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Immunology and Genetics of Autoimmune Biliary Disease

Huang, Wenting
http://orcid.org/0000-0001-8544-7802
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447691320

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Immunology.
Primary biliary cirrhosis (PBC) is a rare, incurable, organ specific autoimmune hepatobiliary disease, being one of top five indications of liver transplantation in USA. PBC is considered as a multifactorial autoimmune disease resulting from a combination of genetic and environmental factors, and is characterized by loss of tolerance to mitochondrial proteins and progressive destruction of cholangiocytes lining the biliary ducts, which leads to cirrhosis, liver function failure and death. Autoreactive T cells, regulatory T cells (Tregs), and the target cells (cholangiocytes) have all been implicated in PBC etiology. PBC is usually asymptomatic until an advanced stage, and thus the early pathogenesis of the disease remains unclear. In this dissertation, we investigated two mouse models with spontaneous onset of PBC-like autoimmune hepatobiliary disease, aiming to understand the early genetic and immunological events contributing to the disease. In dominant-negative TGFß receptor type II transgenic mice (dnTGFßRII), we have previously shown that CD8 T cells can transfer autoimmune biliary disease in an adoptive transfer model In the current dissertation, we have found that the terminally differentiated CD8 T cells (KLRG1+ CD8 T cells) are increased in dnTGFßRII liver. To address whether dnTGFßRII CD8 T cell-mediated disease is intrinsic or extrinsic, we perform mixed bone marrow transfer (dnTGFßRII and B6) and find that mixed bone marrow chimeric mice are protected from biliary disease. This protective effect of B6 bone marrow arises from B6 Tregs, as we show using an adoptive transfer model. B6 Tregs-mediated disease protection is associated with significantly decreased numbers of hepatic dnTGFßRII KLRG1+ CD8 T cells. DnTGFßRII Tregs are defective in suppressing effector CD8 T cell proliferation compared to B6 Tregs. DnTGFßRII CD8 T cells are significantly more cytotoxic to cholangiocytes than B6 CD8 T cells and B6 Tregs can eliminate cholangiocyte toxicity mediated by dnTGFßRII CD8 T cells. Therefore autoimmune biliary disease requires defects in both the T effector and regulatory compartments; an intrinsic T cell effector defect in dnTGFßII is not sufficient to mediate autoimmune biliary disease in the setting of intact immune regulation. In the NOD.Abd3 model, which carries a B6-derived chromosome one allele (Abd3) on NOD background, we show that clinical disease requires the NOD genetic background. Using bone marrow transfers, we demonstrate that autoimmune hepatobiliary disease requires abnormalities in both target tissue cells and hematopoietic cells. RNA-seq of common bile duct from 2-week-old NOD.Abd3 show that the abnormality of target cells arises from defective expression of Polycystic kidney and hepatic disease 1 (Pkhd1). Loss of Pkhd1 expression is the result of DNA insertion in the intron 35 of the gene. These results suggest that loss of functional Pkhd1 on the NOD background initiates early bile duct abnormalities, leading to an autoimmune response that ultimately produces clinical autoimmune biliary disease (ABD) in NOD.Abd3 congenic mice. In summary, our immunological and genetics studies of these two PBC animal models further our understanding of the disease etiology and produce new insights which may ultimately result in novel therapeutic treatment options.
William Ridgway, Ph.D. (Committee Chair)
Jorge Bezerra, M.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
Stacey Huppert, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
133 p.
Immunology
PBC; TGF beta; CD8 T cells; Treg; Pkhd1; cholangiocyte

Recommended Citations

Citations

  • Huang, W. (2015). Immunology and Genetics of Autoimmune Biliary Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447691320

    APA Style (7th edition)

  • Huang, Wenting. Immunology and Genetics of Autoimmune Biliary Disease. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447691320.

    MLA Style (8th edition)

  • Huang, Wenting. "Immunology and Genetics of Autoimmune Biliary Disease." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447691320

    Chicago Manual of Style (17th edition)

ucin1447691320
394
© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.