Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

Water, Judy Van de; Turchany, J. M.; Leung, Patrick S.C.; Lake, John R.; Muñoz, Santiago J.; Surh, Charles D.; Coppel, Ross L.; Ansari, Aftab A.; Nakanuma, Yasuni; Gershwin, M. Eric

doi:10.1172/jci116504

Cited by 191 publications

(123 citation statements)

References 19 publications

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“…This effect is not observed with all AMA reagents: Van de Water 42 has shown that one mouse monoclonal antibody, C 355.1, reacts with the surface epithelium whereas other antibodies that map to a similar epitope on PDC-E2 show only cytoplasmic staining. This finding suggested the presence of a neoantigen that shares a cross-reactive epitope with PDC-E2 but, disappointingly, no such antigen has yet been identified.…”

Section: Aberrant Antigen Expression In the Biliary Epitheliummentioning

confidence: 95%

Pbc and Ama—What Is the Connection?

Neuberger

Thomson²

1999

Hepatology

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Primary Biliary Cirrhosis (PBC) is very closely associated with the presence of antimitochondrial antibodies (AMA); indeed, the presence of these antibodies is virtually disease specific. Despite the major advances made during the last decade in identifying the antigens with which these antibodies react, the reason for the close association remains uncertain. In this review, we examine the clinical correlates of AMA with features of PBC and discuss the possible implications of the association. CLINICAL CORRELATES Epidemiology of PBCThere is geographical variation in the prevalence of PBC, being highest in areas such as the north of England and parts of North America but rare in Africa and the Indian subcontinent. 1 Studies from the north of England suggest that the incidence of PBC is increasing. Clustering of cases is well described. 2 PBC may occur in families, and up to 4% of first-degree relatives may have PBC. Where PBC does occur in families, it may be related to maternally inherited factors and tends to present earlier in the second generation. 3 AMA Are Detectable Before the Clinical and Histological Features of PBCOf 29 asymptomatic patients who were found to have AMA in serum (later confirmed to be reactive with E2 components of pyruvate dehydrogenase) but with normal liver tests only two had normal liver histology. 4 A decade later, 76% had developed symptoms of PBC and 83% had cholestatic liver tests. None had progressed to cirrhosis. 5

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Section: Aberrant Antigen Expression In the Biliary Epitheliummentioning

confidence: 95%

Pbc and Ama—What Is the Connection?

Neuberger

Thomson²

1999

Hepatology

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“…Certain microbial proteins are antigenically similar to the E2 subunit through molecular mimicry. 1 Pathophysiologically, an immune response may be generated to a specific microbe, followed by immune attack of biliary epithelial cells expressing similar antigens.…”

Section: Pbc Overviewmentioning

confidence: 99%

Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation

Faust

2001

Liver Transplantation

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Key Points 1. Recurrent primary biliary cirrhosis (PBC) after transplantation is controversial, but most studies support disease recurrence within the graft. 2. Granulomatous destructive cholangitis should be present, and exclusion of acute and chronic rejection, graft-versus-host disease, biliary obstruction, viral hepatitis, and drug effects is mandatory before making a diagnosis of recurrent PBC. 3. Recurrent primary sclerosing cholangitis (PSC) after transplantation is difficult to diagnose because of the lack of a diagnostic gold standard. 4. Well-defined cholangiographic and histological criteria should be present, and exclusion of preservation injury, blood group type incompatibility between donor and recipient, chronic rejection, hepatic arterial occlusion, and viral infection is mandatory before making a diagnosis of recurrent PSC. 5. Most studies support recurrent autoimmune hepatitis (AIH) after transplantation based on clinical, biochemical, serological, and histological criteria. Exclusion of rejection, viral infection, drug effects, and biliary obstruction is mandatory before making a diagnosis of recurrent AIH. 6. Intermediate-term patient and graft survival are excellent for patients with recurrent autoimmune liver diseases within the transplanted liver, but additional studies are required to address the impact of disease recurrence on long-term patient and graft survival. (Liver Transpl 2001; 7:S99-S108.)

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“…14 The expression of PDC-E2 or a molecule that is cross-reactive to PDC-E2 has been reported to be increased on biliary epithelial cells of patients with PBC. 15,16 The number of human PDC-E2-reactive T cells are significantly increased in the peripheral blood of patients with PBC as compared with healthy subjects. 17 T cells reactive to the human PDC-E2 163-176 peptide were also found in the liver and portal lymph nodes in patients with PBC.…”

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confidence: 99%

Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis

et al. 2000

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The human PDC-E2 163-176 peptide (GDLLAEIETD-KATI) is an immunodominant autoreactive T-cell epitope in patients with primary biliary cirrhosis (PBC), restricted by HLA DRB4*0101. We have previously reported that the ExDK sequence is essential for recognition of this epitope and identified 1 mimicry peptide, Escherichia coli PDC-E2 peptide (EQSLITVEGDKASM), which can activate human PDC-E2 163-176 peptide-reactive T-cell clones. In the present study, to further investigate mimicry peptides possibly involved in PBC, we generated 13 different T-cell clones reactive to the human PDC-E2 163-176 peptide following repeated in vitro stimulation of peripheral T lymphocytes with the human PDC-E2 163-176 peptide (native peptide) and tested for the reactivity of these T-cell clones to 30 different mimicry peptides derived from various self-and nonself proteins that have an ExDK-sequence. We found 7 mimicry peptides derived from microbial proteins that can activate at least 1 of these T-cell clones; 7 of 7 T-cell clones from patients with PBC and 2 of 6 T-cell clones from healthy subjects were activated by at least 1 to 6 different mimicry peptides. Two of 6 T-cell clones from healthy subjects were activated by specific mimicry peptides more strongly than by the native peptide, and 2 of 6 T-cell clones from healthy subjects were not activated by any mimicry peptides tested. Thus, the pattern and degree of activation by mimicry peptides differed in each T-cell clone, indicating the presence of a diverse spectrum of autoreactive T cells that are reactive to a single minimal epitope of the human PDC

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Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

Cited by 191 publications

References 19 publications

Pbc and Ama—What Is the Connection?

Pbc and Ama—What Is the Connection?

Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation

Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis

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