TY - JOUR
T1 - Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency
AU - Nakagome, Yu
AU - Ueno, Yoshiyuki
AU - Kogure, Takayuki
AU - Fukushima, Koji
AU - Moritoki, Yuki
AU - Ridgway, William M.
AU - Eric Gershwin, M.
AU - Shimosegawa, Tooru
N1 - Funding Information:
Supported in part from Health and Labour Sciences Research Grants for the Research on Measures for Intractable Diseases (from the Ministry of Health, Labour and Welfare of Japan), from Grant-in-Aid for Scientific Research C (19590744) from JSPS and from National Institutes of Health grants, DK074768 and DK39588.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autoimmunity
KW - Inflammation
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U2 - 10.1016/j.jaut.2007.03.004
DO - 10.1016/j.jaut.2007.03.004
M3 - Article
C2 - 17482429
AN - SCOPUS:34347339578
VL - 29
SP - 20
EP - 29
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - 1
ER -