biostudies-literatureAdams RAU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIGMS NIH HHS1463-1475https://www.ebi.ac.uk/biostudies/studies/S-EPMC8166958biostudies-literatureUnknown18(6)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⁺Cellular & molecular immunologySerum-circulating His-tRNA synthetase inhibits organ-targeted immune responses.PMC8166958R01 GM0882781R01GM125908-01A15R01GM088278-08R01 GM125908Lundberg IEOgilvie KAmpudia JMertsching ENangle LANotarnicola ARosengren SKing DJFernandes-Cerqueira CSchimmel PLo WSChiang KPCubitt AMendlein JDAdams RAYang XLXu ZJakobsson PJfalseSerum-circulating His-tRNA synthetase inhibits organ-targeted immune responses.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⁺2021-01-01T00:00:00Z2021 Jun2026-07-16T11:07:13.577Z2022-02-10T13:53:28.355ZS-EPMC81669583179790510.1038/s41423-019-0331-0