Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity

IgG fractions from sera of patients with myositis and anti-Jo-1 antibodies, but not myositis and other auto-antibodies or other autoimmune rheumatic disorders, were used for immunoprecipitation of HeLa cell extracts labelled with 35-S-methionine or 32-P-phosphate. A protein of 50,000 kD molecular mass and an RNA species of tRNA size were detected by polyacrylamide gel electrophoresis. All anti-Jo-1-positive sera induced the same reaction. RNase treatment revealed that the anti-Jo-1[ reactivity was retained indicating that the major epitope(s) resided on the protein. Further electrophoretic analyses, including RNA fingerprinting, suggested that the RNA species was a tRNA containing the anticodon for histidine. While it had no effect on the stability of the complex between histidine and its cognate tRNA, anti-Jo-1 IgG inhibited 3-H-histidine joining to its tRNA, but not the charging of tRNAs with other amino acids. This inhibition was highly specific for anti-Jo-1-positive sera, since other sera did not inhibit 3-H-histidine-tRNA interaction. Removal of the Jo-1 antigen from the aminoacyl-tRNA synthetase preparation specifically eliminated the capacity to charge tRNA with histidine. It was concluded that the Jo-1 antigen was histidyl-tRNA synthetase or a functional subunit of this enzyme. Importantly, the antigen appeared to be contained only in the cytoplasm. Finally, the authors speculate on the association of autoimmunity to Jo-1 with infections with myotropic viruses capable of carrying a histidine residue attached to its RNA.