IMMUNOPATHOGEN AUTOIMMUNE INFLAMMATORY MYOPATHIES--POLYMYOSITIS/DERMATOMYOSITIS

两个主要的免疫病理特征表征了自身免疫性 炎性肌病、多发性肌炎、皮肌炎及相关 疾病：肌肉细胞的淋巴细胞破坏，和体液 自身免疫性以一组显著的疾病特异性 自身抗体 虽然肌肉细胞的破坏是由 淋巴细胞，自身抗体，特别是那些针对 功能相关但结构不同的氨酰-tRNA家族 合成酶，似乎提供了一个有用的窗口疾病， 多年来一直是该组织研究的重点。工作 继续，虽然强度减弱，对体液 自身免疫这些研究的目的是设计更好的治疗方法 肌炎 最近，我们的注意力集中在淋巴细胞的破坏和 心肌细胞死亡。 组织损伤，与大多数 自身免疫性组织损伤，主要与CD-8+ 潜入 此外，肌肉是少数几个组织之一，其中MHC I类是组成性缺乏，但在肌炎，它是明显的 在心肌细胞上上调，增加了这种上调 在引发和维持炎症中起作用。 的 今年开展了以下领域的工作：1）综合研究 细胞因子，免疫共刺激分子和MHC的心肌细胞， 对炎症刺激的反应表明，肌肉细胞 对MHC分子，共刺激分子， 和细胞因子，从而建立 肌肉在控制免疫攻击中发挥了更积极的作用。2)的 免疫缺陷患者活检中明显缺乏细胞凋亡， 肌炎中肌肉的破坏促使我们研究 培养的肌肉细胞凋亡，在NIH和合作 和约翰霍普金斯的一个小组合作。3)转基因小鼠，其中MHC I类 在骨骼肌中被组成性上调或被上调 只有，或可以通过四环素的喂养上调或下调， 已经制造或正在培育，以确定是否MHC 上调刺激炎症，因为它已经在其他几个 系统. 4)甲巯咪唑是一种抗甲状腺药物， 在啮齿类动物中下调的I类，正在培养的人 肌细胞和I类肌肉和淋巴细胞 在治疗试验中接受药物（参见Z 01 AR 41076-08 ARB）。第五章） 目前，与自身抗体相关的唯一项目是尝试 为了获得主要自身抗原靶的稳定晶体， 组氨酰-tRNA合成酶。缺少所述蛋白的截短重组体的晶体 氨基末端卷曲螺旋似乎更稳定，现在正在被 由克雷格海德博士研究。

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. Work continues, although at a diminished intensity, on the humoral autoimmunity. The goal of these studies is to design better ways to treat myositis Recently our attention has focused on the lymphocytic destruction and the death of myocytes. The tissue damage, in contrast 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 have been pursued this year: 1) Studies of the synthesis of cytokines, immune co-stimulatory molecules, and MHC by myocytes in response to inflammatory stimuli have shown that muscles cells both respond to and can synthesize MHC molecules, co-stimulatory molecules, and cytokines in response to inflammatory stimuli, thereby establishing a much more active role for muscle in controlling immune attack. 2) The apparent absence of apoptosis in biopsies from patients with immune destruction of muscles in myositis has stimulated us to study the apoptosis of muscle cells in culture, both at NIH and in collaboration with a group at Johns Hopkins. 3) Transgenic mice in which MHC Class I is constitutively up-regulated or is up-regulated in skeletal muscle only, or can be up or down-regulated by the feeding of tetracycline have been made or are currently being bred to determine whether MHC up-regulation incites inflammation as it has done in several other systems. 4) The effect of methimazole, an anti-thyroid drug which down-regulated Class I in rodents, is being studied on cultured human muscle cells and on Class I of muscle and lymphocytes in patients receiving the drug in a therapeutic trial (see Z01 AR 41076-08 ARB). 5) Currently, the only project related to the autoantibodies is an attempt to obtain stable crystals of the principal autoantigenic target, histidyl-tRNA synthetase. Crystals of a truncated recombinant lacking the amino terminal coiled-coil appear to be more stable and are now being studied by Dr. Craig Hyde.