The Journal of Experimental Medicine
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Published online 9 September 2002 doi:10.1084/jem.20020186
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© Rockefeller University Press, 0022-1007/2002/9/781/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 6, September 16, 2002 781-791
Histidyl–tRNA Synthetase and Asparaginyl–tRNA Synthetase, Autoantigens in Myositis, Activate Chemokine Receptors on T Lymphocytes and Immature Dendritic Cells

O.M. Zack Howard1, Hui Fang Dong2, De Yang1, Nina Raben3, Kanneboyina Nagaraju4, Antony Rosen4, Livia Casciola-Rosen4, Michael Härtlein5, Michael Kron6, David Yang7, Kwabena Yiadom7, Sunita Dwivedi3, Paul H. Plotz3 and Joost J. Oppenheim1

1 National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Immunoregulation
2 Intramural Research Support Program, SAIC Frederick, NCI-Frederick, Frederick, MD 21702
3 Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
4 Department of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21218
5 Institute Max von Laue, Paul Langevin
6 Department of Medicine, Michigan State University, East Lansing, MI 48823
7 Department of Biochemistry, Georgetown University, Washington, DC 20057

Address correspondence to O.M. Zack Howard, National Cancer Institute, Center for Cancer Research, Laboratory of Molecular Immunoregulation, P.O. Box B, Frederick, MD 21702. Phone: 301-846-1348; Fax: 301-846-7042; E-mail: howardz{at}mail.ncifcrf.gov

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 NH2-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.

Key Words: myopathy • chemokine receptor • aminoacyl–tRNA synthetase • autoantibody • autoimmunity


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