We submit that primary biliary cirrhosis (PBC) is an environmentally induced autoimmune disease in genetically susceptible hosts, initiated by breach of tolerance to the major mitochondrial autoantigen, the E2 component of pyruvate dehydrogenase (PDC-E2). Data from our lab indicates that this loss of tolerance is initiated either by the creation of neoantigens via chemical xenobiotic modification of PDC-E2 and/or via molecular mimicry. This thesis is based on our analysis of the reactivity of anti-mitochondrial autoantibodies (AMA) to specific xenobiotic chemicals utilizing tools of quantitative structure activity relationships (QSAR). Indeed, AMA's from PBC patients have been shown to recognize chemical mimics as well as or even better than native autoantigen. Furthermore, immunization of mice with one such mimic, 2-octynoic acid (2OA) coupled to BSA in CFA, generates AMA and recapitulates the distinctive portal tract infiltration of human PBC. More recently, our data indicates that an electrophilic modification of lipoic acid within the autoepitope of PDC-E2 is particularly reactive with AMA. One such common electrophilic agent is acetaminophen (APAP). We propose to take advantage of our multi-disciplinary team involving organic, structural and biological chemists, dermatologists and immunologists, to address three critical issues.
Under aim 1 we will define the structural confirmation of PDC-E2 and, in particular, the dynamic changes in the peptide backbone in the presence of endogenous compounds using site-directed spin labeling electron paramagnetic resonance (SDSL-EPR) and NMR. We will also examine PDC-E2 wild type and mutant peptides shown to inhibit AMA recognition and study changes in kinetics when such peptides are conjugated with specific xenobiotics.
Under aim 2 we will explore the use of acetaminophen metabolite functionalization of the lipoylated region in the ? sheet of PDC-E2 to demonstrate that such modification leads to immunoreactivity against PBC sera and immunization of mice leads to PBC like disease. Our work hitherto has primarily focused on combinatorial chemistry and QSAR. In our final aim, we will capitalize on our functional data that autoimmune cholangitis can be induced by immunization of 2OA, a material found in cosmetics. In particular, we will define the role of effector mechanisms in this model that allows dissection of early events. We are also intrigued by our pilot data that supports a rol for the cutaneous immune system in the induction of PBC and in the final component of aim 3, will expand this pilot data to study the dermal immune response following topical application of methyl 2OA and its involvement in liver pathology. The rationale for our three aims and our approaches are based on our previous data on epidemiology that supports exposure via cosmetics as a contributing etiological factor, the presence of AMA in patients who have overdosed on APAP, and finally the observation that the induction of an acute inflammatory response to human biliary blebs requires the presence of AMA.

Public Health Relevance

Primary biliary cirrhosis (PBC) is an autoimmune disease that predominantly affects women and leads to specific destruction of their bile ducts. The etiology of this disease is unknown and there have been no new treatments introduced in nearly 20 years. Our laboratory believes that PBC is induced by environmental factors, including common over-the-counter drugs and cosmetics. We propose to prove this thesis as well as to determine the mechanisms that lead to liver damage;such efforts may lead to future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK067003-10
Application #
8576074
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Sherker, Averell H
Project Start
2003-09-01
Project End
2018-06-30
Budget Start
2013-08-12
Budget End
2014-06-30
Support Year
10
Fiscal Year
2013
Total Cost
$373,932
Indirect Cost
$131,119
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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