Animal Models of Primary Biliary Cirrhosis

Katsumi, Tomohiro; Tomita, Kyoko; Leung, Patrick S.C.; Yang, Guoxiang; Gershwin, M. Eric; Ueno, Yoshiyuki

doi:10.1007/s12016-015-8482-y

Cited by 56 publications

(47 citation statements)

References 103 publications

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“…Such similar chemicals included 2OA . However, the structural effect of xenobiotic conjugation at Lys259 on the PDC‐PP peptide backbone and the immunological consequences of such conformational alterations were unknown . 2‐OA methyl esters are widely used in cosmetics, lipstick, chewing gums, and foods additives …”

Section: Discussionmentioning

confidence: 99%

The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis

et al. 2017

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The identification of environmental factors that lead to loss of tolerance has been coined the Holy Grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC-E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein we successfully applied intein technology to construct a PDC-E2 protein fragment containing amino acid residues 177–314 of PDC-E2 by joining a recombinant peptide spanning residues 177 to 252 (PDC-228) with a 62 residue synthetic peptide from 253 to 314 (PP), which encompasses PDC-E2 ILD. We named this intein-constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA-PPL) and xenobiotic 2-octynoic acid conjugated PPL (2OA-PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA modified PDC-E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC-E2 peptide. Interestingly, this unique AMA subfraction is of the IgM isotype and more dominant in early stage PBC, suggesting that exposure to 2OA-PPL-like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition we analyzed PPL, LA-PPL and 2OA-PPL using electron paramagnetic resonance spectroscopy, with confirmations by ELISA, immunoblotting and affinity antibody analysis. We demonstrate that the conformation of PDC-E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid. In conclusion a molecular understanding of the conformation of xenobiotic modified PDC-E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity.

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Section: Discussionmentioning

confidence: 99%

The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis

et al. 2017

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“…There have been extraordinary and extensive studies of the genetic basis, the immunological features, and the molecular characteristics of not only human PBC but also of several mouse models [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis

Yang

Wang

et al. 2015

Clinic Rev Allerg Immunol

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Although a variant of primary biliary cirrhosis (PBC) characterized by features of autoimmune hepatitis (AIH) has been recognized for many years, few studies with ample numbers of patients have focused on its natural history. This study aimed to clarify the natural history, prognosis, and response to therapy in a cohort of patients with PBC with AIH features. We retrospectively analyzed 277 PBC patients without AIH features and 46 PBC patients with AIH features seen between September 2004 and April 2014. The 5-year adverse outcome-free survival of PBC patients with AIH features was 58% compared to 81% in PBC patients without AIH features. Multivariate analysis in the patients with AIH features indicated that total bilirubin ≥ 2.70× the upper limit of normal predicted a poor prognosis (p = 0.008, relative risk 8.39, 95% confidence interval (CI) 1.73, 40.73). Combination therapy with ursodeoxycholic acid (UDCA) and immunosuppression provided better short-term responses in PBC patients with AIH features, defined by multiple criteria. Higher aspartate aminotransferase (AST) level at accession suggested better prognosis for PBC patients with AIH features while worse prognosis for PBC patients without AIH features. PBC patients with AIH features differ from those without AIH features in terms of natural history, prognostic indicators, and response to therapy.

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“…Although there have been intensive efforts at understanding the genetic basis of PBC and major advances in dissecting underlying immunological defects, such data has not led to major new therapeutic agents (27–30). Characteristically, the disease is strongly associated with autoimmune phenomena such as the appearance of serum anti-mitochondrial autoantibodies and portal infiltrating T cells against the inner lipoyl domain in the E2 component of the pyruvate dehydrogenase complex (PDC-E2) (27, 31, 32). Although PBC is an autoimmune disease, there is not a clear benefit from immunosuppressive therapy, including corticosteroids, azathioprine, cyclosporine, and methotrexate (33).…”

Section: Discussionmentioning

confidence: 99%

AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis

Hsueh

Chang

Loh

et al. 2016

Journal of Autoimmunity

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There remain significant obstacles in developing biologics to treat primary biliary cholangitis (PBC). Although a number of agents have been studied both in murine models and human patients, the results have been relatively disappointing. IL-22 is a member of the IL-10 family and has multiple theoretical reasons for predicting successful usage in PBC. We have taken advantage of an IL-22 expressing adeno-associated virus (AAV-IL-22) to address the potential role of IL-22 in not only protecting mice from autoimmune cholangitis, but also in treating animals with established portal inflammation. Using our established mouse model of 2-OA-OVA immunization, including α-galactosylceramide (α-GalCer) stimulation, we treated mice both before and after the onset of clinical disease with AAV-IL-22. Firstly, AAV-IL-22 treatment given prior to 2-OA-OVA and α-GalCer exposure, i.e. before the onset of disease, significantly reduces the portal inflammatory response, production of Th1 cytokines and appearance of liver fibrosis. It also reduced the liver lymphotropic chemokines CCL5, CCL19, CXCL9, and CXCL10. Secondly, and more importantly, therapeutic use of AAV-IL-22, administered after the onset of disease, achieved a greater hurdle and significantly improved portal pathology. Further the improvements in inflammation were negatively correlated with levels of CCL5 and CXCL10 and positively correlated with levels of IL-22. In conclusion, we submit that the clinical use of IL-22 has a potential role in modulating the inflammatory portal process in patients with PBC.

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Animal Models of Primary Biliary Cirrhosis

Cited by 56 publications

References 103 publications

The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis

The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis

The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis

AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis

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