Epitope studies indicate that histidyl-tRNA synthetase is a stimulating antigen in idiopathic myositis

The most frequently found myositis-specific antibody, the anti-Jo-1 antibody (anti-HRS), binds to histidyl-tRNA synthetase (HRS). Although this antibody reacts with HRS, it is unclear whether HRS is the stimulating antigen or is merely a protein that cross-reacts with a yet undefined antigen. Because antibody directed against an unrelated antigen would not be expected to cross-react with HRS at multiple sites, we mapped the epitopes on HRS to resolve this issue. We found by Western blot analyses that immunoglobulins G (IgG) from 18 of 19 anti-HRS positive patient sera react with amino acids 2-44 and 286-509 of HRS. Patient IgG specific for these two epitopes were found not to inhibit HRS enzyme activity. Instead, the inhibitory property of anti-HRS was found to be associated with antibodies that do not react to HRS in immunoblots, indicating the presence of other epitopes. In addition, antibodies that react in immunoblots were found to represent only a small fraction of total anti-HRS antibody. Our finding that patient IgG recognized at least three distinct epitopes on HRS strongly suggests that the immunological response at some point in the disease is directed against HRS and not against a cross-reactive antigen.