Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses.
Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses.
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DOI：
10.1038/s41423-019-0331-0
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发表时间：
2021-06
影响因子：
24.1
通讯作者：
Schimmel P
中科院分区：
文献类型：
--
作者：
Adams RA;Fernandes-Cerqueira C;Notarnicola A;Mertsching E;Xu Z;Lo WS;Ogilvie K;Chiang KP;Ampudia J;Rosengren S;Cubitt A;King DJ;Mendlein JD;Yang XL;Nangle LA;Lundberg IE;Jakobsson PJ;Schimmel P
His-tRNA合成酶（HARS）是慢性和急性炎症性抗jo -1阳性抗合成酶综合征的自身抗体的靶标。免疫细胞向肺和肌肉的广泛激活和迁移与肺间质性疾病、肌炎和发病率有关。目前尚不清楚HARS的隔离是一种附带现象还是在疾病中起因果作用。在这里，我们发现HARS在健康个体中循环，但在抗jo -1阳性抗合成酶综合征患者的血清中基本上检测不到。在培养的原代人骨骼肌成肌细胞（HSkMC）中，HARS在向肌管分化的过程中释放量不断增加。我们进一步表明，HARS调节免疫细胞接合，抑制CD4+和CD8+ t细胞活化。在小鼠和啮齿动物急性炎症性疾病模型中，HARS可下调免疫激活。相反，在组织损伤期间，通过高滴度抗体反应中和细胞外HARS会增加对免疫攻击的易感性，这与抗jo -1阳性疾病患者的情况类似。总的来说，这些数据表明细胞外HARS在正常受试者中是稳态的，其隔离有助于抗jo -1阳性抗合成酶综合征的发病率。
His-tRNA synthetase (HARS) is targeted by autoantibodies in chronic and acute inflammatory anti-Jo-1-positive antisynthetase syndrome. The extensive activation and migration of immune cells into lung and muscle are associated with interstitial lung disease, myositis, and morbidity. It is unknown whether the sequestration of HARS is an epiphenomenon or plays a causal role in the disease. Here, we show that HARS circulates in healthy individuals, but it is largely undetectable in the serum of anti-Jo-1-positive antisynthetase syndrome patients. In cultured primary human skeletal muscle myoblasts (HSkMC), HARS is released in increasing amounts during their differentiation into myotubes. We further show that HARS regulates immune cell engagement and inhibits CD4+ and CD8+ T-cell activation. In mouse and rodent models of acute inflammatory diseases, HARS administration downregulates immune activation. In contrast, neutralization of extracellular HARS by high-titer antibody responses during tissue injury increases susceptibility to immune attack, similar to what is seen in humans with anti-Jo-1-positive disease. Collectively, these data suggest that extracellular HARS is homeostatic in normal subjects, and its sequestration contributes to the morbidity of the anti-Jo-1-positive antisynthetase syndrome.
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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。
影响因子：
15.3
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
通讯作者：
Oppenheim, Joost J
影响因子：
14.8
作者：
Guo, Min;Schimmel, Paul
通讯作者：
Schimmel, Paul
影响因子：
64.8
作者：
Arif A;Terenzi F;Potdar AA;Jia J;Sacks J;China A;Halawani D;Vasu K;Li X;Brown JM;Chen J;Kozma SC;Thomas G;Fox PL
通讯作者：
Fox PL
影响因子：
--
作者：
Eloranta, Maija-Leena;Helmers, Sevim Barbasso;Lundberg, Ingrid E.
通讯作者：
Lundberg, Ingrid E.
影响因子：
--
作者：
Kron, Michael A.;Metwali, Ahmed;Elliott, David
通讯作者：
Elliott, David