Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Brindley, Stephen; Lanham, Allison M.; Karrer, Frederick M.; Tucker, Rebecca M.; Fontenot, Andrew P.; Mack, Cara L.

doi:10.1002/hep.24807

Cited by 99 publications

(86 citation statements)

References 56 publications

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“…Recent studies have identified lower numbers of Tregs in BA patients compared with controls. 19 This is similar to the situation in many autoimmune diseases and suggests that impaired ability to inhibit inflammation and autoreactive immune responses following a perinatal CMV infection might allow bile duct injury to progress further. In the current study, a Treg-depleted mouse was infected with LD-CMV as a model to study human BA and to determine whether decreased Treg percentages and/or LD-CMV infection could induce immune responses to result in further bile duct injury.…”

Section: Discussionmentioning

confidence: 53%

“…A study from Sweden showed that CMV DNA was present in 50% of BA cases. 33 Mack et al 19,30 found that 56% of BA patients had significant increases in liver T-cell numbers in response to CMV. 19 Both of these findings indicate that nearly half of BA patients had previous CMV infection.…”

Section: Discussionmentioning

confidence: 99%

“…33 Mack et al 19,30 found that 56% of BA patients had significant increases in liver T-cell numbers in response to CMV. 19 Both of these findings indicate that nearly half of BA patients had previous CMV infection. Furthermore, BA shares features with several autoimmune diseases, such as being triggered by a viral infection and the presence of serum autoantibodies and aberrant MHC expression in the bile duct epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…Based on previous findings in both BA patients and animal models, 19,25 Tregs were depleted by injecting neonatal mouse with 20 mg/mice anti-CD25 antibody or 20 mg/mice isotype-matched IgG antibody (injection schedule is shown in Figure 1a). Anti-CD25 antibody injection significantly reduced the frequency of CD25 þ Foxp3 þ Tregs in both CD4 þ T-cell subset and lymphocyte cell subsets in the spleen at 12 days post-CMV or saline injection (Figures 2a and b).…”

Section: Ld-cmv Inoculated Neonatal Mice Experienced Growth Retardatimentioning

confidence: 99%

“…[15][16][17] Recently, it was reported that 56% of BA patients had significantly higher liver T-cell numbers in response to CMV and that a positive correlation exists between plasma anti-CMV IgM and CMV-specific T cells in the liver of BA patients. [17][18][19][20][21] Regulatory T cells (Tregs) are defined by expression of the surface markers CD4 and CD25 and the transcription factor Foxp3. 22 Tregs represent a small percentage of CD4 þ T cells and are indispensable for the maintenance of peripheral tolerance and the prevention of autoimmune diseases.…”

mentioning

confidence: 99%

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Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

Wen¹,

Xiao²,

Wang

et al. 2015

Laboratory Investigation

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Recent studies have indicated that perinatal infection with cytomegalovirus (CMV) may promote bile duct damage in biliary atresia (BA) and that the decreased regulatory T cell (Treg) percentage associated with BA may further amplify the bile duct damage. Although a majority of BA patients have had previous CMV infections and lower percentages of Tregs, it is unknown whether an initial exposure to a low dose of CMV could induce exaggerated and progressive biliary injury. A Treg-depleted neonatal mouse was infected with low-dose CMV (LD-CMV) as a model to study BA patients. LD-CMV infection in Treg-depleted mice induced extensive inflammation in both the intrahepatic and extrahepatic bile ducts, accompanied with injury to and atresia of intrahepatic bile ducts and partial obstruction of the extrahepatic bile ducts. Serum total and direct bilirubin amounts were also elevated. Evidence for the involvement of cellular and humoral autoimmune responses in LD-CMV-infection of Treg-depleted mice was also obtained through detection of increased percentages of CD3 and CD8 mononuclear cells and serum autoantibodies reactive to bile duct epithelial proteins, one of which was identified as a-enolase. Depletion of Tregs that can lead to the decreased inhibition of aberrantly activated hepatic T-lymphocytes and generation of autoantibodies may lead to further injury. Increased hepatic expression of Th1-related genes (TNF-a), IFN-g-activated genes (STAT-1) and Th1 cytokines (TNF-a, lymphotactin, IL-12p40 and MIP À 1g) were also identified. In conclusion, autoimmune-mediated and inflammatory responses induced by LD-CMV infection in Treg-depleted mice results in increased intrahepatic and extrahepatic bile duct injury and contributed to disease progression.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ld-cmv Inoculated Neonatal Mice Experienced Growth Retardatimentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

Wen¹,

Xiao²,

Wang

et al. 2015

Laboratory Investigation

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Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia

et al. 2012

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CD8 T-lymphocytes are effector cells of cholangiocyte injury in human and in rhesus rotavirus (RRV) induced experimental biliary atresia (BA). Here, we hypothesize that neonatal deficiency in CD25+CD4+ regulatory T cells (Tregs) leads to aberrant activation of hepatic T-lymphocytes in BA. We found that adoptive transfer of total CD4 cells, but not of CD25-depleted CD4 cells, prior to RRV inoculation reduced expansion of CD8 cells, plasma bilirubin levels, ductal inflammation and bile duct epithelial injury at 7 days postinfection (dpi) compared with age-matched infected controls without adoptive transfer. Searching for mechanisms, we found that in vitro production of IFNγ by naïve CD8 cells upon polyclonal stimulation was enhanced in co-culture with hepatic dendritic cells (DC)s from RRV infected, but not with DCs from non-infected mice which was correlated with an increased proportion of CD11b+ myeloid (m)DCs and up-regulation of the costimulatory molecule CD86 on RRV-primed DCs. Furthermore, DC-dependent T-lymphocyte activation was blocked by anti-CD86 antibody in dose dependent fashion. Importantly, expression of CD86 on mDCs was down-regulated by Tregs in vitro, and adoptive transfer of Treg-containing CD4 cells decreased expression of CD86 on hepatic mDCs at 7dpi. On the contrary, in mice resistant to experimental BA, CD25+ cell depletion aggravated bile duct injury at 12dpi after RRV inoculation, as plasma bilirubin levels were elevated by >20fold compared with non-depleted infected controls. Increased susceptibility to hepatobiliary injury in Treg-depleted mice was linked to hepatic CD8 expansion and enhanced stimulatory capacity of hepatic DCs. Conclusion Activation of hepatic T-lymphocytes driving biliary obstruction in BA is regulated by mDCs via CD86-dependent costimulation and is susceptible to inhibition by Tregs.

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

et al. 2017

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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.

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Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Cited by 99 publications

References 56 publications

Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia

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

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