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

  1. Author:
    Howard, O. M. Z.
    Dong, H. J. F.
    Yang, D.
    Raben, N.
    Nagaraju, K.
    Rosen, A.
    Casciola-Rosen, L.
    Hartlein, M.
    Kron, M.
    Yiadom, K.
    Dwivedi, S.
    Plotz, P. H.
    Oppenheim, J. J.

  2. Author Address

    NCI, Ctr Canc Res, Mol Immunoregulat Lab, POB B, Frederick, MD 21702 USA NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA Johns Hopkins Univ, Sch Med, Dept Rheumatol, Baltimore, MD 21218 USA Inst Max Von Laue Paul Langevin, F-38042 Grenoble, France Michigan State Univ, Dept Med, E Lansing, MI 48823 USA Georgetown Univ, Dept Biochem, Washington, DC 20057 USA Howard OMZ NCI, Ctr Canc Res, Mol Immunoregulat Lab, POB B, Frederick, MD 21702 USA
    1. Year: 2002
  2. Journal: Journal of Experimental Medicine
    1. 196
    2. 6
    3. Pages: 781-791
  4. Type of Article: Article
  1. Abstract:

    Autoantibodies to histidyl-tRNA synthetase (HisRS) or to alanyl-, asparaginyl-, glycyl-, isoleucyl-, or threonyl-tRNA synthetase occur in similar to25% of patients with polymyositis or dermatomyositis. We tested the ability of several aminoacyl- tRNA synthetases to induce leukocyte migration. I 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 DC. 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.

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