Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with primary biliary cirrhosis (PBC). The AMA is not only highly directed, but also very specific to the lipoyl domain of PDC-E2, the major mitochondrial autoantigen. Modification of this lipoyl domain, with specific small molecular mimics of lipoic acid, results in structures that react as well as and often better to PBC sera than the native molecule. We have also shown that guinea pigs, and now most recently NOD.1101 mice, immunized with xenobiotic-BSA, without any PDC-E2 in the immunogen, develop self-reacting AMA and biliary specific pathology. We propose that PBC is caused by a highly directed multicell lineage response to PDC-E2 and that chemical modification of PDC-E2 in genetically susceptible hosts begins the long natural history of disease. Our current work has provided several clues regarding this issue, including the identification of chemicals as potential modifiers of PDC-E2 and triggers of PBC. To prove our thesis, we will now define the molecular recognition requirements of AMA binding of both our peptide and xenobiotic conjugates using a series of synthetic analogues. The ?-sheet structure of PDC-E2 appears essential for AMA specificity and we must define the critical amino acids in this region. We also recognize the possibility that peptides other than PDC-E2 may be involved in the initial AMA eliciting event and we will take advantage of our expertise in xenobiotic combinatorial peptide technology to study epitope diversity. Previously we have developed and studied CD4 and CD8 cloned T cell lines and we will now extend these observations to study PBMCs from patients and controls using unmodified PDC-E2 and xenobiotic modified PDC-E2 to test the thesis that xenobiotic modified PDC-E2 activates and amplifies specific T cells more efficiently than unmodified autoantigen and that such T cells will cross-react with native mitochondrial autoantigen. Finally, we will take advantage of our exciting new data on the induction of biliary specific pathology in NOD.1101 mice immunized with the lipoic acid mimic, 2-octynamido-BSA. We will now expand this data to rigorously define the serology, liver histology, immunobiology and natural history of disease. We submit that the results from these experiments will prove our thesis that PBC is induced by a xenobiotic chemical exposure that breaks tolerance and that the multi-cell lineage response to PDC-E2 will be the pathologic effector mechanism of this disease. Public Health Relevance: Primary biliary cirrhosis is a liver disease that primarily affects women and is believed to be secondary to an immune attack by the patient against their own bile ducts. The etiology of this disease is enigmatic but we believe the disease begins when a person makes an immune response to mitochondrial proteins. We believe that this immune attack begins by an environmental modification of the patient's own mitochondrial proteins. In this application we will study the chemistry of this reaction. We will also immunize mice with these chemicals and believe that these mice will develop the clinical features of afflicted human patients that will allow us to focus and define disease etiology and future potential treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067003-09
Application #
8247148
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
2003-09-01
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$284,916
Indirect Cost
$97,471
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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