人综合征(SPS)。在炎症性肌病中，研究了T细胞侵袭的机制和抗原驱动的T细胞反应。具体地说，研究了细胞因子，转化生长因子-β，白介素1，金属蛋白酶-2和基质金属蛋白酶-9，在促进淀粉样蛋白形成和持续性内膜炎症中的作用。通过检测T细胞受体图谱和CDR3区序列，研究肌内T细胞的抗原特异性和原位克隆扩增。研究了肌纤维作为抗原提呈细胞并与其T细胞上的配体CTLA-4和CD28结合的能力。通过对IAP样蛋白及其信使核糖核酸的研究，探讨了肌肉和肌内T细胞缺乏凋亡的原因。在实验上，利用纤维连接蛋白多肽作为新的治疗方法，研究了转化生长因子-β双基因敲除小鼠对肌内膜炎症反应的抑制作用。在脱髓鞘神经病中，发现雪旺细胞表现为抗原提呈细胞。它们表达BB1，而自侵袭性的CD4T细胞在蛋白和mRNA水平上表达共刺激分子CTLA和CD28。在核苷类似物引起的神经病变中，轴突和雪旺细胞出现线粒体膜功能障碍，并且由于伽马-DNA聚合酶的抑制而导致神经mtDNA的耗竭。在SPS患者中，鞘内合成了抗GAD特异性抗体。用MRS检测脑脊液和脑组织中的GABA水平，探讨抗GAD抗体在体内抑制GABA合成的作用。研究了与心肌病相关的远端肌病的原因，并鉴定了结蛋白基因的突变。研究了这些突变在转基因细胞系中的功能作用，并探索了突变的结蛋白细丝的溶解性。这种突变的患者现在进行了表型/基因相关研究。大剂量静脉注射免疫球蛋白的随机对照临床试验已经在皮肌炎、包涵体肌炎和SPS患者中完成。治疗后检测细胞因子谱和抗GAD65抗体效价的变化，并与临床疗效进行相关性分析。

Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various neuromuscular diseases and design effective therapies. Current studies involve patients with inflammatory myopathies (polymyositis, dermatomyositis, inclusion body myositis), motor neuron disorders with emphasis on post-polio syndrome, demyelinating polyneuropathies, hypokalemic periodic paralysis, dystrophies with emphasis on desmin and desmin related myopathies, and the stiff-person syndrome (SPS). In inflammatory myopathies, the mechanism of T cell invasion and the antigen-driven T cell responses are examined. Specifically, the role of cytokines, TGF-beta, 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 was studied by examining the T cell receptor profile and sequencing of the CDR3 region. The capacity of the muscle fibers to behave as antigen-presenting cells and bind to their ligands CTLA-4 and CD28 on T cells, was studied. The lack of apoptosis in the muscle and endomysial T cells was explored by studying IAP- like proteins and their mRNA's. Experimentally, the suppression of endomysial inflammatory response was studied in TGF-beta double knock-out mice, using fibronectin peptide motifs as novel therapies. In demyelinating neuropathies it was found that the Schwann cells behave as Antigen Presenting Cells. They express BB1, while the autoinvasive CD4+ T cells express the co-stimulatory molecules CTLA and CD28 at the protein and mRNA level. In the neuropathies caused by nucleoside analogues, there was mitochondiral dysfunction in the axon and Schwann cell and depletion of the nerve's mtDNA due to inhibition of the gamma-DNA polymerase. In patients with SPS, intrathecal synthesis of anti-GAD specific IgG antibodies was documented. The role of anti-GAD antibodies in suppressing the synthesis of GABA in vivo was explored by examining the GABA level in the CSF and the brain using MRS spectroscopy. The cause of distal myopathies associated with cardiomyopathies was examined and mutations in the desmin gene were identified. The functional role of these mutations was studied in transfected cell lines and the solubility of mutant desmin filaments was explored. A phenotype/genotype correlation is now performed in patients with this mutation. Randomized-controlled clinical trials with high-dose intravenous immunoglobulin have been completed in patients with dermatomyositis, inclusion body myositis and SPS. Changes in the cytokines profile and the anti-GAD65 antibody titers were determined after therapy and correlated with clinical response.