Cholangiocytes as immune modulators in rotavirus‐induced murine biliary atresia

Abstract

Background/Aims Biliary atresia (BA) is a progressive disease characterized by bile duct inflammation and fibrosis. The aetiology is unknown and may be due to a virus-induced, autoimmune-mediated injury of cholangiocytes. Cholangiocytes are not only targets of injury but may also modulate hepatic inflammation. The aim of this study was to determine the immune profile of murine cholangiocytes and the ability to function as antigen-presenting cells (APCs) in culture with Rhesus rotavirus (RRV), poly I:C (viral mimic) or interferon-γ/tumour necrosis factor-α. Methods/Results Both the cholangiocyte cell line (long-term culture) and fresh, ex vivo cholangiocytes expressed APC surface markers major histocompatibility complex (MHC)-class I and II and CD40, while only the cultured cell line expressed costimulatory molecules B7-1 and B7-2. Despite APC expression, cultured cholangiocytes were unable to function as competent APCs in T-cell proliferation assays. Furthermore, both cultured and ex vivo cholangiocytes expressed RNA transcripts for many pro-inflammatory cytokines and chemokines. Conclusions Although cholangiocytes contain APC molecules, they are incompetent at antigen presentation and cannot elicit effective T-cell activation. Upregulation of MHC-class I and II found in BA mice may serve to prime the cholangiocyte as a target for immune-mediated injury. Cholangiocytes produced many pro-inflammatory cytokines and chemokines in the setting of RRV infection and T-helper type 1 cytokine milieu, suggesting a role of cholangiocytes as immune modulators promoting the ongoing inflammation that exists in RRV-induced BA.

Dendritic Cells Regulate Natural Killer Cell Activation and Epithelial Injury in Experimental Biliary Atresia

“…CD4 + and CD8 + T cell proliferation profiles induced by RRV-primed panDCs (and by cDCs alone for CD8 + cells) are consistent with the activating properties of DCs, a function previously attributed to cholangiocytes in livers from infants with biliary atresia (7, 17, 18). In view of recent work questioning this property of cholangiocytes (19), we cocultured a BALB/c-derived cholangiocyte cell line (mCL) infected with RRV with hepatic CD4 + or CD8 + T lymphocytes purified from control mice by means of a similar experimental strategy used for DCs. We found that cholangiocytes were unable to stimulate proliferation in lymphocytes (fig.…”

“…When considering viruses as triggers of injury to bile ducts in neonates, α 2 β 1 integrins regulate RRV infection of cholangiocytes, an event that has been long viewed as key to the release of inflammatory signals and induction of lymphocyte proliferation (19, 24, 25). Contrary to this view, we did not find evidence for induction of lymphocyte proliferation by a cholangiocyte cell line infected with RRV.…”

How Do Lampreys Avoid Cholestasis After Bile Duct Degeneration?

“…Mack et al proposed that bile duct infection or injury due to rotavirus infection could be inciting factors leading to progressive, autoimmune-mediated damage of the biliary tree after recovery from infection (Mack & Sokol, 2005;Barnes et al, 2009). Incidentally, it has been revealed that programmed cell death in amphibian metamorphosis is induced by a selective auto-immune response, and that the immune system may contribute to the remodeling processes in vertebrate morphogenesis, universally (Mukaigasa et al, 2009).…”

Advances in biliary atresia: from patient care to research

“…In a series of experiments, investigators showed that RRV-infected cholangiocytes express both major histocompatibility complex (MHC) class I and aberrant MHC class II (21). Although they had all necessary markers for effective antigen presentation, cultured cholangiocytes were not shown to function as antigen-presenting cells in T-cell proliferation assays.…”