Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells

O. M. Zack Howard, Hui Fang Dong, Yang De Yang, Nina Raben, Kanneboyina Nagaraju, Antony Rosen, Livia Casciola-Rosen, Michael Härtlein, Michael Kron, David Yang, Kwabena Yiadom, Sunita Dwivedi, Paul H. Plotz, Joost J. Oppenheim

Research output: Contribution to journalArticlepeer-review

Abstract

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 NH 2-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. Non-autoantigenic 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.

Original languageEnglish (US)
Pages (from-to)781-791
Number of pages11
JournalJournal of Experimental Medicine
Volume196
Issue number6
DOIs
StatePublished - Sep 16 2002

Keywords

  • Aminoacyl-tRNA synthetase
  • Autoantibody
  • Autoimmunity
  • Chemokine receptor
  • Myopathy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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