Bidirectional Cross-Talk between Biliary Epithelium and Th17 Cells Promotes Local Th17 Expansion and Bile Duct Proliferation in Biliary Liver Diseases.

There is no effective treatment for autoimmune biliary diseases. Therefore, understanding their immunopathology is crucial. The biliary epithelial cells (BEC), expressing TLR-4, are constantly exposed to gut microbes and bacterial wall LPS, and in settings of inflammation, the immune infiltrate is dense within the peribiliary region of human liver. By dual immunohistochemistry, we affirm human intrahepatic T cell infiltrate includes CCR6+CD4+ and AhR+CD4+ T cells with potential for plasticity to Th17 phenotype. Mechanistically, we demonstrate that Th1 and Th17 inflammatory cytokines and LPS enhance human primary BEC release of the CCR6 ligand CCL20 and BEC secretion of Th17-polarizing cytokines IL-6 and IL-1ß. Cell culture assays with human BEC secretome showed that secretome polarizes CD4 T cells toward a Th17 phenotype and supports the survival of Th17 cells. BEC secretome did not promote Th1 cell generation. Additionally, we give evidence for a mutually beneficial feedback of the type 17 cell infiltrate on BEC, showing that treatment with type 17 cytokines increases BEC proliferation, as monitored by Ki67 and activation of JAK2-STAT3 signaling. This study identifies human BEC as active players in determining the nature of the intrahepatic immune microenvironment. In settings of inflammation and/or infection, biliary epithelium establishes a prominent peribiliary type 17 infiltrate via recruitment and retention and enhances polarization of intrahepatic CD4 cells toward Th17 cells via type 17 cytokines, and, reciprocally, Th17 cells promote BEC proliferation for biliary regeneration. Altogether, we provide new insight into cross-talk between Th17 lymphocytes and human primary biliary epithelium in biliary regenerative pathologies.

Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis.

UNLABELLED: Chronic hepatitis occurs when effector lymphocytes are recruited to the liver from blood and retained in tissue to interact with target cells, such as hepatocytes or bile ducts (BDs). Vascular cell adhesion molecule 1 (VCAM-1; CD106), a member of the immunoglobulin superfamily, supports leukocyte adhesion by binding α4ß1 integrins and is critical for the recruitment of monocytes and lymphocytes during inflammation. We detected VCAM-1 on cholangiocytes in chronic liver disease (CLD) and hypothesized that biliary expression of VCAM-1 contributes to the persistence of liver inflammation. Hence, in this study, we examined whether cholangiocyte expression of VCAM-1 promotes the survival of intrahepatic α4ß1 expressing effector T cells. We examined interactions between primary human cholangiocytes and isolated intrahepatic T cells ex vivo and in vivo using the Ova-bil antigen-driven murine model of biliary inflammation. VCAM-1 was detected on BDs in CLDs (primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic liver disease, and chronic hepatitis C), and human cholangiocytes expressed VCAM-1 in response to tumor necrosis factor alpha alone or in combination with CD40L or interleukin-17. Liver-derived T cells adhered to cholangiocytes in vitro by α4ß1, which resulted in signaling through nuclear factor kappa B p65, protein kinase B1, and p38 mitogen-activated protein kinase phosphorylation. This led to increased mitochondrial B-cell lymphoma 2 accumulation and decreased activation of caspase 3, causing increased cell survival. We confirmed our findings in a murine model of hepatobiliary inflammation where inhibition of VCAM-1 decreased liver inflammation by reducing lymphocyte recruitment and increasing CD8 and T helper 17 CD4 T-cell survival. CONCLUSIONS: VCAM-1 expression by cholangiocytes contributes to persistent inflammation by conferring a survival signal to α4ß1 expressing proinflammatory T lymphocytes in CLD.

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent apoptosis, but are insensitive to direct activation with exogenous Fas ligand.

INTRODUCTION: Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. AIMS: To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. RESULTS: Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. CONCLUSIONS: 1) Both primary and malignant cholangiocytes are relatively resistant to Fas-mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes.

An area-level model of vehicle-pedestrian injury collisions with implications for land use and transportation planning.

There is growing awareness among urban planning, public health, and transportation professionals that design decisions and investments that promote walking can be beneficial for human and ecological health. Planners need practical tools to consider the impact of development on pedestrian safety, a key requirement for the promotion of walking. Simple bivariate models have been used to predict changes in vehicle-pedestrian injury collisions based on changes in traffic volume. We describe the development of a multivariate, area-level regression model of vehicle-pedestrian injury collisions based on environmental and population data in 176 San Francisco, California census tracts. Predictor variables examined included street, land use, and population characteristics, including commute behaviors. The final model explained approximately 72% of the systematic variation in census-tract vehicle-pedestrian injury collisions and included measures of traffic volume, arterial streets without transit, land area, proportion of land area zoned for neighborhood commercial and residential-neighborhood commercial uses, employee and resident populations, proportion of people living in poverty and proportion aged 65 and older. We have begun to apply this model to predict area-level change in vehicle-pedestrian injury collisions associated with land use development and transportation planning decisions.

Outcomes of the California ban on pharmaceutical lindane: clinical and ecologic impacts.

INTRODUCTION: There are increasing concerns over the presence and implications of pharmaceutical agents in water. In 2002, California banned pharmaceutical use of lindane because of concerns about water quality, as lindane treatment for head lice and scabies was found to be a significant factor adversely affecting wastewater quality. OBJECTIVES: In this article we describe the effects the ban has had on wastewater quality, unintentional exposures, and clinical practice. This is the first time that a pharmaceutical has been outlawed to protect water quality. As such, this ban provides a rare opportunity to evaluate the possible or potential outcomes of future public health interventions aimed at reducing pharmaceutical water contamination. METHODS: We compiled data on lindane in wastewater treatment plant effluent for several large plants in California and one outside of California. Data on exposures to lindane were obtained from records of the California Poison Control System. We assessed the impact on clinical practice via a survey of 400 pediatricians RESULTS: Wastewater treatment plant monitoring showed that lindane declined in California after the ban. Similarly, unintentional exposure calls declined. Most physicians were aware of the ban (81%) and had used lindane previously (61%), but they did not notice any difficulties with the ban (78%). CONCLUSIONS: The California experience suggests that elimination of pharmaceutical lindane produced environmental benefits, was associated with a reduction in reported unintentional exposures, and did not adversely affect head lice and scabies treatment. This ban serves as a model for governing bodies considering limits on the use of lindane or other pharmaceuticals.