Required Role of Apoptotic Myogenic Precursors and Toll-like Receptor Stimulation for the Establishment of Autoimmune Myositis in Experimental Murine Models
Required Role of Apoptotic Myogenic Precursors and Toll-like Receptor Stimulation for the Establishment of Autoimmune Myositis in Experimental Murine Models
复制标题
DOI：
10.1002/art.38985
复制
发表时间：
2015-03-01
影响因子：
13.3
通讯作者：
Rovere-Querini, Patrizia
中科院分区：
文献类型：
--
作者：
Sciorati, Clara;Monno, Antonella;Rovere-Querini, Patrizia
Objective.肌肉再生是特发性炎性肌病（IIMs）的标志，IIMs是一组以白细胞浸润和骨骼肌功能障碍为特征的自身免疫性疾病。尽管有详细的研究描述了IIM的临床和组织病理学特征，但这些疾病的免疫发病机制仍不明确。本研究的目的是探讨小鼠自身免疫性肌炎模型的免疫病理过程。在急性损伤或营养不良肌肉的小鼠、炎性白细胞和纯化的卫星细胞中分析自身抗原组氨酰转移RNA合成酶（HisRS）的表达。在存在或不存在Toll样受体7（TLR-7）激动剂R848的情况下，在肌肉损伤和用凋亡卫星细胞或C2 C12成肌细胞免疫的小鼠中评估抗HisRS抗体和肌炎诱导。肌肉坏死，白细胞浸润，和肌纤维再生诱导的毒性剂（心脏毒素或甘油）或促进基因破坏的α-肌聚糖/肌营养不良蛋白复合物在小鼠中一致上调表达的HisRS。尽管已知再生肌纤维和纯化的卫星细胞在这些环境中显示出增加的HisRS表达，但未检测到抗HisRS抗体。然而，在存在R848的情况下，用紫外线B照射的、表达HisRS的凋亡成肌细胞进行肌内免疫引发了抗HisRS IgG抗体的产生以及持续的淋巴细胞浸润和延长/延迟的肌肉再生。相反，单独肌肉注射R848或与活的或凋亡后/坏死的成肌细胞联合肌肉注射R848不能产生这种肌炎表型。在TLR/佐剂信号和潜在的肌肉损伤的存在下，表达高水平自身抗原的凋亡肌源性前体可以引起自身抗体形成和肌肉组织的淋巴细胞浸润，有效地复制IIM的特征。
Objective. Muscle regeneration is a hallmark of the idiopathic inflammatory myopathies (IIMs), a group of autoimmune disorders that are characterized by leukocyte infiltration and dysfunction of the skeletal muscle. Despite detailed studies describing the clinical and histopathologic features of IIMs, the immunopathogenesis of these disorders remains undefined. The aim of this study was to investigate the immunopathologic processes of autoimmune myositis in experimental murine models.Methods. Expression of the autoantigen histidyl-transfer RNA synthetase (HisRS) was analyzed in mice with acutely injured or dystrophic muscles, in inflammatory leukocytes, and in purified satellite cells. Anti-HisRS antibodies and myositis induction were assessed in mice after muscle injury and immunization with apoptotic satellite cells or C2C12 myoblasts, in the presence or absence of the Toll-like receptor 7 (TLR-7) agonist R848.Results. Muscle necrosis, leukocyte infiltration, and myofiber regeneration induced by toxic agents (cardiotoxin or glycerol) or promoted by genetic disruption of the alpha-sarcoglycan/dystrophin complex in mice were uniformly associated with up-regulated expression of HisRS. Although regenerating myofibers and purified satellite cells are known to show increased expression of HisRS in these settings, anti-HisRS antibodies were not detectable. However, intramuscular immunization with ultraviolet B-irradiated, HisRS-expressing apoptotic myoblasts in the presence of R848 triggered the production of anti-HisRS IgG antibodies as well as persistent lymphocyte infiltration and prolonged/delayed muscle regeneration. Conversely, intramuscular administration of R848 alone or in combination with living or postapoptotic/necrotic myoblasts failed to generate this myositis phenotype.Conclusion. In the presence of TLR/adjuvant signals and underlying muscle injury, apoptotic myogenic precursors expressing high levels of autoantigen can provoke autoantibody formation and lymphocytic infiltration of muscle tissue, effectively replicating the features of IIM.