Abnormal expression of PDC-E2 on the apical surface of biliary epithelial cells in patients with antimitochondrial antibody—negative primary biliary cirrhosis

doi:10.1016/0270-9139(95)90150-7

Hepatology

Volume 22, Issue 5, November 1995, Pages 1440-1446

https://doi.org/10.1016/0270-9139(95)90150-7 Get rights and content

Abstract

The presence of antimitochondrial antibodies (AMA) is a major criterion for the diagnosis of primary biliary cirrhosis (PBC). Although it is not clear that AMA are involved in the pathogenesis of the disease, the study of these autoantibodies has enabled much information to be accumulated about the specificity of this response. The autoantigens have been identified as components of a functionally related enzyme family, the 2-oxo-acid-dehydrogenase complex. Within this complex, pyruvate dehydrogenase E₂ subunit (PDC-E₂) has been determined to be the immunodominant autoantigen. Using a panel of mouse monoclonal antibodies and human combinatorial autoantibodies, it has been demonstrated that patients with PBC, but not controls, have an abnormal expression of either PDC-E₂ or a cross-reacting molecule in the apical region of biliary epithelium. Others have shown a similar reaction using rabbit sera directed to PDC-E₂. Our previous studies have concentrated on AMA-positive patients. In this study, the presence of PDC-E₂, class II, immunoglobulin (Ig) A, and B7/BB1 in the bile duct epithelial cells of AMA-positive as well as AMA-negative patients is addressed. Most patients with AMA-negative PBC (seven of nine) react in a fashion similar to AMA-positive patients with intense staining of the apical region of the bile duct epithelial cells for “PDC-E₂,” increased IgA expression, and little major histocompatibility complex (MHC) class II staining in the early-stage patients. Interestingly, the two AMA-negative patients that did not express PDC-E₂ on the apical side of their biliary epithelium had anticentromere antibodies and Sjögren's syndrome. Based on these data, it can be concluded that the disease process for both AMA-positive and AMA-negative patients with PBC has a similar pathogenic mechanism, which is likely to involve the abnormal expression of PDC-E₂ or a molecular mimic of PDC-E₂, and does not require MHC class II expression.

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As a result, the antigen–antibody complexes further promote the activation of immune responses and apoptosis of cholangiocytes, leading to unremitting inflammation. Despite the ubiquitous existence of mitochondria in all cells, the selective damage of small bile ducts is a unique phenomenon in PBC, which is consistent with the observation of intense and PBC-specific staining at the apical surface of small bile ducts using monoclonal antibodies against PDC-E2.50,51 This observation firmly supports the mainstream hypothesis that the excessive immune responses targeting BECs with the loss of tolerance to PDC-E2 is the central culprit of PBC pathogenesis.
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Clinicopathological and serological studies did not find any significant difference between groups and therapy response was also similar [12–16]. More importantly, pyruvate dehydrogenase (PDH) E2 was expressed on the apical membrane of biliary epithelial cells in autoimmune cholangitis cases similar to PBC cases [17]. Therefore, this term has been replaced by ‘AMA-negative PBC’, and currently these cases are not different from classical PBC except AMA negativity [18].
Autoimmune liver diseases are heterogenous disorders that share largely non-specific clinical, serological and pathological features. The correct diagnosis requires discriminative features which are highly specific, for example high-titer antimitochondrial antibodies (AMA) and florid duct lesion in primary biliary cholangitis (PBC). However, the imperfect sensitivities of these characteristic features and abuse of scoring systems led to many artificial diagnoses such as overlap syndromes and outliers for example “autoimmune cholangitis” which is now called as “AMA-negative PBC”. Patients lacking detectable AMA (up to 20% in indirect immunofluorescence – IF), but otherwise presenting signs and symptoms of PBC should be regarded as affected by “AMA-negative PBC” because they seem to follow a natural history similar to that of their AMA positive counterparts. The complementary use of IF, ELISA and immunoblotting have disclosed that the majority of patients initially considered AMA-negative are in fact AMA positive. Moreover, the use of PBC-specific ANA's like Gp210 and sp100 have diminished the AMA-negative cases (if truly exists!) to less than 5%. The histological spectrum of PBC includes typical florid duct lesions and/or compatible features such as non-specific hepatitic and biliary findings. In the absence of florid duct lesion and AMA positivity, histology alone cannot differentiate PBC from other biliary disorders. However, the analysis of compatible histological features with the clinical, serological and imaging findings usually points to a specific diagnosis. In this review, we present serological, clinical and pathological pitfalls regarding AMA-negative PBC including illustrative cases and a diagnostic algorithm.

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^☆: Supported by National Institutes of Health, grant no. DK39588, Bethesda, MD.

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Other clinical studyAbnormal expression of PDC-E2 on the apical surface of biliary epithelial cells in patients with antimitochondrial antibody—negative primary biliary cirrhosis☆

Abstract

Gastroenterology

Hepatology

Gastroenterology

Hum Pathol

Clin Immunol Immunopathol

Primary biliary cirrhosis

N Engl J Med

Liver biopsy interpretation

Staining of chronic nonsuppurative destructive cholangitis (Syndrome of primary biliary cirrhosis)

Virchows Arch A

The autoepitope of the 74 kD mitochondrial autoantigen of primary biliary cirrhosis corresponds to the functional site of dehydrolipoamide acetyltransferase

J Exp Med

Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis

Antimitochondrial autoantibodies in primary biliary cirrhosis recognize cross-reactive epitope(s) on protein X and dihydrolipoamide acetyl transferase of pyruvate dehydrogenase complex

Hepatology

Primary biliary cirrhosis: inhibition of pyruvate dehydrogenase complex activity by autoantibodies specific for E1-alpha, a nonlipoic acid containing mitochondrial enzyme

J Immunol

Detection of autoantibodies to recombinant mitochondrial proteins in patients with primary biliary cirrhosis

N Engl J Med

Use of designer recombinant mitochondrial antigens in the diagnosis of primary biliary cirrhosis

Hepatology

Immunoreactivity to M2 proteins in antimitochondrial auto-antibodies are characteristically present in the serum of patients with primary biliary cirrhosis (PBC)

J Gastroenterol Hepatol

Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis

Gut

Other clinical study
Abnormal expression of PDC-E₂ on the apical surface of biliary epithelial cells in patients with antimitochondrial antibody—negative primary biliary cirrhosis☆