Document Detail

The immunobiology and pathophysiology of primary biliary cirrhosis.
MedLine Citation:
PMID:  23347352     Owner:  NLM     Status:  In-Data-Review    
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
Gideon M Hirschfield; M Eric Gershwin
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Annual review of pathology     Volume:  8     ISSN:  1553-4014     ISO Abbreviation:  Annu Rev Pathol     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101275111     Medline TA:  Annu Rev Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  303-30     Citation Subset:  IM    
Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham B15 2TT, United Kingdom.
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