Combined Clinical, Viral And Immunological Studies In Ne

临床、实验室和治疗研究是为了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)炎症性肌病，重点是包涵体肌炎(IBM)；b)中间丝相关疾病，重点是结蛋白相关的神经肌肉疾病；c)脱髓鞘多神经病；d)僵人综合征(SPS)。 在炎症性肌病中，检测T细胞受体的特异性和肌内T细胞的原位克隆性增殖。研究表明，IBM的T细胞是由特定的抗原驱动的。为了寻找可能的抗原(S)，已经从肌内T细胞浸润物中建立了T细胞克隆；目前利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。已经发现，在IBM中，细胞因子与类阿尔茨海默病的β-APP淀粉样沉积具有共同的抗原决定因素，这促使一项正在进行的研究探索淀粉样蛋白在触发肌内膜炎中的作用。这些信息将有助于IBM寻求抗淀粉样蛋白策略作为潜在的治疗方法。为了抑制T细胞的肌细胞毒作用及其在促进β-APP形成中的可能作用，设计了一项使用人源化单抗CamPath的治疗性和研究性临床试验，该抗体可诱导成熟T细胞的持续耗竭，从而产生耐受性T细胞反应。 在脱髓鞘神经病中，雪旺细胞表达抗原提呈细胞的标志，而自身侵袭性的CD4T细胞在蛋白和mRNA水平上表达共刺激分子CTLA和CD28。IVIg在影响这些分子和其他自身抗体方面的作用机制已经被解决。为了确定导致脱髓鞘神经病的周围神经抗原并寻找有效的治疗方法，利用人源化的抗B细胞克隆的单抗设计了一项新的对照治疗研究。这项研究将临床反应与IgM与抗糖结合抗体的结合亲和力联系起来。 在僵人综合征(SPS)患者中，鞘内合成了抗GAD特异性抗体。抗GAD抗体似乎抑制了体内GABA的合成，支持了GABA水平降低与患者症状相关的观点。由于GABA介导的抑制性中间神经元功能障碍而表现出的僵硬和高度敏感性的表现，已经通过发现脑干神经元间回路的超兴奋性得到了电生理学的支持。在SPS患者中进行了大剂量静脉注射免疫球蛋白的随机对照临床试验，证明了该药物的有效性，证实了该疾病的自身免疫性。治疗后，抗GAD65抗体滴度下降。这是第一个被证明对这种疾病有效的免疫疗法。为了寻找相关的自身抗原，从几个SPS患者的脑脊液中建立了T细胞克隆；GAD和其他多肽作为抗原的作用目前还在探索中。 在对IBM患者的调查中，根据临床病理标准，发现了一组与心肌病相关的独特的遗传性远端肌病。更多的研究表明，这种疾病是由结蛋白基因的致病突变引起的。研究了突变在细胞系中的功能作用，并对突变结蛋白细丝的溶解性进行了研究。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(细丝病)。

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 cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, prompting an ongoing study that 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, it was found that the Schwann cells express markers for Antigen Presenting Cells while the autoinvasive CD4+ T cells express the co-stimulatory molecules CTLA and CD28 at the protein and mRNA level. The mechanism of action of IVIg in affecting these molecules and other autoantibodies has been addressed. In an effort to identify peripheral nerve antigens responsible for the demyelinating neuropathy and find effective therapies, a new controlled therapeutic study has been designed using a humanized monoclonal antibody against B cell clones. This study correlates clinical responses with the binding affinity of IgM to anti-glycoconjugate antibodies. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented. 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. A randomized-controlled clinical trial with high-dose intravenous immunoglobulin was conducted in SPS patients and demonstrated efficacy of the drug, confirming the autoimmune nature of the disease. After treatment, the anti-GAD65 antibody titers diminished. This is the first immunotherapy proven effective in the disease. In an effort to find the responsible autoantigen, T cell clones were established from the CSF of several patients with SPS; the role of GAD as well as other peptides serving as antigens is currently explored. During the investigation of patients with IBM, a group of distinct hereditary distal myopathies associated with cardiomyopathy was identified on the basis of clinicopathological criteria. Additional studies have shown that this disease is 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).