title: Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells.
abstract: Autoantibodies to histidyl-tRNA synthetase (HisRS) or to alanyl-, asparaginyl-, glycyl-, isoleucyl-, or threonyl-tRNA synthetase occur in approximately 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. Nonautoantigenic 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.
authors.affiliation: National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Immunoregulation, Frederick, MD 21702, USA. howardz@mail.ncifcrf.gov
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Hui Fang
authors.initials: HF
authors.lastname: Dong
authors.forename: De
authors.initials: D
authors.lastname: Yang
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Livia
authors.initials: L
authors.lastname: Casciola-Rosen
authors.forename: Michael
authors.initials: M
authors.lastname: Härtlein
authors.forename: Michael
authors.initials: M
authors.lastname: Kron
authors.forename: David
authors.initials: D
authors.lastname: Yang
authors.forename: Kwabena
authors.initials: K
authors.lastname: Yiadom
authors.forename: Sunita
authors.initials: S
authors.lastname: Dwivedi
authors.forename: Paul H
authors.initials: PH
authors.lastname: Plotz
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000502:physiology*; D001226:Aspartate-tRNA Ligase; D001324:Autoantigens / Q000502:physiology*; D002465:Cell Movement; D003713:Dendritic Cells / Q000502:physiology*; D006643:Histidine-tRNA Ligase / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D009220:Myositis / Q000276:immunology*; D012346:RNA, Transfer, Amino Acyl; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000502:physiology; D019707:Receptors, Chemokine / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D001324:Autoantigens; C515334:CCR2 protein, human; C515350:CCR3 protein, human; D007376:Interleukin-2; D012346:RNA, Transfer, Amino Acyl; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D010566:Virulence Factors, Bordetella; D000604:Amino Acyl-tRNA Synthetases; D001226:Aspartate-tRNA Ligase; D006643:Histidine-tRNA Ligase; C029194:asparaginyl-tRNA synthetase