Fine specificity of autoantibodies to soluble liver antigen and liver/pancreas.
Autoantibodies to soluble liver antigen and liver pancreas (SLA/LP) have been described as specific markers for Autoimmune Hepatitis (AIH), occurring in about 20% of patients with AIH. The high degree of specificity for SLA/LP in autoimmune liver disease suggests a possible role in its pathogenesis. This study aims to map the exact epitope(s) recognized by SLA/LP autoantibodies and to assess the role of molecular mimicry between microbial antigens and self-epitopes. Using SLA/LP-reactive sera of 18 individual AIH patients and a pool of 15 patient sera, we found the dominant immune reactivity directed to peptide p395-414 and a less prominent immune response to 2 other epitopes adjacent to the dominant epitope. Immunodominance of peptide p395-414 was confirmed by absorption experiments. The SLA/LP autoantibodies of all tested AIH patients were mainly of the IgG1 type, suggesting that SLA/LP autoantibodies may arise by a common and specific underlying immune stimulus. Based on sequence homologies of the SLA/LP antigenic region with viral proteins, it was hypothesized that molecular mimicry may drive autoimmunity to SLA/LP. However, the homologous virus-derived peptides were not recognized by SLA/LP autoantibodies. Similarly, the only known procaryotic homologue, MJ0610 of Methanococcus jannaschii, was only weakly recognized by SLA/LP-positive sera. Thus, no evidence could be found for molecular mimicry being the causative mechanism for the development of SLA/LP autoantibodies. In conclusion, the exquisite epitope specificity and IgG subtype are evidence for the maturity of the SLA/LP autoantibody response; a specific autoantigen-driven process underlying the immunopathogenesis is likely.
Herkel
Johannes
J
I. Department of Medicine, Johannes Gutenberg-Universität, Mainz, Germany.
Heidrich
Birgit
B
Nieraad
Nicole
N
Wies
Ingrid
I
Rother
Michael
M
Lohse
Ansgar W
AW
D000918:Antibody Specificity; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D003429:Cross Reactions; D000939:Epitopes; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000276:immunology; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000276:immunology
D000942:Antigens, Bacterial; D000956:Antigens, Viral; D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D010446:Peptide Fragments; C046431:liver antigen LA-1