Abstract
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.
Highlights
Autoantibodies to aminoacyl-transfer RNA synthetases are key features of antisynthetase syndrome (ASS), a condition characterized by multiple organ involvement, primarily interstitial lung disease (ILD) and myositis that are often accompanied by nonerosive arthritis, Raynaud’s phenomenon, fever, and “mechanic’s hands”
Extracellular HARS is present in the circulation of healthy individuals and is reduced in the presence of anti-Jo-1 antibodies Numerous splice variants and proteomic fragments are generated from the human aminoacyl-tRNA synthetase (aaRS) gene family, and they have differential tissue expression and the ability to elicit a wide range of potential biological activities in cell-based assays.[22]
We demonstrate that extracellular HARS is in circulation in normal individuals and is absent or reduced in anti-Jo-1-positive ASS patients
Summary
Autoantibodies to aminoacyl-transfer RNA (tRNA) synthetases are key features of antisynthetase syndrome (ASS), a condition characterized by multiple organ involvement, primarily interstitial lung disease (ILD) and myositis that are often accompanied by nonerosive arthritis, Raynaud’s phenomenon, fever, and “mechanic’s hands”.1,2 Autoantibodies to eight different synthetases have been described, with the most common target being histidyl-tRNA synthetase, HARS; the antibodies elicited against HARS are known as anti-Jo-1 autoantibodies.[3,4] Anti-Jo-1 autoantibodies are the most prevalent myositis-specific autoantibody characteristic of idiopathic inflammatory myopathies (IIM, collectively termed myositis), which is a heterogeneous systemic autoimmune disease characterized by inflammation of the skeletal muscle and frequently the lungs.IIM can be subclassified into polymyositis (PM), dermatomyositis (DM), juvenile dermatomyositis (JDM), and inclusion body myositis (IBM).[5]. Autoantibodies to aminoacyl-transfer RNA (tRNA) synthetases are key features of antisynthetase syndrome (ASS), a condition characterized by multiple organ involvement, primarily interstitial lung disease (ILD) and myositis that are often accompanied by nonerosive arthritis, Raynaud’s phenomenon, fever, and “mechanic’s hands”.1,2. Autoantibodies to eight different synthetases have been described, with the most common target being histidyl-tRNA synthetase, HARS; the antibodies elicited against HARS are known as anti-Jo-1 autoantibodies.[3,4] Anti-Jo-1 autoantibodies are the most prevalent myositis-specific autoantibody characteristic of idiopathic inflammatory myopathies (IIM, collectively termed myositis), which is a heterogeneous systemic autoimmune disease characterized by inflammation of the skeletal muscle and frequently the lungs. Anti-Jo-1-positive ASS is characterized by extensive immune cell infiltration into affected tissues.[7,8] The pathogenesis of anti-Jo-1-positive ASS remains unknown despite a number of proposed mechanisms; there is a correlation of disease activity with antibody levels,[9] and during disease progression, there is apparent maturation of the anti-Jo-1 response.[10,11]
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