Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis.
OBJECTIVE
The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA).


METHODS
To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences.


RESULTS
For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope.


CONCLUSIONS
These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.
Shimoda
Shinji
S
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. sshimoda@intmed1.med.kyushu-u.ac.jp
Nakamura
Minoru
M
Ishibashi
Hiromi
H
Kawano
Akira
A
Kamihira
Takashi
T
Sakamoto
Norihiro
N
Matsushita
Sho
S
Tanaka
Atsushi
A
Worman
Howard J
HJ
Gershwin
M Eric
ME
Harada
Mine
M
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000209:etiology* / Q000276:immunology; D024101:Mitochondrial Proteins / Q000276:immunology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins