IMMUNOPATHOGEN AUTOIMMUNE INFLAMMATORY MYOPATHIES--POLYMYOSITIS/DERMATOMYOSITIS

自身免疫的两个主要免疫病理特征 炎症性肌病、多发性肌炎、皮肌炎及相关疾病 疾病：肌肉细胞的淋巴细胞破坏和体液 自身免疫以一组引人注目的疾病特异性 自身抗体。尽管肌肉细胞的破坏是由 淋巴细胞，自身抗体，特别是那些针对 功能相关但结构多样的氨基酰基-tRNA家族 合成酶，似乎为了解这种疾病提供了一个有用的窗口，并一直 这是该小组多年来研究的重点。这 工作仍在继续，尽管强度有所减弱。目前，主要的 与自身抗体相关的项目是一种试图获得稳定的 晶体的主要自身抗原靶，组氨酰-tRNA合成酶。 杆状病毒制备的令人满意的重组蛋白 产生的晶体产生了不令人满意的x射线反射，所以 细菌版正在建造中。 最近，我们的注意力集中在淋巴细胞的破坏上。这个 组织损伤，与大多数自身免疫组织损伤相比，是 与以CD-8+为主的浸润液有关。此外，肌肉是 这是为数不多的缺乏MHC I类物质的组织之一，但 在肌炎中，它在心肌细胞上显著上调，提高了 这种上调可能在启动和 维持发炎状态。目前正在进行以下方面的工作：1) 炎症患者肌肉活检组织中细胞因子和趋化因子的研究 似乎致炎细胞因子通常是缺失的，但是 趋化因子MIP-1α几乎普遍存在。2)研究 MHC-I类分子在培养的肌肉细胞中的调控，包括 细胞因子和趋化因子对其调控的影响。3)尝试 MHC-I类基因转基因小鼠的构建 在心肌细胞中上调以确定这是否是足够的刺激 煽动组织损伤和炎症，就像在其他几个 系统。4)尝试识别占据MHC的任何独特的多肽 在培养的肌肉细胞中存在I类，但在来自 同一个人，期望这样的多肽成为 以肌炎为特征的组织特异性细胞毒性发作。5) 抗甲状腺药物他巴唑的疗效研究 啮齿类动物肌肉和淋巴细胞I类基因表达下调 在治疗试验中接受药物治疗的患者(见Z01 AR 41076-08 ARB)。

Two principal Immunopathogenetic features characterize the autoimmune inflammatory myopathies, polymyositis, dermatomyositis, and related diseases: lymphocytic destruction of muscle cells, and humoral autoimmunity distinguished by a striking set of disease-specific autoantibodies. Although the muscle cell destruction is mediated by lymphocytes, the autoantibodies, particularly those directed against the family of functionally related but structurally diverse aminoacyl-tRNA synthetases, seem to offer a useful window on the disease and have been the focus of much of this group's research for a number of years. This work continues, although at a diminished intensity. Currently, the major project related to the autoantibodies is an attempt to obtain stable crystals of the principal autoantigenic target, histidyl-tRNA synthetase. The apparently satisfactory recombinant protein made in baculovirus yielded crystals that gave unsatisfactory x-ray reflections, so a bacterial version is under construction. Recently our attention has focused on the lymphocytic destruction. The tissue damage, in contract to the majority of autoimmune tissue damage, is associated with a predominantly CD-8+ infiltrate. Furthermore, muscle is one of the few tissues in which MHC Class I is constitutively absent, but in myositis, it is markedly up-regulated on myocytes, raising the possibility that this up-regulation plays a role in initiating and sustaining the inflammation. The following areas are being pursued: 1) Study of the cytokines and chemokines in inflamed patient muscle biopsies. It appears that the pro-inflammatory cytokines are usually absent, but that the chemokine, MIP-1alpha is almost universally present. 2) Study of the regulation of MHC Class I in cultured muscle cells, including the influence of cytokines and chemnokines on its regulation. 3) Attempts to construct transgenic mice in which MHC Class I is constitutively up-regulated in myocytes to determine whether that is sufficient stimulus to incite tissue damage and inflammation as it has been in several other systems. 4) Attempts to identify any unique peptides which occupy MHC Class I in cultured muscle cells but not in other cells (B cells) from the same individual in the expectation that such peptides are the targets of the tissue-specific cytotoxic attack that characterizes myositis. 5) Studying the effect of methimazole, an anti-thyroid drug which down-regulated Class I in rodents, on Class I of muscle and lymphocytes in patients receiving the drug in a therapeutic trial (see Z01 AR 41076-08 ARB).