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: O M Zack Howard, Hui Fang Dong, 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 196 Issue 6 Pg. 781-91 (Sep 16 2002) ISSN: 0022-1007 [Print] United States
• PMID: 12235211 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Autoantigens
• CCR2 protein, human
• CCR3 protein, human
• Interleukin-2
• RNA, Transfer, Amino Acyl
• Receptors, CCR2
• Receptors, CCR3
• Receptors, CCR5
• Receptors, Chemokine
• Virulence Factors, Bordetella
• Amino Acyl-tRNA Synthetases
• Aspartate-tRNA Ligase
• Histidine-tRNA Ligase
• asparaginyl-tRNA synthetase

Topics

• Amino Acyl-tRNA Synthetases (physiology)
• Aspartate-tRNA Ligase
• Autoantigens (physiology)
• Cell Movement
• Dendritic Cells (physiology)
• Histidine-tRNA Ligase (physiology)
• Humans
• Interleukin-2 (pharmacology)
• Myositis (immunology)
• RNA, Transfer, Amino Acyl
• Receptors, CCR2
• Receptors, CCR3
• Receptors, CCR5 (physiology)
• Receptors, Chemokine (physiology)
• T-Lymphocytes (physiology)
• Virulence Factors, Bordetella (pharmacology)