Clinical, Viral/mmune Studies In Neuromuscular Diseases

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。目前的研究涉及以下患者：a）炎症性肌病，重点是包涵体肌炎（IBM）; B）遗传性空泡性肌病，重点是由于GNE突变和结蛋白相关肌病引起的遗传性IBM; c）脱髓鞘性多发性神经病; d）脊髓灰质炎后综合征;和e）僵硬人综合征（SPS）。 在炎性肌病中，纵向检查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，在IBM中，T细胞由特定抗原驱动。为了寻找推定的抗原，已经从肌内膜T细胞浸润中建立了T细胞克隆;目前使用组合肽文库探索了驱动T细胞应答并用作自身抗原的候选免疫显性肽。已经发现，在IBM中，趋化因子和共刺激分子如ICOS、ICOS-L和PDI被上调，并且肌纤维可以作为抗原呈递细胞发挥功能。由于细胞因子与阿尔茨海默样β-APP淀粉样沉积物具有共同的抗原决定簇，因此探索了这些分子之间的相互关系。不仅在患者肌肉中，而且在体外人肌管中，细胞因子、趋化因子和淀粉样蛋白相关变性分子之间均存在线性关系。在临床层面，已经完成了一项纵向研究，检查IBM的自然史。为了抑制T细胞的肌细胞毒性作用，已经开始使用CAMPATH进行治疗性和研究性临床试验，CAMPATH是一种人源化单克隆抗体，其诱导成熟T细胞的持续消耗，从而允许耐受原性T细胞应答。到目前为止，已经治疗了6名患者。这项研究正在进行中。 在与MAG和糖脂的IgM自身抗体相关的脱髓鞘性神经病中，使用针对B细胞克隆的人源化单克隆抗体进行了一项新的对照治疗研究。该研究现已完成，所有要求的23名患者均已入组。该研究将临床反应与IgM对髓鞘上各种糖缀合物的结合亲和力相关联。目前正在分析结果。 为了在患有僵直人综合征（SPS）的患者中找到负责的自身抗原，从CSF建立T细胞克隆，并针对组合肽文库进行测试。使用患者血清中的蛋白质组学，发现抗原肽GABARAP（GABA受体相关蛋白）减少。随后发现GABARAP的减少与高达65%的SPS患者中检测到的抗GABARAP抗体相关。由于GABARAP是稳定GABAA受体的基础，功能障碍的GABARAP可能与脑GABA水平降低有关，如MRS光谱所检测到的，并在SPS的发病机制中发挥作用。一个新的双盲临床试验使用B细胞耗竭单克隆抗体利妥昔单抗已经开始。今年有4名患者入选。恐惧症是SPS患者的一个常见特征，其起源正在通过一系列神经认知测量进行探索。据发现，恐惧症是继发于残疾，而不是由于原发性疾病。 在患有脊髓灰质炎后综合征和严重疲劳的患者中，已经进行了使用莫达非尼的双盲研究。现在对结果进行分析。 在GNE基因突变导致的遗传性IBM患者中，我们观察到肌肉蛋白糖基化缺陷和α-肌营养不良蛋白聚糖减少。一项临床试验现在准备开始使用静脉注射免疫球蛋白来增加肌肉糖基化。由于结蛋白基因的致病性突变，遗传性肌病患者的表型/基因型相关性已经完成。结论是结蛋白肌病是一种影响中间纤维的独特疾病（肌纤维肌病），突变类型可能决定临床严重程度或心肌病的存在。

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) inherited vacuolar myopathies with emphasis on hereditary IBM due to GNE mutations and desmin-related myopathies; c) demyelinating polyneuropathies; d) postpolio syndrome; and e) 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 are examined longitudinally. 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, ICOS-L and PDI are upregulated and the muscle fiber may function as Antigen Presenting cell. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an interrelationship between these molecules was explored. A linear relationship was found between cytokines, chemokines and amyloid-related degenerating molecules not only in vivo in the patient's muscles but also in vitro in human myotubes. At the clinical level, a longitudinal study examining the natural history of IBM has been completed. To suppress the myocytotoxic effect of T cells, a therapeutic and investigational clinical trial has begun using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. Six patients have been treated up to now. The study is ongoing. In demyelinating neuropathies associated with IgM autoantibodies to MAG and glycolipids,a new controlled therapeutic study was performed using a humanized monoclonal antibody against B cell clones. The study is now completed and all required 23 patients have been enrolled. The study correlates clinical responses with the binding affinity of IgM to various glycoconjugates on the myelin sheath. The results are currently analyzed. In an effort to find responsible autoantigens in patients with Stiff Person Syndrome (SPS), T cell clones were established from the CSF and being tested against combinatorial peptide libraries. Using proteomics in the patients' serum, an antigenic peptide GABARAP (GABA-Receptor Associated Protein) was found to be reduced. The reduction of GABARAP was subsequently found to be associated with anti-GABARAP antibodies which were detected in up to 65% of SPS patients. Because GABARAP is fundamental in stabilizing GABAA receptors, a dysfunctional GABARAP is probably associated with the reduced level of brain GABA, as detected with MRS spectroscopy, and play a role in the pathogenesis of SPS. A new double-blind clinical trial using the B cell-depleting monoclonal antibody Rituximab has began. Up to 4 patients have enrolled this year. The origin of phobias, a common feature in SPS patients, was being explored using a series of neurocognitive measurements. It was found that the phobias are secondary to disabillity and not due to the primary disease. In patients with postpolio syndrome and severe fatigue, a double blind study using Modafinil has been conducted. The results are now analyzed. In patients with hereditary IBM due to mutations in the GNE gene we observed defect in glycosylation of muscle proteins and reduction of alpha-dystroglycan. A clinical trial is now ready to begin using intravenous immunoglobulin in an effort to increase muscle glycosylation. A phenotype/genotype correlation has been completed in patients with hereditary myopathies due to pathogenic mutations in the desmin gene. It has been concluded that desmin myopathy is a distinct disease affecting intermediate filaments (filamentopathy) and that the type of mutations may dictate clinical severity or presence of cardiomyopathy.