Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses

Cell Mol Immunol. 2021 Jun;18(6):1463-1475. doi: 10.1038/s41423-019-0331-0. Epub 2019 Dec 4.

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.

Keywords: Autoimmunity; HARS; Immunology; Synthetase; tRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / blood
  • Case-Control Studies
  • Cell Differentiation / drug effects
  • Disease Models, Animal
  • Female
  • Histidine-tRNA Ligase / blood*
  • Histidine-tRNA Ligase / immunology
  • Humans
  • Immunity* / drug effects
  • Immunomodulation / drug effects
  • Insulin-Like Growth Factor I / pharmacology
  • Lung / drug effects
  • Lung / pathology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Muscle Cells / drug effects
  • Muscle Cells / enzymology
  • Muscles / drug effects
  • Muscles / pathology
  • Myositis / blood
  • Myositis / diagnostic imaging
  • Myositis / immunology
  • Organ Specificity* / drug effects
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tomography, X-Ray Computed

Substances

  • Autoantibodies
  • Insulin-Like Growth Factor I
  • Histidine-tRNA Ligase

Supplementary concepts

  • Antisynthetase syndrome