Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection.
Autoantibodies to nuclear and smooth muscle are common in hepatitis B virus (HBV) infection. To understand their origin, we scanned protein databases and found that HBV-DNA polymerase (HBV-pol) shares 7-9 amino acid sequences with nuclear (MHC II trans-activator, nuclear pore core protein, nuclear mitotic apparatus, and polymyositis sclerosis Ag) and smooth muscle proteins (caldesmon and myosin). Twenty-mer peptides with relevant homologues and an irrelevant control peptide were constructed and ELISAs were established. Sixty-five children with chronic HBV infection, 104 patients with other chronic liver diseases (CLD), 36 patients with extrahepatic autoimmune diseases, and 24 healthy controls were investigated. Double reactivity to HBV-pol peptides and corresponding self homologues was observed in 40% of HBV-positive patients as compared with four (4%) with other chronic liver diseases, two (6%) with extrahepatic autoimmune diseases, and in none of the healthy controls (p < 0.001 for all). Double reactivity to myosin or caldesmon peptides and their HBV-pol homologues was associated with anti-smooth muscle Ab positivity by immunofluorescence (p < 0.05 for both). HBV-positive sera double reactive for myosin or caldesmon and their homologous HBV-pol peptides also reacted with the native proteins on immunoblot. Fifty to ninety percent Ab inhibition to individual HBV-pol and HBV-pol99-118 peptides was noted by preincubation with individual HBV-pol/self homologue peptide and native proteins, respectively, but not with control peptide. Our results show that cross-reactive immunity targeting homologous sequences of viral and self proteins may partly account for autoantibody production in HBV infection.
Gregorio
G V
GV
Institute of Hepatology, University College London Medical School, London, United Kingdom.
Choudhuri
K
K
Ma
Y
Y
Vegnente
A
A
Mieli-Vergani
G
G
Vergani
D
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000974:Antibodies, Antinuclear / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000235:genetics; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000276:immunology*; D005260:Female; D015684:Gene Products, pol / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000276:immunology; D009130:Muscle, Smooth / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid