Novel conformation of histidyl-transfer RNA synthetase in the lung: The target tissue in Jo-1 autoantibody-associated myositis

Stuart M. Levine, Nina Raben, Dan Xie, Frederic B. Askin, Rubin Tuder, Marissa Mullins, Antony Rosen, Livia A. Casciola-Rosen

Research output: Contribution to journalArticle

Abstract

Objective. We previously proposed that novel expression and/or conformation of autoantigens in the target tissue may play a role in generating phenotype-specific immune responses. The strong association of autoantibodies to histidyl-transfer RNA synthetase (HisRS, Jo-1) with interstitial lung disease in patients with myositis led us to study HisRS expression and conformation in the lung. Methods. Normal human tissue specimens were probed with a novel anti-HisRS antibody recognizing its granzyme B-cleavable conformation by immunoblotting and immunohistochemistry. The HisRS granzyme B site was mapped using site-directed mutagenesis, and its relationship to the antibody recognition domain was evaluated in tandem immunoprecipitation/granzyme B cleavage studies. Results. The HisRS α-helical coiled-coil N-terminal domain recognized by autoantibodies is bounded by a granzyme B cleavage site. In immunoprecipitation studies with patient sera, HisRS was found to exist in 2 conformations, defined by sensitivity to cleavage by granzyme B and modification by autoantibody binding. Despite similar global expression of HisRS in different tissue, expression of its granzyme B-cleavable form was enriched in the lung and localized to the alveolar epithelium. Conclusion. A proteolytically sensitive conformation of HisRS exists in the lung, the target tissue associated with this autoantibody response. We thus propose that autoimmunity to HisRS is initiated and propagated in the lung.

Original languageEnglish (US)
Pages (from-to)2729-2739
Number of pages11
JournalArthritis and rheumatism
Volume56
Issue number8
DOIs
StatePublished - Aug 1 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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