XENOBIOTICS AND PRIMARY BILIARY CIRRHOSIS

Project: Research project

Description

Primary biliary cirrhosis (PBC) is an autoimmune disease that primarily affects women and includes destruction of intrahepatic bile ducts and antimitochondrial antibodies (AMAs). AMAs are directed at the E2 components of the 2-oxo acid dehydrogenase pathway, particularly PDC-E2; 95 percent of patients with PBC have a positive AMA. The etiology of PBC likely occurs via the interaction of genetics and environment. Although there is no correlation between sera AMAs and clinical severity, a positive AMA using recombinant auto-antigens is virtually pathognomonic of PBC. We also have data suggesting that IgA AMAs may be causally related to biliary pathology. Halogen substituted organic compounds such as chlorofluorohydrocarbon substitutes can form protein adducts through acyl halide intermediates and covalently attach to L-lysine. Antibodies to trifluoroacetic acid (TFA)-albumin recognize a similar epitope on PDC-E2 as AMAs. We hypothesize that exposure to a molecule similar to TFA will interact with the lipoic acid-lysine region of the inner lipoyl domain (the immunodominant T and B cell epitope) of PDC-E2. This conjugation will either lead directly to cell death or, alternatively, to a mucosal IgA response. We propose to extend the finding that exposure to fluorinated acylating compounds results in antibodies that react with PDC-E2 by exploring the true mechanistic insult that induces PBC. Our hypothesis for this exploratory grant evolved after an unsuccessful exhaustive search for infectious agents in PBC. The overall data puts into focus the distinct possibility that PBC may be related to exposure to a xenobiotic agent. Thus our thesis is that a molecule similar to TFA alters the immunogenicity of PDC-E2 and leads to an autoimmune response and immunopathology. Our strategy to address this thesis will be to 1) synthesize a family of organic molecules starting with the basic structure of TFA; 2) couple these compounds to the inner lipoyl domain of PDC-E2; 3) develop in vitro assays to screen these modified peptides to define the motif recognized by AMAs and 4) develop an animal model, based on our knowledge of mucosal immune responses, that will lead to an AMA response and potential liver pathology.
StatusFinished
Effective start/end date9/30/999/29/03

Funding

  • National Institutes of Health
  • National Institutes of Health: $146,083.00
  • National Institutes of Health: $146,750.00

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Biliary Liver Cirrhosis
Xenobiotics
Antibodies
Trifluoroacetic Acid
Immunoglobulin A
Lysine
Pathology
B-Lymphocyte Epitopes
Keto Acids
Intrahepatic Bile Ducts
Thioctic Acid
Immunodominant Epitopes
Mucosal Immunity
Halogens
T-Lymphocyte Epitopes
Organized Financing
Autoimmunity
Autoimmune Diseases
Antibody Formation
Epitopes

ASJC

  • Environmental Science(all)
  • Medicine(all)