Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia

Abstract

Biliary atresia (BA) is an inflammatory cholangiopathy of infancy. A proposed mechanism regarding the pathogenesis of BA is that of a virus-induced, immune-mediated injury to bile ducts. The rotavirus (RRV)-induced murine model of BA was utilized to determine the hepatic inflammatory response related to ductal obstruction and if the immune response recapitulated human BA. One week after infection, there was a significant increase in liver CD4 + T cells producing IFN-γ and in macrophages producing TNF-α. The intrahepatic pattern of inflammation evolved rapidly from an initial predominant CD4 + Th1 cellular response to a subsequent influx of activated macrophages producing TNF-α and iNOS. This immune response persisted despite viral clearance and was representative of the hepatic immune profile present in human BA. Utilization of the murine model of BA yielded mechanistic data that can provide much needed insight into the role played by different arms of the immune system related to the pathogenesis of human BA.

Serial circulating markers of inflammation in biliary atresia—Evolution of the post-operative inflammatory process

“…19 There has been some clinical and experimental evidence that BA exhibits a polarized, specifically Th1 immune response, at least in the early stages of the disease (i.e., up to the time of KP). 16,20,21,22 For instance, Mack et al 16 using immunocytochemistry and RT-PCR showed a CD4ϩ and CD8ϩ T cell infiltrate within portal tracts with a localized increased expression of the cytokines IL-2, IFN␥, TNF␣ and IL-12 (but not IL-4 or IL-5). Experimentally (using a rotavirus-induced murine BA model) the same group 20 has shown significant increases in CD4ϩ T cells producing IFN␥ (i.e., Th1 response) with a later influx of activated macrophages producing TNF␣.…”

Effector Role of Neonatal Hepatic CD8+ Lymphocytes in Epithelial Injury and Autoimmunity in Experimental Biliary Atresia

“…10, 11 As seen in children with biliary atresia, livers of neonatal mice with experimental atresia undergo expansion of CD3+ cells and overexpress Ifng at the time of duct obstruction. 8, 19 We previously reported that the loss of Ifng attenuates the tropism of lymphocytes to bile ducts and prevents the development of the biliary atresia phenotype. 10 Therefore, we hypothesized that neonatal hepatic CD3+ cells that express Ifng induce the development of biliary atresia.…”

Corticosteroid treatment in biliary atresia: Tonic or toast?

“…6 A similar T helper 1 response is replicated in the most promising animal model of BA, the rhesus rotavirus-infected newborn mouse model. [7][8][9] The innate immune response is also activated in the human BA liver, as demonstrated by the later appearance of cells of the CD68ϩ macrophage/ monocyte family in portal tracts and evidence of chemokine and cytokine release by these and related cells. 7 Abnormal expression of cellular adhesion molecules (intercellular cell adhesion molecule, CD54, vascular cell adhesion molecule, CD62E) on biliary epithelium and vascular endothelium and elevated circulating levels of soluble adhesion molecules have also been observed.…”

“…[7][8][9] The innate immune response is also activated in the human BA liver, as demonstrated by the later appearance of cells of the CD68ϩ macrophage/ monocyte family in portal tracts and evidence of chemokine and cytokine release by these and related cells. 7 Abnormal expression of cellular adhesion molecules (intercellular cell adhesion molecule, CD54, vascular cell adhesion molecule, CD62E) on biliary epithelium and vascular endothelium and elevated circulating levels of soluble adhesion molecules have also been observed. 10 Furthermore, a variety of other cytokines, chemokines, and growth factors are released that stimulate downstream amplification of the inflammatory cascade and induction of fibrogenesis (Fig.…”