The Fingerprint of Antimitochondrial Antibodies and the Etiology of Primary Biliary Cholangitis (original) (raw)
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Antimitochondrial Antibodies: from Bench to Bedside
Clinical Reviews in Allergy & Immunology
Anti-mitochondrial antibodies (AMA) are directed against the E2 subunits of the 2-oxo acid dehydrogenase complexes (PDC-E2) and are the typical biomarkers of primary biliary cholangitis (PBC), being present in 90-95% of patients, with increasing sensitivity at increasing titers. Albeit being highly specific for PBC diagnosis, AMA can be detected in less than 1% of healthy subjects, and thus the management subjects with no sign or symptom of liver disease is still a challenge and data concerning clinical risk of developing PBC in this subgroup of patients are controversial. Moreover, AMA can also be detected in patients affected by overlap syndrome, as well as hepatic diseases (i.e., NASH and viral hepatitis), while the association with autoimmune diseases, in particular Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus, is well established. Furthermore, new associations are being identified with inflammatory myositis and heart disease. AMA are directed towards the pyruvate dehydrogenase multi enzyme complex (PDC-E2) subunit, which represents an epithelial specific autoantigen for PBC. This review focuses on the main characteristics of AMA, their association with autoimmune diseases and liver diseases.
Hepatology, 1996
the 135 control sera from patients with primary scleros-The detection of antimitochondrial autoantibodies ing cholangitis (PSC), chronic autoimmune hepatitis (AMAs) is critical in the diagnosis of primary biliary cir-(CAH), systemic lupus erythematosus (SLE), or healthy rhosis (PBC). However, conventional laboratory assays volunteers showed significant reactivity against pMLto detect AMA are dependent on the time-consuming MIT3 recombinant fusion protein in the ELISA assay. method of immunofluorescence microscopy, a method
The Journal of Immunology, 2004
Previous work has demonstrated that immunization of rabbits with the xenobiotic 6-bromohexanoate coupled to BSA breaks tolerance and induces autoantibodies to mitochondria in rabbits. Such immunized rabbits develop high-titer Abs to pyruvate dehydrogenase complex (PDC)-E2, the major autoantigen of primary biliary cirrhosis. In efforts to map the fine specificity of these autoantibodies, rabbits were immunized biweekly with 6-bromohexanoate-BSA and screened for reactivity using a unique xenobiotic-peptide-agarose microarray platform with an emphasis on identifying potential structures that mimic the molecular image formed by the association of lipoic acid with the immunodominant PDC-E2 peptide. Essentially, a total of 23 xenobiotics and lipoic acid were coupled to the 12-mer peptide backbones, PDC, a mutant PDC, and albumin. As expected, we succeeded in breaking tolerance using this small organic molecule coupled to BSA. However, unlike multiple experimental methods of breaking tolerance, we report in this study that, following continued immunization, the rabbits recover tolerance. With repeated immunization, the response to the rPDC-E2 protein increased with a gradual reduction in autoantibodies against the lipoic acid-peptide, i.e., the primary tolerance-breaking autoantigen. Detailed analysis of this system may provide strategies on how to restore tolerance in patients with autoimmune disease.
The Journal of Immunology, 2003
The E2 subunit of pyruvate dehydrogenase complex (PDC-E2) is the major autoantigen recognized by antimitochondrial Abs (AMA) in primary biliary cirrhosis (PBC). Recently, we replaced the lipoic acid moiety of PDC-E2 with a battery of synthetic structures designed to mimic a xenobiotically modified lipoyl hapten on a 12-aa peptide that was found within the immunodominant autoepitope of PDC-E2 and demonstrated that AMA in PBC reacted against several organic modified mimotopes as well as, or sometimes significantly better than, the native lipoyl domain. Based on this data, we immunized rabbits with one such xenobiotic organic compound, 6-bromohexanoate, coupled to BSA. One hundred percent of immunized rabbits developed AMA that have each and every characteristic of human AMAs with reactivity against PDC-E2, E2 subunit of branched chain 2-oxo-acid dehydrogenase, and E2 subunit of 2-oxoglutarate dehydrogenase complex. The rabbit AMA also inhibited enzymatic function of PDC-E2 and, importantly, binds to peptide sequences not present in the xenobiotic carrier immunogen. In contrast, BSA-immunized controls did not produce such activity. Our observation that animals immunized with a xenobiotic BSA complex produce autoantibodies that react not only with the xenobiotic, but also with mitochondrial autoantigens recognized by autoimmune PBC sera, suggests that environmental xenobiotic agents can be a risk factor for the induction of PBC.
