A possible mouse model for spontaneous cholangitis: serological and histological characteristics of MRL/lpr mice.
OBJECTIVE
MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop lymphadenopathy, hypergammaglobulinaemia, serum auto-antibodies, and a generalised auto-immune disease including glomerulonephritis and arthritis, and have been used as a model for the study of systemic lupus erythematosus. Recently, MRL/lpr mice were also reported as a potentially suitable animal model of primary biliary cirrhosis (PBC). The aim of this study was to determine the suitability of MRL/Mp-lpr/lpr (MRL/lpr) mice as an experimental auto-immune-mediated cholangitis model for PBC.


METHODS
We investigated the serum hepatobiliary enzymes, histopathological findings, and the target antigen of antimitochondrial antibodies (AMA) in MRL/lpr mice.


RESULTS
Serum levels of total bilirubin and hepatobiliary enzymes including alanine aminotransferase (ALT), leucine aminopeptidase (LAP), and gamma-glutamyl transpeptidase (G-GTP) in older-aged (over 20 weeks old) MRL/lpr or MRL/Mp-+/+ (MRL/+) mice were not significantly higher than those in younger (8-12 weeks old) MRL/lpr, MRL/+, or older-aged control mice (C3H/HeJ and BALB/C mice). Histopathologically, 24 of 47 (51%) older-aged MRL/lpr mice showed evidence of cholangitis, compared with two of 20 (10%) younger MRL/lpr mice. Especially, epithelioid granuloma and/or bile duct loss were seen in 11 out of 47 (23%) older-aged MRL/lpr mice, whereas such findings were seen in only one of 20 (5%) younger MRL/lpr mice. None of the MRL/+, C3H/HeJ, and BALB/C mice developed cholangitis. The target antigens of AMA were not pyruvate dehydrogenase complex but 2-oxoglutarate dehydrogenase complex and/or branched-chain oxo-acid dehydrogenase complex as confirmed by immunoblotting. There was no significant correlation between the presence of AMA and severity of histological lesions in older-aged MRL/lpr mice, and there were no significant differences in these biochemical data, the proportion of mice with portal inflammation, cholangitis and AMA between male and female MRL/lpr mice.


CONCLUSIONS
Although several clinical features were incompatible with PBC, the serological and histopathological features of MRL/lpr mice indicate that these mice can be used as an experimental immune-mediated cholangitis model for PBC.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Kazuo
K
Ohba
Katsuhisa
K
Omagari
Kunihiko
K
Murase
Hiroaki
H
Hazama
Jun-Ichi
J
Masuda
Hideki
H
Kinoshita
Hajime
H
Isomoto
Yohei
Y
Mizuta
Masanobu
M
Miyazaki
Ikuo
I
Murata
Shigeru
S
Kohno
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D001663:Bilirubin / Q000097:blood; D002761:Cholangitis / Q000097:blood / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D005260:Female; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000235:genetics*
D004798:Enzymes; D001663:Bilirubin