Humoral autoimmune response heterogeneity in the spectrum of primary biliary cirrhosis

Dellavance, Alessandra; Cançado, Eduardo Luiz Rachid; Abrantes-Lemos, Clarice Pires; Harriz, Michelle; Marvulle, Valdecir; Andrade, Luís Eduardo Coelho

doi:10.1007/s12072-012-9413-0

Cited by 23 publications

(21 citation statements)

References 23 publications

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“…We thank Dellavance et al for their interesting comment. We agree that both their results (1) and ours (2) lend support to the hypothesis that emergence of primary biliary cholangitis (PBC) is not related to antimitochondrial antibodies (AMA) positivity per se, but rather to quantitative and qualitative escalating changes in autoreactivity and humoral response preceding the clinical phase of the disease. Although the two studies differ in terms of initial design and AMA screening methods (cytoplasmic AMA-like pattern in the ANA-Hep-2 immunofluorescence [IF] assay in the Brazilian study and IF assay on rat liver, kidney, and stomach tissue sections in the French study), both found a high proportion of AMA-positive patients with no clinical evidence of PBC (54% and 32%, respectively).…”

supporting

confidence: 86%

“…In the Brazilian study, higher titers of AMA, high-avidity anti-PDC-E2, and response to three or more antigenic cell domains were independently associated with established PBC. (1) In the French study, female sex, younger age, higher AMA titers, higher rate of AMA-positive dotting/blotting tests, and higher detection rate of PBC-specific (PBC-sp.) antinuclear antibodies (ANAs) were individually associated with definite PBC.…”

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confidence: 96%

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“…It is established that AMA-M2 is more specific to PBC than to AIH (13); therefore, the AMA-M2 titer is a common test for PBC (25,26). A problem with this is that patients with AIH can still test positive for AMA-M2 (21).…”

Section: Discussionmentioning

confidence: 99%

Anti-mitochondrial M2 antibody-positive autoimmune hepatitis

Tomizawa

Shinozaki

Fugo

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Anti-mitochondrial M2 antibody (AMA-M2) is specific to primary biliary cirrhosis (PBC), but can also be found in certain patients with autoimmune hepatitis (AIH). Effective methods of differentiating between PBC and AIH are required, as their clinical course and management are different. Titers of AMA-M2 were analyzed before and after follow-up in patients with PBC or AIH. Patients who underwent liver biopsy and were diagnosed with either AIH (10 patients) or PBC (3 patients) were enrolled in the study. The AMA-M2 antibody titers of these patients were analyzed upon hospital admission. AMA-M2 reacted with the pyruvate dehydrogenase complex-E2, branched-chain 2-oxo acid dehydrogenase complex and 2-oxoglutaric acid dehydrogenase complex in the assay utilized for this study. The cut-off value for AMA-M2 was 5. Six AIH patients were AMA-M2(-) and 4 were AMA-M2(+). The titer for the AIH patients who were AMA-M2(+) was 24.8±14.8, compared with 324±174 in the patients with PBC (P= 0.0138). Three AMA-M2(+) AIH patients were followed-up after liver biopsy. The AMA-M2 levels had decreased in all 3 patients, becoming undetectable in 2 of them. In conclusion, certain patients with AIH in this study were found to be AMA-M2(+), but the titers were significantly lower than those in the patients with PBC. At follow-up, the AIH patients exhibited decreased AMA-M2 titers. IntroductionAutoimmune hepatitis (AIH) is caused by an immune attack on the hepatocytes (1). Patients with AIH are positive for auto-antibodies, such as anti-nuclear, anti-smooth muscle and liver-kidney microsomal type 1 antibodies (2). Chronic inflammation in the liver can progress to liver cirrhosis (3). One major problem of AIH is that an acute presentation or exacerbation of the disease can progress to liver failure (4,5). Furthermore, patients with AIH can be susceptible to hepatocellular carcinoma (6); therefore, patients should be followed-up for exacerbation and hepatocellular carcinoma (7). Primary biliary cirrhosis (PBC) is characterized by nonsuppurative cholangitis and autoimmune-mediated destruction of the small or medium-sized bile ducts (8). Inflammation causes cholestasis and the liver develops cirrhosis (9). AIH is treated with immunosuppressive drugs, such as prednisolone or azathioprine (10,11), while PBC is treated with ursodeoxycholic acid (10). It is important to differentiate AIH from PBC due to the differences in the clinical course and management of the two diseases.Anti-mitochondrial antibody (AMA) can be tested via indirect immunofluorescence (12). In this technique, unfixed sections of the kidney and stomach of Wistar rats are used. AMA is used for the diagnosis of PBC (13), as 90-95% of patients with PBC are positive for AMA (14); however, the use of AMA as a differential test is problematic, as 5% of patients with AIH are positive for AMA (15), and the interpretation of a positive AMA result in AIH is difficult.The auto-antigens of AMA have been identified as pyruvate dehydrogenase complex-E2 (PDC-E2), branched-chain 2-oxo...

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“…reported that IgG and IgA AMA titers are positively associated with Mayo risk score in a cohort of 103 patients with PBC but none of the isotypes could be used to predict disease outcome [74]. Analysis of AMA reactivity by IIF and PDC-E2 ELISA between serum samples from AMA positive PBC patients and individuals with AMA without clinical or biochemical evidence of disease, showed that high-titer IIF-AMA and high-avidity anti-PDC-E2 were associated with established PBC [89]. In another study, the presence of intense granular staining of PDC-E2 and an autophagy marker, microtubule-associated protein-light chain 3β in damaged small bile ducts of PBC patients suggests that dysregulated autophagy together with abnormal expression of mitochondrial antigens may be involved in the bile duct pathology of PBC [90].…”

Section: Ama and Pathogenesis Of Pbcmentioning

confidence: 99%

A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis

Leung

Choi

Yang

et al. 2016

Expert Review of Molecular Diagnostics

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Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. The AMA epitope is mapped within the E2 lipoic acid binding domain, which is particularly important for oxidative phosphorylation. In addition, lipoic acid, which serves as a swinging arm to capture electrons, is particularly susceptible to an electrophilic attack and may provide clues to the etiology of PBC. This review emphasizes the molecular characteristics of AMAs, including detection, immunochemistry and the putative role in disease. These data have significance not only specifically for PBC, but generically for autoimmunity.

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Humoral autoimmune response heterogeneity in the spectrum of primary biliary cirrhosis

Cited by 23 publications

References 23 publications

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Anti-mitochondrial M2 antibody-positive autoimmune hepatitis

A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis

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