scholarly journals Characterization of Autoantibodies against the E1 Subunit of Branched-Chain 2-Oxoacid Dehydrogenase in Patients with Primary Biliary Cirrhosis

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Tsutomu Mori ◽  
Hiromasa Ohira ◽  
Masahito Kuroda ◽  
Masaki Kato ◽  
Yoshiki Yamaguchi ◽  
...  

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs) that react with the lipoyl-containing E2 subunits of 2-oxoacid dehydrogenase complexes such as BCOADC and PDC. The lipoyl domains of E2 contain the major epitopes essential for immunopathology. However, the non-lipoyl-containing E1 subunits are also frequently targeted. Since anti-E1 antibodies always appear in combination with anti-E2 antibodies, the mechanisms underlying the autoimmunity against E1 may be linked to, but distinct from, those against E2. Here, we demonstrate that intermolecular and intramolecular determinant spreading underlies the autoimmunity against E1. We performed characterizations and epitope mapping for anti-BCOADC-E1 antibodies from both the intermolecular and intramolecular points of view. The antibody reactivities form a cluster against the BCOADC complex that is distinct from that against the PDC complex, and the anti-BCOADC-E1 antibodies arise as part of the cluster against the BCOADC complex. Multiple epitopes are present on the surface of the BCOADC-E1 molecule, and the major epitope overlaps with the active center. Sera with anti-BCOADC-E1 antibodies strongly inhibited the enzyme activity. These findings suggest that the E1 subunit as part of the native BCOADC complex is an immunogen, and that determinant spreading is involved in the pathogenesis of AMA production.

1993 ◽  
Vol 85 (3) ◽  
pp. 289-293 ◽  
Author(s):  
Jeremy M. Palmer ◽  
Margaret F. Bassendine ◽  
Oliver F. W. James ◽  
Stephen J. Yeaman

1. The sera of more than 90% of patients with primary biliary cirrhosis contain antimitochondrial antibodies which react with the E2 component of the pyruvate dehydrogenase complex, identified as the major autoantigen in primary biliary cirrhosis. All previous studies in this area have utilized protein derived from animal tissue or have used recombinant human pyruvate dehydrogenase complex E2 expressed in Escherichia coli. 2. We report the preparation and characterization of native pyruvate dehydrogenase complex and pyruvate dehydrogenase complex E2 from human heart tissue and its application in studies of immune reactivity with the sera of patients with primary biliary cirrhosis. 3. The immune reactivity of sera from patients with primary biliary cirrhosis versus the bovine and human E2/X components of pyruvate dehydrogenase complex was indistinguishable in both immunoblotting and the more sensitive e.l.i.s.a. 4. These findings suggest that the reactivity of sera from patients with primary biliary cirrhosis against the major autoantigen of the disease is a property of that antigen, independent of its human or bovine origin. Furthermore, this justifies the use of bovine pyruvate dehydrogenase complex in past and future work on primary biliary cirrhosis antibody reactivity.


Hepatology ◽  
2007 ◽  
Vol 45 (3) ◽  
pp. 659-665 ◽  
Author(s):  
Sabine Oertelt ◽  
Roman Rieger ◽  
Carlo Selmi ◽  
Pietro Invernizzi ◽  
Aftab A. Ansari ◽  
...  

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Cristina Rigamonti ◽  
Dimitrios P. Bogdanos ◽  
Maria G. Mytilinaiou ◽  
Daniel S. Smyk ◽  
Eirini I. Rigopoulou ◽  
...  

Patients with primary biliary cirrhosis (PBC) often have concurrent limited systemic sclerosis (SSc). Conversely, up to one-fourth of SSc patients are positive for PBC-specific antimitochondrial antibodies (AMA). The mechanisms responsible for the co-occurrence of these diseases are largely unknown. Genetic, epigenetic, environmental, and infectious factors appear to be important for the pathogenesis of the disease, but the hierarchy of events are not well defined. Patients with SSc and PBC have an increased morbidity and mortality compared with the general population, but whether the presence of both diseases in an affected individual worsens the prognosis and/or outcome of either disease is not clear. Some case reports suggested that the presence of SSc in PBC patents is associated with a more favorable prognosis of the liver disease, whereas others report an increased mortality in patients with PBC and SSc compared to patients with PBC alone. This paper discusses the features of patients with PBC-associated SSc. Our aims are to clarify some of the pathogenetic, diagnostic, and clinical challenges that are currently faced in the routine management of these patients. We also intend to provide some practical hints for practitioners that will assist in the early identification of patients with PBC-associated SSc.


Gut ◽  
2009 ◽  
Vol 58 (7) ◽  
pp. 983-989 ◽  
Author(s):  
M Feuchtinger ◽  
S Christ ◽  
B Preuss ◽  
J Dengjel ◽  
S Duman ◽  
...  

Hepatology ◽  
1999 ◽  
Vol 30 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Jeremy M. Palmer ◽  
David E. Jones ◽  
Janet Quinn ◽  
Anna McHugh ◽  
Stephen J. Yeaman

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