Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells.
Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells.
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组酰基TRNA合成酶和天冬酰基-TRNA合成酶，肌炎中的自身抗原，激活T淋巴细胞上的趋化因子受体和未成熟的树突状细胞。
DOI：
10.1084/jem.20020186
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发表时间：
2002-09-16
影响因子：
15.3
通讯作者：
Oppenheim, Joost J
中科院分区：
文献类型：
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作者：
Howard, O M Zack;Dong, Hui Fang;Yang, De;Raben, Nina;Nagaraju, Kanneboyina;Rosen, Antony;Casciola-Rosen, Livia;Hartlein, Michael;Kron, Michael;Yang, David;Yiadom, Kwabena;Dwivedi, Sunita;Plotz, Paul H;Oppenheim, Joost J
组氨酰-tRNA合成酶（HisRS）或丙氨酰-、天冬酰胺酰-、甘氨酰-、异亮氨酰-或苏氨酰-tRNA合成酶的自身抗体发生在约25%的多发性肌炎或皮肌炎患者中。我们测试了几种氨酰-tRNA合成酶诱导白细胞迁移的能力。HisRS诱导CD 4+和CD 8+淋巴细胞、白细胞介素（IL）-2激活的单核细胞和未成熟树突状细胞（iDC）迁移，但不诱导中性粒细胞、成熟DC或未刺激的单核细胞迁移。一个NH 2-末端结构域，1-48 HisRS，对淋巴细胞和活化的单核细胞具有趋化性，而一个缺失突变体，HisRS-M，则无活性。HisRS选择性激活CC趋化因子受体（CCR）5转染的HEK-293细胞，通过与细胞外结构域3相互作用诱导迁移。此外，单克隆抗CCR 5阻断HisRS诱导的趋化性，相反，HisRS阻断抗CCR 5结合。天冬酰胺酰-tRNA合成酶诱导淋巴细胞、活化的单核细胞、iDC和CCR 3转染的HEK-293细胞的迁移。丝氨酰-tRNA合成酶诱导CCR 3转染的细胞迁移，但不诱导iDC迁移。非自身抗原性的氨酰-tRNA和赖氨酰-tRNA合成酶不具有趋化性。因此，自身抗原性氨酰-tRNA合成酶，可能从受损的肌肉细胞中释放，可能通过募集诱导先天性和适应性免疫应答的单核细胞而使肌炎的发展永久化。因此，选择自身分子作为自身抗体应答的靶标可能是分子本身促炎特性的结果。
Autoantibodies to histidyl–tRNA synthetase (HisRS) or to alanyl–, asparaginyl–, glycyl–, isoleucyl–, or threonyl–tRNA synthetase occur in ∼25% of patients with polymyositis or dermatomyositis. We tested the ability of several aminoacyl–tRNA synthetases to induce leukocyte migration. HisRS induced CD4+ and CD8+ lymphocytes, interleukin (IL)-2–activated monocytes, and immature dendritic cells (iDCs) to migrate, but not neutrophils, mature DCs, or unstimulated monocytes. An NH2-terminal domain, 1–48 HisRS, was chemotactic for lymphocytes and activated monocytes, whereas a deletion mutant, HisRS-M, was inactive. HisRS selectively activated CC chemokine receptor (CCR)5-transfected HEK-293 cells, inducing migration by interacting with extracellular domain three. Furthermore, monoclonal anti-CCR5 blocked HisRS-induced chemotaxis and conversely, HisRS blocked anti-CCR5 binding. Asparaginyl–tRNA synthetase induced migration of lymphocytes, activated monocytes, iDCs, and CCR3-transfected HEK-293 cells. Seryl–tRNA synthetase induced migration of CCR3-transfected cells but not iDCs. Nonautoantigenic aspartyl–tRNA and lysyl–tRNA synthetases were not chemotactic. Thus, autoantigenic aminoacyl–tRNA synthetases, perhaps liberated from damaged muscle cells, may perpetuate the development of myositis by recruiting mononuclear cells that induce innate and adaptive immune responses. Therefore, the selection of a self-molecule as a target for an autoantibody response may be a consequence of the proinflammatory properties of the molecule itself.