Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation.
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). We earlier reported that the bacterial lipoteichoic acid was detected at the sites of inflammation around damaged bile ducts in the livers of PBC, and PBC patients' sera showed high titers against streptococcal histone-like protein. Here, we investigated whether chronic bacterial exposure could trigger PBC-like epithelial cell damage in normal mouse. BALB/c mice were repeatedly inoculated with various bacteria for 8 weeks. At 1 week (Group 1) and 3, 4, or 20 months (long term; Group 2) after the final inoculation, mice were killed to obtain samples. In the livers of the Streptococcus intermedius (S.i.)-inoculated mice in Group 1, cellular infiltration was predominantly observed around the bile ducts over the hepatic parenchyma. In the S.i.-inoculated mice in Group 2, portal but not parenchymal inflammation was observed in the livers, and periductal cellular infiltrates were detected in the salivary glands. Both S.i.-inoculated Groups 1 and 2 BALB/c mice sera had antibodies against HuCCT1 biliary epithelial cells, anti-nuclear antibodies, and anti-gp210 antibodies, but not anti-mitochondrial antibodies. Immunoreactivity to histone-like DNA-binding protein of S.i. (S.i.-HLP) was detectable around the sites of chronic nonsuppurative destructive cholangitis in the portal area in the livers of both S.i.-inoculated Groups 1 and 2 BALB/c mice. Furthermore, anti-S.i.-HLP antibody bound to synthetic gp210 peptide, as well. Bacteria triggered PBC-like cholangitis, multifocal epithelial inflammation, and autoantibody production. Bacteria are likely involved in the pathogenesis of PBC and of associated multifocal epithelial inflammation.
Haruta
Ikuko
I
Departments of Microbiology and Immunology, Tokyo Women's Medical University, 8-1 Kawada-cho, Tokyo, Shinjuku-ku, Japan. haruta@research.twmu.ac.jp
Kikuchi
Ken
K
Hashimoto
Etsuko
E
Nakamura
Minoru
M
Miyakawa
Hiroshi
H
Hirota
Katsuhiko
K
Shibata
Noriyuki
N
Kato
Hidehito
H
Arimura
Yutaka
Y
Kato
Yoichiro
Y
Uchiyama
Takehiko
T
Nagamune
Hideaki
H
Kobayashi
Makio
M
Miyake
Yoichiro
Y
Shiratori
Keiko
K
Yagi
Junji
J
D000818:Animals; D000974:Antibodies, Antinuclear / Q000502:physiology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000382:microbiology / Q000503:physiopathology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000382:microbiology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D028861:Nuclear Pore Complex Proteins / Q000276:immunology; D034367:Streptococcus intermedius / Q000276:immunology* / Q000472:pathogenicity
D000974:Antibodies, Antinuclear; D028861:Nuclear Pore Complex Proteins; C512902:Nup210 protein, mouse