Quantitative Measurement of Autoantibodies to Recombinant Mitochondrial Antigens in Patients With Primary Biliary Cirrhosis: Relationship of Levels of Autoantibodies to Disease Progression

Abstract

AMAs are detectable by indirect immunofluorescence (IF)We examined the clinical usefulness of measurements on tissue substrates in 93% to 99% of patients with PBC, but of antimitochondrial autoantibodies (AMA) in prethis method also detects AMAs of differing specificities in dicting disease progression in patients with primary bilother diseases. The mitochondrial antigens recognized by iary cirrhosis (PBC). We determined the relationships AMAs in patients' sera have been classified numerically as between AMA levels measured by indirect immunofluo-M1 through M9, with the M2 antigen complex recognized by rescence (IF) and those measured by quantitative enAMAs in sera from 95% to 99% of PBC patients. M2 antigen is zyme immunoassays (EIAs) using recombinant 2-oxocomposed of enzyme proteins of the 2-oxo-acid dehydrogenase acid dehydrogenase complex (2-OADC) proteins and the complex (2-OADC) family that are located on inner mitochonMayo Risk Score, an established indicator of disease prodrial membranes. Included in this group of autoantigens are gression in primary biliary cirrhosis (PBC). Results of tests for AMA by either method correlated weakly (r Å pyruvate dehydrogenase complex (PDC), branched-chain 2-.24 to .30) with disease progression as indicated by Mayo oxo-acid dehydrogenase complex (BCOADC), and 2-oxo-gluRisk Scores. The levels of AMA to 2-OADC proteins var-tarate dehydrogenase complex (OGDC). The 2-OADC enied by more than 200-fold between patients but re-zymes are complex multimers composed of E1, E2, and E3 mained relatively constant over time in individual pa-subunits; the E2 subunits contribute immunodominant epitients. Despite being positively correlated with Mayo topes recognized by anti-M2 autoantibodies. 3 ImmunoreacRisk Score results, the levels of AMA to 2-OADC proteins tive epitopes of the E2 subunits of 2-OADC enzymes have were not useful for predicting disease progression in been cloned, and enzyme immunoassays (EIAs) that use reindividual patients with PBC. In addition, we found no combinant PDC-E2 and BCOADC-E2 proteins as capture ansignificant differences in the levels of autoantibodies to tigens detect autoantibodies in sera from more than 95% of 2-OADC proteins among patients with different histolog-patients with PBC. 4 Approximately 10% of sera from PBC ical stages of disease. Our results show that measure-patients contain autoantibodies to BCOADC-E2 but not PDCments of AMA by IF or by quantitative EIA methods with E2. Recently, Leung et al. 5 constructed a recombinant hybrid recombinant 2-OADC proteins are not useful parameters molecule that contains the immunodominant epitopes of both for predicting disease progression in patients with PBC. PDC-E2 and BCOADC-E2, and this hybrid molecule is recog-(HEPATOLOGY 1997;25:6-11.)nized by AMAs specific for either antigen. No study to date has reported on the levels of AMA to 2-OADC enzyme proteins in sera from a large number of PBC Primary biliary cirrhosis (PBC) is a progressive liver dispatients who have been followed up longitudinally throu...

Pbc and Ama—What Is the Connection?

“…There does not appear to be any clinical correlation with the pattern of AMA reactivity, 14 and levels of AMA do not correlate with disease progression. 15 …”

Autoimmune liver serology: Current diagnostic and clinical challenges

“…AIH-2 patients with anti-LC1 antibodies have histologically more severe disease compared to those without anti-LC1 antibodies [35,123,124] . PBC AMA titres do not seem to be associated with disease severity but those of the IgG3 subclass may identify patients prone to develop more severe disease compared to those without AMA-IgG3 [116,125] . PBC-specific ANA have been found more frequently in patients with advanced disease in a number of cross-sectional studies.…”

“…Autoimmune liver serology immunosuppressive treatment [3,6] . AMA titres do not relate to the stage of PBC and their fluctuation over time does not seem to have pathogenic significance [1,9,116] , although "activity" of the PBC process is not as readily measurable as that of AIH. Practically AMA are only tested at presentation to help establish the diagnosis and repeat tests are normally requested only in cases seronegative for AMA at presentation but with clinical or laboratory findings compatible with PBC [1,2,117] .…”

The Role ofE. coliInfection in the Pathogenesis of Primary Biliary Cirrhosis

“…Most researchers have concluded that CD4 and CD8 T cells rather than antibodies per se are involved in causing BEC destruction [3,4,37,48]. A profusion of studies in experimental models of PBC have revealed a significant role of CD4 and CD8 T-cells in the induction of pathological features resembling those in man, while early reports investigating the role for AMA have led to the conclusion that AMA have little to do with diseases pathogenesis [2,3,43,59,60]. Thus, it was shown that immunization with recombinant human PDC-E2 can induce high AMA titres in experimental animals, with no evidence of liver damage despite the presence of these autoantibodies for a lengthy period of time [59].…”