Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency.

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J

Autoimmun.

2007 Aug;29(1):20-9. Epub

2007

Autoimmune cholangitis

in NOD.c3c4 mice is associated with cholangiocyte-specific

Fas antigen deficiency.

Nakagome Y, Ueno Y, Kogure T, Fukushima K, Moritoki Y, Ridgway WM, Gershwin M, Shimosegawa T.

Division

of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan.

A major handicap in understanding the pathogenesis of

autoimmune cholangitis has been the absence of an

informative mouse model. Recently, autoimmune cholangitis, with several features similar to PBC, has been

described in NOD.c3c4 mice, including anti-mitochondrial antibodies, lymphocytic portal tract infiltrates, biliary destruction

and the adoptive transfer of disease to naïve recipients using liver-derived

lymphocytes. A unique feature, and a characteristic

quite distinct from human PBC, is the presence of bile cyst formation. We have addressed the issue of cysts in NOD.c3c4 mice by

performing comprehensive microarray analysis using cholangiocytes from NOD.c3c4 mice compared to NOD controls. Several key differences in gene expression were noted in

NOD.c3c4 cholangiocytes. First,

there was consistent impairment in the expression of Fas

antigen (CD95). Second, cholangiocytes

were PCNA positive but TUNEL negative, suggesting an absence of apoptosis

despite abnormal proliferation. In conclusion, we

propose that autoimmune cholangitis develops in

NOD.c3c4 mice secondary to impaired biliary cell apoptosis with exposure of

mitochondrial antigens, loss of tolerance and subsequent development of

multi-lineage anti-mitochondrial responses. 

PMID: 17482429 [PubMed - indexed for MEDLINE]

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