MECHANISMS AND PATHOGENESIS OF PRIMARY BILIARY CIRRHOSIS

Project: Research project

Project Details

Description

Primary biliary cirrhosis is a severe, progressive, autoimmune
liver disease of unknown etiology characterized by the presence of
antibodies to mitochondria. These antibodies are directed against
a complex of proteins of 70, 45 and 39 kd, found in the
mitochondria of all human tissues and in the mitochondria of many
other species. More than 95% of PBC patients have antibodies to
at least one of these proteins, most commonly to the 70 kd protein.
An understanding of the clinical relevance of the antimitochondrial
response found in PBC requires that these proteins be characterized
at the molecular level. We have cloned and sequenced a 1.4 kb cDNA
from a rat liver library that encodes part of the 70 kd
mitochondrial antigen. The 1.4 kb cDNA expresses a fragment of
the 70 kd antigen as a fused polypeptide that is capable of
absorbing all anti 70 kd antibodies from patient serum. We have
used this probe to begin cloning the human cDNA equivalent.
Finally, we have shown that this fused polypeptide, when injected
into mice, elicits a-specific antimitochondrial response. Using
these tools, we will determine the complete sequence of the 70 kd
mitochondrial gene in both the rat and human. We will identify
regions in the human sequence that are the binding sites for
autoantibodies found in PBC patients. We will synthesize peptides
corresponding to these sequences and use them to assay titer and
class of patient antibody and determine any relationship to
prognosis. We will similarly identify regions in the human
sequence that stimulate peripheral blood T lymphocytes of PBC
patients and synthesize peptides corresponding to these regions.
Some patients with PBC also have antibodies to a 45 and 39 kd
mitochondrial autoantigen. We will clone these genes and determine
relatedness of their sequences to that of the full length 70 kd
gene. Finally, we will begin a pilot program to immunize mice with
the purified fused polypeptide and monitor T cell reactivity,
antibody responses and liver histology. The identification of
reactive epitopes for B and T cells will allow the generation
StatusFinished
Effective start/end date5/1/883/31/16

Funding

  • National Institutes of Health: $361,600.00
  • National Institutes of Health
  • National Institutes of Health: $323,228.00
  • National Institutes of Health: $334,679.00
  • National Institutes of Health
  • National Institutes of Health: $334,950.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $357,984.00
  • National Institutes of Health: $383,438.00
  • National Institutes of Health: $334,125.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $368,677.00
  • National Institutes of Health
  • National Institutes of Health: $314,364.00
  • National Institutes of Health: $334,125.00
  • National Institutes of Health: $332,156.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $361,600.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $378,750.00
  • National Institutes of Health: $334,125.00
  • National Institutes of Health: $334,950.00
  • National Institutes of Health: $333,844.00
  • National Institutes of Health

ASJC

  • Medicine(all)

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