Hepatology, 2001
Antimitochondrial antibodies (AMA) are the serologic hallmark of primary biliary cirrhosis (PBC). However, depending on the clinical laboratory, from 5% to 17% of PBC patients are consistently AMA-negative, using native mitochondrial antigens and a variety of conventional assays including immunofluorescence (IMF) and enzyme-linked immunosorbent assay (ELISA). The major immunoreactive mitochondrial autoantigens are the E2 members of the 2-oxo-acid dehydrogenase complex family, including pyruvate dehydrogenase complex-E2 (PDC-E2), branched chain 2-oxo acid dehydrogenase complex-E2 (BCOADC-E2), and oxo-glutarate dehydrogenase complex-E2 (OGDC-E2); cD-NAs of these proteins have now been cloned, sequenced, and their B-cell epitopes defined. In the present study, we cloned cDNAs encoding these proteins from human, not bovine, sources, and expressed the recombinant proteins in a newly developed ELISA that employs a unique Escherichia coli buffer, and compared the data with previous assays using both AMA-positive and -negative patients. Using this new assay and our criteria for positive as an optical density (OD) greater than 10 SD above the mean of control sera, the AMA-positive rate of 191 PBC sera was 94% (179 of 191) compared with 84% (161 of 191) by IMF. None of the 316 control sera were reactive. Using our recombinant assays, we focused attention on the 30 IMF-AMA-negative patients. Twenty-two of 30 (73%) of these patients were positive using this new ELISA. The group of 30 IMF-AMA-negative/ ELISA-positive patients did not differ significantly from a comparable population of IMF-AMA-positive patients with respect to age, sex distribution, liver function tests, eleva-Address reprint requests to: M.
Antimitochondrial and other autoantibodies
Clinics in Liver Disease, 2003
The nature of primary biliary cirrhosis (PBC), a disease first recognized by Addison and Gull in 1851, became clearer around the 1960s when first its apparent and then its unequivocal association [2], with antimitochondrial antibody were described. In 1958, Mackay [1] reported a case of PBC with high titers of complement-fixing antibodies to tissue homogenates. Absorption studies showed that the antibody reactivity could be abolished using a mitochondrial fraction of rat liver . A milestone for the clinical hepatologist was the observation in 1965 by Walker, Doniach, Roitt, and Sherlock [4] that antimitochondrial antibodies (AMAs) were present in all their patients with PBC and in none of the controls, which included patients with extrahepatic bile-duct obstruction, drug-induced cholestasis, and viral hepatitis. Ever since the description of this close association, AMAs have acted as a powerful diagnostic tool. Soon it became clear that positivity for AMAs was able to direct toward the correct diagnosis in the work-up of cholestatic conditions, at times avoiding invasive procedures such as explorative laparotomy. In addition to revealing a diagnostic marker, the paper by Walker et al had two additional and connected merits: it showed what antimitochondrial reactivity looks like under a fluorescent microscope, and it provided a straightforward technique for its detection. Almost 40 years on, detection of AMAs is routinely done as first described in the laboratory of Professor Deborah Doniach . In 1967, Berg et al [6] demonstrated that PBC sera reacted in vitro with isolated mitochondria, the antigen being later localized to the inner membrane . New clinical studies confirmed the AMAs' power in the diagnosis of PBC, whether it was tested by complement fixation or by immunofluorescence . PBC-specific AMAs were shown to react with trypsin-sensitive antigens, named as M2 antigens. This designation arose within an arbitrary classification system of 1089-3261/03/$ -see front matter D
Antimitochondrial Antibodies in Primary Biliary Cirrhosis
Seminars in Liver Disease, 1997
Primary biliary cirrhosis is an enigmatic autoimmune disease of women characterized by antimitochondrial antibodies and destruction of intrahepatic bile ducts. The etiology of PBC is unknown, but we present data herein that the disease may be induced by xenobiotic (i.e. chemicals) exposure. In particular, we postulate that halogenated compounds will bind to the autoantigen, break tolerance, and lead to an intense mucosal response. ᮊ Take-home messages • Primary biliary cirrhosis is an autoimmune liver disease, predominantly of women, that is characterized by antimitochondrial antibodies. • The antimitochondrial antibodies react with a family of enzymes within the 2-oxoacid dehydrogenase complex.
Anti-mitochondrial autoantibodies
Clinical and Applied Immunology Reviews, 2002
Anti-mitochondrial antibodies (AMA) are a serological hallmark of primary biliary cirrhosis (PBC). The major autoantibody targets are located in the inner mitochondrial membrane, are encoded by nuclear genes and are components of the 2-oxo acid dehydrogenase complexes. Greater than 90% of PBC patients react with one or more of these autoantigens. The major epitopes have been mapped to the lipoic acid binding domain. The apparent hepatic targets of immune destruction, the apical biliary epithelial cells, express proteins that mimic these epitopes. Nevertheless, the role of AMA in biliary pathology is not clear and observed abnormalities may be due to T-cells that respond to similar epitopes. AMAs are often accompanied by autoantibodies to other intracellular components such as the nuclear pore complex, centromeres/kinetochores, and other nuclear antigens. The origin or inciting agent(s) of AMA is not known but epidemiological and immunological evidence implicates environmental agents.
The Journal of …, 2005
Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC). We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n ؍ 47), primary sclerosing cholangitis (n ؍ 15), and healthy volunteers (n ؍ 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PDC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.