Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA

Autoimmunity is postulated in the pathogenesis of primary biliary cholangitis (PBC), however, the mechanisms underlying the female predominance are largely unknown. Here, we investigated the gender difference in murine... [ view full abstract ]

Autoimmunity is postulated in the pathogenesis of primary biliary cholangitis (PBC), however, the mechanisms underlying the female predominance are largely unknown. Here, we investigated the gender difference in murine cholangitis induced by synthetic double-stranded RNA, which resembles human PBC. Female C57Bl/6 mice given repeated intraperitoneal injections of poly I:C (5μg/g, twice/week) for 16-24 weeks developed overt inflammatory infiltration surrounding bile ducts in the portal area, whereas male mice showed minimal pathological changes. Serum anti-mitochondria M2 antibody (AMA-M2) levels were increased following chronic poly I:C treatment only in female, but not in male mice. Following a single injection of poly I:C, hepatic TNFα and IFNβ mRNA levels were transiently elevated, reaching the peak levels in male mice only 2/3 and 1/2 of female peaks, respectively. Hepatic expression levels of TLR3, as well as MDA5, were not different between genders prior to injection of poly I:C. In sharp contrast, hepatic mRNA and protein levels for RIG-I were significantly higher in female mice as compared to those in male mice before injection of poly I:C. Further, hepatic TLR3 mRNA levels were elevated transiently following a single poly I:C injection, the values in females reaching almost 1.5-fold higher than those in males. In conclusion, These findings clearly indicated that female mice exclusively develop autoimmune cholangiopathy induced by poly I:C, where female-predominant expression of hepatic RIG-I levels elicits enhanced innate immune reactions. It is therefore hypothesized that gender difference in innate immune responses plays a pivotal role in the pathogenesis of autoimmune cholangiopathies including PBC.