The immunogenetics of primary biliary cirrhosis: A comprehensive review

Gwilym Webb, K A Siminovitch, G M Hirschfield

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)
168 Downloads (Pure)


Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.

Original languageEnglish
Pages (from-to)42–52
JournalJournal of Autoimmunity
Early online date3 Aug 2015
Publication statusPublished - Nov 2015


  • Genome-wide association study
  • Immunochip
  • HLA
  • CD4+ T cell
  • Animal models
  • Regulatory T cell


Dive into the research topics of 'The immunogenetics of primary biliary cirrhosis: A comprehensive review'. Together they form a unique fingerprint.

Cite this