title: Role of innate immunity in a murine model of histidyl-transfer RNA synthetase (Jo-1)-mediated myositis.
abstract: OBJECTIVE
  Previous studies in humans and in animal models support a key role of histidyl-transfer RNA synthetase (HisRS; also known as Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HisRS to trigger adaptive immune responses, in vitro studies clearly indicate that HisRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HisRS to direct innate immune responses in a murine model of myositis.
  
  
  METHODS
  Following intramuscular immunization with soluble HisRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. Enzyme-linked immunosorbent assay-based assessment of autoantibody formation and carboxyfluorescein succinimidyl ester proliferation studies provided complementary measures of B cell and T cell responses triggered by HisRS immunization.
  
  
  RESULTS
  Compared to appropriate control proteins, a murine HisRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days postimmunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/RAG-2(-/-) and C3H/HeJ (TLR-4(-/-) ) mice indicated that the ability of murine HisRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require Toll-like receptor 4 signaling.
  
  
  CONCLUSIONS
  Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Soejima
authors.forename: Eun Ha
authors.initials: EH
authors.lastname: Kang
authors.forename: Xinyan
authors.initials: X
authors.lastname: Gu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Paula R
authors.initials: PR
authors.lastname: Clemens
authors.forename: Dana P
authors.initials: DP
authors.lastname: Ascherman
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006643:Histidine-tRNA Ligase / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009220:Myositis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006643:Histidine-tRNA Ligase