Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells.
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.
Howard
O M Zack
OM
National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Immunoregulation, Frederick, MD 21702, USA. howardz@mail.ncifcrf.gov
Dong
Hui Fang
HF
Yang
De
D
Raben
Nina
N
Nagaraju
Kanneboyina
K
Rosen
Antony
A
Casciola-Rosen
Livia
L
Härtlein
Michael
M
Kron
Michael
M
Yang
David
D
Yiadom
Kwabena
K
Dwivedi
Sunita
S
Plotz
Paul H
PH
Oppenheim
Joost J
JJ
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
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