title: Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis.
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.
authors.affiliation: From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Pangu BioPharma, Hong Kong, China.
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zhou
authors.affiliation: From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Pangu BioPharma, Hong Kong, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Pangu BioPharma, Hong Kong, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Pangu BioPharma, Hong Kong, China.
authors.forename: Wing-Sze
authors.initials: WS
authors.lastname: Lo
authors.affiliation: From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and Pangu BioPharma, Hong Kong, China.
authors.forename: Ching-Fun
authors.initials: CF
authors.lastname: Lau
authors.affiliation: aTyr Pharma, San Diego, California 92121.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
authors.affiliation: aTyr Pharma, San Diego, California 92121.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.affiliation: aTyr Pharma, San Diego, California 92121.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Ashlock
authors.affiliation: aTyr Pharma, San Diego, California 92121.
authors.forename: John D
authors.initials: JD
authors.lastname: Mendlein
authors.affiliation: From the IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, and The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D017398:Alternative Splicing; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006643:Histidine-tRNA Ligase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009220:Myositis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017434:Protein Structure, Tertiary
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D006643:Histidine-tRNA Ligase
keywords: Aminoacyl-tRNA Synthetase; Anti-Jo-1 Autoantibody; Autoimmune Disease; Dermatomyositis; Epitope Mapping; Immunology; Myositis; Secretion