Myositis induced by naked DNA immunization with the gene for histidyl-tRNA synthetase.
Polymyositis is regarded as an autoimmune inflammatory muscle disease. A major subgroup of patients have autoantibodies to cellular histidyl-transfer RNA synthetase (HRS). We have analyzed the role of the autoantigen HRS in the induction of murine myositis in a comparative study of inoculation of BALB/c mice with recombinant HRS protein versus naked DNA coding for HRS. Adult BALB/c mice produced antibodies to human HRS following inoculation with HRS protein and adjuvant, but myositis was not observed. Alternatively, expression plasmid DNA constructs encoding full-length and truncated human HRS were inoculated intramuscularly in gene transfer studies. DNA-inoculated mice produced relatively low anti-HRS antibody titers. However, in contrast to recombinant HRS protein-inoculated mice, HRS gene transfer induced pathology with evidence of cellular infiltration of perivascular and endomysial regions of the inoculated muscle. Multiple inoculations of a plasmid construct encoding a hybrid molecule consisting of HRS and the transferrin receptor cytoplasmic tail induced the highest levels of antibodies and persisting cellular infiltration. Unlike HRS, expression of influenza virus hemagglutinin (HA) following inoculation of an HA plasmid did not induce myositis. Transfer of naked DNA constructs expressing HRS is likely to provide valuable information on the autoimmune response to this protein and its role in the development of myositis.
Blechynden
L M
LM
Australian Neuromuscular Research Institute and Department of Medicine, University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands.
Lawson
M A
MA
Tabarias
H
H
Garlepp
M J
MJ
Sherman
J
J
Raben
N
N
Lawson
C M
CM
D000818:Animals; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D018014:Gene Transfer Techniques; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000494:pharmacology; D006643:Histidine-tRNA Ligase / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology; D009220:Myositis / Q000139:chemically induced / Q000276:immunology*; D017285:Polymyositis / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011994:Recombinant Proteins; D006643:Histidine-tRNA Ligase