Combined Clinical, Viral And Immunological Studies In Ne

进行临床和实验室研究，以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（多肌炎、皮肌炎、包体体肌炎）、运动神经元疾病（重点是脊髓灰质炎后综合征）、脱髓鞘性多神经病变、低钾性周期性麻痹、营养不良（重点是desmin和desmin相关的肌病）和僵硬人综合征（SPS）的患者。在炎性肌病，机制的T细胞入侵和抗原驱动的T细胞反应进行了检查。具体来说，研究了细胞因子tgf - β、IL-1和金属蛋白酶MMP-2和MMP-9在促进淀粉样蛋白形成和持续肌内膜炎症中的作用。通过检测T细胞受体谱和CDR3区序列，研究肌内膜T细胞的抗原特异性和原位克隆扩增。研究了肌肉纤维作为抗原呈递细胞并与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mRNA的研究，探讨了肌和肌内膜T细胞缺乏凋亡的原因。实验中，在tgf - β双敲除小鼠中研究了肌内膜炎症反应的抑制，使用纤维连接蛋白肽基序作为新疗法。在脱髓鞘性神经病中，雪旺细胞表现为抗原提呈细胞。它们表达BB1，而自身侵袭性CD4+ T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，轴突和雪旺细胞存在线粒体功能障碍，神经mtDNA由于γ - dna聚合酶的抑制而耗竭。在SPS患者中，记录了鞘内合成抗gad特异性IgG抗体。利用MRS波谱法检测脑脊液和脑内GABA水平，探讨抗gad抗体在体内抑制GABA合成中的作用。研究了与心肌病相关的远端肌病的原因，并确定了desmin基因的突变。在转染细胞系中研究了这些突变的功能作用，并探讨了突变蛋白丝的溶解度。现在对这种突变的患者进行表型/基因型相关性分析。大剂量静脉注射免疫球蛋白治疗皮肌炎、包涵体肌炎和SPS患者的随机对照临床试验已经完成。治疗后测定细胞因子谱和抗gad65抗体滴度的变化，并与临床反应相关。

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.