What is the clinical evidence from this study?

Study design: Other. Population: Myositis (n=15). Intervention: Histidyl-tRNA Synthetase (HisRS) vs. Medium control. Primary outcome: Chemotactic index of unfractionated lymphocytes (C.I. 2.2, p=<0.0001).

September 9, 2002Open Access

Histidyl–tRNA Synthetase and Asparaginyl–tRNA Synthetase, Autoantigens in Myositis, Activate Chemokine Receptors on T Lymphocytes and Immature Dendritic Cells

Q: What are the key findings of this study?

Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, induced chemotaxis of T lymphocytes and immature dendritic cells via CCR5 and CCR3 activation.

Key Result

Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, induced chemotaxis of T lymphocytes and immature dendritic cells via CCR5 and CCR3 activation.

Structured PICO

Population

Primary human leukocytes, HEK-293 cells transfected with chemokine receptors (CCR1, CCR3, CCR5), immature dendritic cells, and muscle tissues/blood from myositis patients (n=15 total: 7 anti-Jo-1 myositis, 8 unaffected controls; plus 8 myositis patients for tissue).

Intervention

Recombinant human aminoacyl-tRNA synthetases (HisRS, AsnRS, SerRS, LysRS, AspRS) and HisRS fragments (1-48 HisRS, HisRS-M)

Comparator

Medium alone, nonautoantigenic synthetases, or known chemokines (CCL4, CCL5)

Outcome

Leukocyte and transfected cell migration (chemotaxis index)surrogate

Autoantigenic aminoacyl-tRNA synthetases like HisRS and AsnRS can directly induce leukocyte migration by activating chemokine receptors, suggesting these autoantigens possess intrinsic proinflammatory properties that may perpetuate myositis.

Main Result

Effect estimate: C.I. 2.2

Absolute Event Rate: 2.2% vs 1%

p-value: p=<0.0001

Limitations

In vitro and ex vivo study design limits direct in vivo clinical conclusions
Radiolabeled HisRS did not retain chemotactic activity, limiting direct binding assays
Small sample size for patient blood and tissue analyses

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.

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