Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.
The etiology of primary biliary cirrhosis (PBC) remains enigmatic. One theory that has attracted attention proposes that PBC is induced via molecular mimicry with Escherichia coli. If molecular mimicry is responsible for the immunogenic response in PBC, then T cell clones specific for E. coli antigens should stimulate and be cross-reactive with peptides specific for the human immunodominant autoepitopes. To address this issue, we developed T cell clones specific for E. coli OGDC-E2 peptide. Importantly, we demonstrate the presence of T cell clones specific for E. coli OGDC-E2 that react promiscuously with the human mitochondrial equivalents. Indeed, there was a significant increase in the liver derived T cell precursor frequency of such reactivity and such liver clones were only found in patients with PBC. In conclusion, these data suggest that PBC is a multi-hit disease involving a genetic predisposition, a mucosal response, and activation of promiscuous T cells; such activation may occur either directly from bacterial antigens, or indirectly through chemically-modified bacterial antigens. Dissection of the mechanisms involved will lead not only to understanding the immunogenetic basis of PBC, but likely its pathogenic etiology.
Tanimoto
Hironori
H
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Shimoda
Shinji
S
Nakamura
Minoru
M
Ishibashi
Hiromi
H
Kawano
Akira
A
Kamihira
Takashi
T
Matsushita
Sho
S
Gershwin
M Eric
ME
Harada
Mine
M
D000217:Acyltransferases / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000235:genetics; D001324:Autoantigens / Q000235:genetics; D003429:Cross Reactions; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000209:etiology / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics; D066298:In Vitro Techniques; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000209:etiology* / Q000276:immunology*; D008213:Lymphocyte Activation; D008928:Mitochondria / Q000276:immunology; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000942:Antigens, Bacterial; D001324:Autoantigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C021515:dihydrolipoamide succinyltransferase