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J Biol Chem. 2014 Jul 11;289(28):19269-75. doi: 10.1074/jbc.C114.571026. Epub 2014 Jun 4.

Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis.

Author information

1
From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Pangu BioPharma, Hong Kong, China.
2
aTyr Pharma, San Diego, California 92121.
3
From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and The Scripps Research Institute, La Jolla, California 92037, and.
4
From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
5
From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and The Scripps Research Institute, La Jolla, California 92037, and Scripps Florida, Jupiter, Florida 33458 schimmel@scripps.edu.

Abstract

Inflammatory and debilitating myositis and interstitial lung disease are commonly associated with autoantibodies (anti-Jo-1 antibodies) to cytoplasmic histidyl-tRNA synthetase (HisRS). Anti-Jo-1 antibodies from different disease-afflicted patients react mostly with spatially separated epitopes in the three-dimensional structure of human HisRS. We noted that two HisRS splice variants (SVs) include these spatially separated regions, but each SV lacks the HisRS catalytic domain. Despite the large deletions, the two SVs cross-react with a substantial population of anti-Jo-l antibodies from myositis patients. Moreover, expression of at least one of the SVs is up-regulated in dermatomyositis patients, and cell-based experiments show that both SVs and HisRS can be secreted. We suggest that, in patients with inflammatory myositis, anti-Jo-1 antibodies may have extracellular activity.

KEYWORDS:

Aminoacyl-tRNA Synthetase; Anti-Jo-1 Autoantibody; Autoimmune Disease; Dermatomyositis; Epitope Mapping; Immunology; Myositis; Secretion

PMID:
24898250
PMCID:
PMC4094037
DOI:
10.1074/jbc.C114.571026
[Indexed for MEDLINE]
Free PMC Article

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