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Addison's other disease: primary biliary cirrhosis as a model autoimmune disease
1Centre for Liver Research, University of Newcastle, Newcastle-upon-Tyne. D.E.J.Jones@ncl.ac.uk
Insights
Primary biliary cirrhosis (PBC) is an autoimmune liver disease where immune cells damage bile ducts. Research suggests T cells targeting pyruvate dehydrogenase complex (PDC) cause this damage, offering insights into autoimmunity.
Area of Science:
- Immunology
- Hepatology
- Autoimmune Diseases
Background:
- Thomas Addison is a foundational figure in autoimmunity research.
- Primary biliary cirrhosis (PBC) is a less recognized but significant autoimmune liver disease.
- PBC serves as a model for studying autoimmune disease due to advanced knowledge of its immunopathogenesis.
Purpose of the Study:
- To explore the immunopathogenesis of primary biliary cirrhosis (PBC).
- To investigate the role of T cells and pyruvate dehydrogenase complex (PDC) in PBC.
- To understand the mechanisms of immune tolerance breakdown in autoimmunity.
Main Methods:
- Analysis of classical pathological lesions in PBC.
- Identification of autoantibodies, particularly against pyruvate dehydrogenase complex (PDC).
- Investigation using human studies and a novel murine disease model.
Main Results:
- Apoptotic damage to biliary epithelial cells is the hallmark of PBC.
- Autoantibodies to PDC are nearly universal in PBC and aid diagnosis.
- CD8+ cytotoxic T cells targeting self-PDC epitopes are implicated in biliary cell damage.
Conclusions:
- Breakdown of immune tolerance to self-PDC is key to PBC pathogenesis.
- Understanding PBC offers broader insights into general autoimmune disease mechanisms.
- Further research in human and animal models illuminates autoimmune processes.
Abstract:
Thomas Addison described three of the classical autoimmune diseases, so can justifiably be regarded as one of the fathers of the study of autoimmunity. The least well recognised of these conditions, the autoimmune liver disease primary biliary cirrhosis (PBC), is in some ways the most interesting. As a result of the relatively advanced state of knowledge of its immunopathogenesis, it represents a good model for the study of autoimmune disease. The classical pathological lesion of PBC is apoptotic damage to the biliary epithelial cells lining the small intrahepatic bile ducts. The disease is typified by two symptom sets: fatigue and pruritus, which can occur at any stage of the disease process, and the features of advanced liver disease, which occur when secondary liver damage results from bile retention. Although autoantibodies directed at, in particular, pyruvate dehydrogenase complex (PDC) are almost universally present in PBC (and represent an important diagnostic tool), it appears likely that CD8+ cytotoxic T cells reactive with self-PDC derived epitopes are directly responsible for target cell damage. Recent studies in humans and a novel murine disease model have shed light on the mechanism of breakdown of immune tolerance to self-PDC; they provide important insights into the pathogenesis of PBC in particular and of autoimmunity in general.