Primary Biliary Cirrhosis (PBC) is a chronic inflammatory liver disease that usually progresses to liver failure and death unless liver transplantation is performed. Although the etiology of PBC is not well understood, both genetic and environmental factors are known to contribute. Recent clinical studies strongly suggest that infection with Novosphingobium aromaticivorans (N. aro) is specifically associated with development of PBC in predisposed individuals. Utilizing a mouse model, we have recently shown that N. aro infection of mice results in the development of PBC-like liver lesions, which are dependent upon the production of IFN-3 and IL-17 through activation of NKT and conventional T cells. Based on our preliminary data that NOD mice expressing the B6 CD101 allele or mice deficient in CD101 expression exhibit more severe PBC than their congenic or wildtype littermates, we propose that the CD101 gene, which lies within the Idd10 diabetes locus that encodes the expression of the negative co-stimulatory molecule, is a novel PBC susceptibility gene. Thus the overall goal of this proposal is to determine the role of CD101 in susceptibility/resistance to severe PBC. Although the exact mechanisms by which CD101 susceptibility alleles regulate T cell activation and PBC are unknown, our preliminary findings support the hypothesis that diminished/altered signaling by the B6 CD101 allele on the NOD background mediates enhanced T cell signals through Vav3 activation and/or lack of PTPN22 induction that impair the balance between regulatory and effector T cells and leads to enhanced inflammation and liver disease. To test this hypothesis, we aim to: 1) further explore the role of CD101 in the acute and chronic phases of N. aro-induced PBC;2) determine whether genetic differences in CD101 increase DC-mediated activation of NKT and/or conventional T cells, and, thereby susceptibility to the chronic phase of disease;and 3) determine whether the differential regulation of T cell function in B6 CD101 congenic mice results from alterations in CD101-mediated regulation of Vav3 and/or PTPN22. Identification of CD101 as a susceptibility gene for PBC should provide valuable insight into the development of novel therapeutics to treat this life-threatening disease, but may also allow the identification of common targets in autoimmune disease for clinical intervention in the future.

Public Health Relevance

Environmental factors and genetic predisposition determine the susceptibility of an individual to autoimmune disease. In this regard, we have identified a single molecule, CD101 as """"""""risk factor"""""""" for an incurable human liver disease, Primary Biliary Cirrhosis in response to infection with a ubiquitous alphaproteobacterium. Using CD101 as readout system for different immune cell responses, this proposal will explore the cellular mechanisms by which the genetic background and bacterial infection influence the susceptibility of a mouse to chronic liver inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084054-02
Application #
7837668
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$371,250
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Danzer, Claudia; Koller, Anna; Baier, Julia et al. (2016) A mutation within the SH2 domain of slp-76 regulates the tissue distribution and cytokine production of iNKT cells in mice. Eur J Immunol 46:2121-36
Schey, R; Dornhoff, H; Baier, J L C et al. (2016) CD101 inhibits the expansion of colitogenic T cells. Mucosal Immunol 9:1205-17
Schey, Regina; Danzer, Claudia; Mattner, Jochen (2015) Perturbations of mucosal homeostasis through interactions of intestinal microbes with myeloid cells. Immunobiology 220:227-35
Nau, David; Altmayer, Nora; Mattner, Jochen (2014) Mechanisms of innate lymphoid cell and natural killer T cell activation during mucosal inflammation. J Immunol Res 2014:546596
Mattner, Jochen (2013) Natural killer T (NKT) cells in autoimmune hepatitis. Curr Opin Immunol 25:697-703
Danzer, Claudia; Mattner, Jochen (2013) Impact of microbes on autoimmune diseases. Arch Immunol Ther Exp (Warsz) 61:175-86
Rainbow, Daniel B; Moule, Carolyn; Fraser, Heather I et al. (2011) Evidence that Cd101 is an autoimmune diabetes gene in nonobese diabetic mice. J Immunol 187:325-36
Fusakio, Michael E; Mohammed, Javid P; Laumonnier, Yves et al. (2011) C5a regulates NKT and NK cell functions in sepsis. J Immunol 187:5805-12
Mohammed, Javid P; Fusakio, Michael E; Rainbow, Daniel B et al. (2011) Identification of Cd101 as a susceptibility gene for Novosphingobium aromaticivorans-induced liver autoimmunity. J Immunol 187:337-49
Mohammed, Javid P; Mattner, Jochen (2009) Autoimmune disease triggered by infection with alphaproteobacteria. Expert Rev Clin Immunol 5:369-379