Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome

Hill, Richard; Quaglia, Alberto; Hussain, Munther J.; Hadžić, Nedim; Mieli‐Vergani, Giorgina; Vergani, Diego; Davenport, Mark

doi:10.1016/j.jpedsurg.2015.02.005

Cited by 58 publications

(21 citation statements)

References 44 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, abundance of periductal IL‐17A + cells is associated with periportal infiltration of CD68 + iMΦ, and these portal IL‐17A + cells persist in the liver of patients with progressive disease. An increased number of periductal IL‐17A + cells was linked to worse surgical outcome of KPE in Europe, and elevated plasma levels of IL‐17A‐associated cytokines were determined in an Asian cohort of infants with BA . Whether infiltration of the liver with Th17 lymphocytes and CD68 + iMΦ at the time of diagnosis is linked to progressive intrahepatic bile duct injury following KPE in North America will require further investigations.…”

Section: Discussionmentioning

confidence: 99%

The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia

et al. 2016

View full text Add to dashboard Cite

Biliary atresia is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. IL-17A-GFP, CD11c/DTR and IL17RA−/− mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment and biliary injury in rhesus-rotavirus induced biliary atresia. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with biliary atresia. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge while innate immune responses were waning. Plasma IL-17A levels rose concomitant with hepatic accumulation of Th17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL17A induced expression of CCL2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine receptor CCR2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with downregulation of hepatic Ccl2/Ccr2 mRNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages and improved survival. In the liver of infants with biliary atresia, cholangiocytes were found to express IL-17 receptor A and the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoing liver transplantation. Conclusion Our findings identify the dendritic cell-Th17-macrophage axis as target for the development of strategies to block progression of intrahepatic bile duct injury in patients with biliary atresia.

show abstract

Section: Discussionmentioning

confidence: 99%

The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Both T-cell [51,52] and B-cell-mediated autoimmunity [50,53] have been implicated as well as dysfunction of regulatory T-cells [54,55], activation of innate immunity and NK cells [56] and dendritic cells [57], activation of a pro-inflammatory gene footprint in liver tissue [58] and the loss of cholangiocyte primary cilia [59]. Recently, the contribution of interleukin-17 to the inflammation and destruction of the biliary system has been demonstrated, both in infants with BA and in the RRV newborn mouse model [60,61].…”

Section: Developments In Understanding Of the Pathogenesis Of Biliarymentioning

confidence: 99%

Biliary atresia and other cholestatic childhood diseases: Advances and future challenges

Verkade

Bezerra

Davenport

et al. 2016

Journal of Hepatology

Self Cite

140

View full text Add to dashboard Cite

Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

show abstract

“…Analysis of human tissue reveals that high expression of IL-17 producing T cells was associated with need for liver transplant. Hill et al found high levels of Th17 cells in portal tracts of BA patients at diagnosis and the number of Th17 cells positively correlated with serum bilirubin levels, suggesting that IL-17 was directly responsible for bile duct injury [79]. …”

Section: T-cell Immunitymentioning

confidence: 99%

Update on investigations pertaining to the pathogenesis of biliary atresia

Kilgore

Mack

2017

Pediatr Surg Int

View full text Add to dashboard Cite

Biliary atresia is a devastating biliary disease of neonates that results in liver transplantation for the vast majority. The etiology of biliary atresia is unknown and is likely multifactorial, with components of genetic predisposition, environmental trigger and autoimmunity contributing to disease pathogenesis. This review highlights recent work related to investigations of disease pathogenesis in biliary atresia.

show abstract

Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome

Abstract: Background: Biliary atresia (BA), a cholangiopathy of unknown aetiology affecting infants, is

Cited by 58 publications

References 44 publications

The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia

The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia

Biliary atresia and other cholestatic childhood diseases: Advances and future challenges

Update on investigations pertaining to the pathogenesis of biliary atresia

Contact Info

Product

Resources

About