Location: Endemic Poultry Viral Diseases ResearchTitle: T-bet deficiency attenuates bile duct injury in experimental biliary atresia
|DONNELLY, BRYAN - Cincinnati Children'S Research Hospital
|TEMPLE, HELEY - Cincinnati Children'S Research Hospital
|BONDOC, ALEXANDER - Cincinnati Children'S Research Hospital
|MCNEAL, MONICA - Cincinnati Children'S Research Hospital
|TIAO, GREG - Cincinnati Children'S Research Hospital
Submitted to: Cells
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/6/2021
Publication Date: 12/8/2021
Citation: Mohanty, S.K., Donnelly, B., Temple, H., Bondoc, A., Mcneal, M., Tiao, G. 2021. T-bet deficiency attenuates bile duct injury in experimental biliary atresia. Cells. 10(12):3461. https://doi.org/10.3390/cells10123461.
Interpretive Summary: Biliary atresia (BA) is caused by blockage of bile ducts which prevents the bile to be drained from the liver eventually leading to liver cirrhosis or cancer. A surgery may restore bile flow, but most patients ultimately require liver transplantation for survival. At diagnosis, immune cells pattern within the liver of patients with BA are similar to those seen by experimental virus infected mice livers which develop the disease. A protein named T-bet is required to control the function of the above mentioned immune cells. Here we used mice in which the T-bet gene has been removed to identify the the role of T-bet in development of the disease. Infection of newborn mice (which had a removal of T-bet gene, called T-bet negative) with the virus resulted in a decreased signaling proteins when compared to infected regular mice. Analysis of the immune cells from T-bet negative mice showed a significant decrease in the total number of immune cell types and different cytotoxic molecules produced by these cells. Even though the percentage of T-bet negative mice showing symptoms of an bile duct blockage and overall death rate was not different compared to regular mice, the bile ducts of T-bet negative mice remained opened.
Technical Abstract: Biliary atresia (BA) is an obstructive neonatal cholangiopathy leading to liver cirrhosis and end stage liver disease. A Kasai portoenterostomy may restore biliary drainage, but most patients ultimately require liver transplantation for survival. At diagnosis, immune cells within the liver of patients with BA demonstrate a T-helper 1 (Th1) inflammatory profile similar to rhesus rotavirus (RRV)-infected mice livers developing BA. The transcription factor Tbx21 (T-bet) is essential for induction of a Th1 immune response in both the adaptive and innate immune system. Here we used animals with targeted deletion of the T-bet gene to determine its role in the progression of BA. Infection of newborn T-bet knockout (KO) pups with RRV resulted in a decreased Th1 inflammatory chemokine/cytokine profile when compared to infected wild-type mice. Analysis of the mononuclear cells profile from T-bet KO mice revealed both a significant decrease in the total number of CD3, CD4, and CD8 T cells and their effector molecules granzyme A, perforin, and FasL. Even though the percentage of T-bet KO mice displaying symptoms of an obstructive cholangiopathy and overall mortality rate was not different compared to wild-type mice, the extrahepatic bile ducts of T-bet KO mice remained patent.