Primary biliary cirrhosis: lessons learned from an organic-specific disease

Nishio, Akiyoshi; Keeffe, Emmet B.; Gershwin, M. Eric

doi:10.1007/s102380100000

Cited by 3 publications

(3 citation statements)

References 81 publications

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“…PBC is a female dominant autoimmune liver disease, characterized by the destruction of intrahepatic bile ducts and the production of high-titer anti-mitochondrial Abs (AMA). The major mitochondrial autoantigens recognized by AMA are the E2 components of the 2-oxo-dehydrogenase pathway, particularly pyruvate dehydrogenase complexes (PDC-E2) (4). One of the hallmarks of these autoantigens is that they are each lipoylated in a region localized to the immunodominant peptide recognized by both humoral and cellular autoimmune responses by PBC patients (5)(6)(7)(8).…”

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confidence: 99%

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Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible

Amano

Leung

et al. 2004

The Journal of Immunology

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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.

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confidence: 99%

“…Recently, we have shown that organic molecules known as xenobiotic agents can be used to induce an autoimmune response that mimics the one found in primary biliary cirrhosis (PBC) 4 (3). PBC is a female dominant autoimmune liver disease, characterized by the destruction of intrahepatic bile ducts and the production of high-titer anti-mitochondrial Abs (AMA).…”

mentioning

confidence: 99%

Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible

Amano

Leung

et al. 2004

The Journal of Immunology

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“…It is accepted that liver fibrosis is reversible, whereas cirrhosis is generally irreversible. 26,31 The regenerative ability of the liver is excellent. The process is influenced by several growth factors and cytokines.…”

Section: Overview Of Liver Alterationsmentioning

confidence: 99%

Pluripotent plasticity of stem cells and liver repopulation

Gennero

Roos

Sperber

et al. 2010

Cell Biochemistry & Function

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Different types of stem cells have a role in liver regeneration or fibrous repair during and after several liver diseases. Otherwise, the origin of hepatic and/or extra-hepatic stem cells in reactive liver repopulation is under controversy. The ability of the human body to self-repair and replace the cells and tissues of some organs is often evident. It has been estimated that complete renewal of liver tissue takes place in about a year. Replacement of lost liver tissues is accomplished by proliferation of mature hepatocytes, hepatic oval stem cells differentiation, and sinusoidal cells as support. Hepatic oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial cells found in the liver, hepatocytes, and bile ductular cells. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy, and acute or chronic hepatopaties. In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs. The promise of liver stem cells lie in their potential to provide a continuous and readily available source of liver cells that can be used for gene therapy, cell transplant, bio-artificial liver-assisted devices, drug toxicology testing, and use as an in vitro model to understand the developmental biology of the liver.

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Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

Basavalingappa

Massilamany

Krishnan

et al. 2016

The American Journal of Pathology

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Heart failure, a leading cause of death in humans, can emanate from myocarditis. Although most individuals with myocarditis recover spontaneously, some develop chronic dilated cardiomyopathy. Myocarditis may result from both infectious and noninfectious causes, including autoimmune responses to cardiac antigens. In support of this notion, intracellular cardiac antigens, like cardiac myosin heavy chain-a, cardiac troponin-I, and adenine nucleotide translocator 1 (ANT 1 ), have been identified as autoantigens in cardiac autoimmunity. Herein, we demonstrate that ANT 1 can induce autoimmune myocarditis in A/J mice by generating autoreactive T cells. We show that ANT 1 encompasses multiple immunodominant epitopes (namely, ANT 1 21-40, ANT 1 31-50, ANT 1 171-190, and ANT 1 181-200). Although all four peptides induce comparable T-cell responses, only ANT 1 21-40 was found to be a major myocarditogenic epitope in immunized animals. The myocarditis-inducing ability of ANT 1 21-40 was associated with the generation of T cells producing predominantly IL-17A, and the antigen-sensitized T cells could transfer the disease to naïve recipients. These data indicate that cardiac mitochondrial proteins can be target autoantigens in myocarditis, supporting the notion that the antigens released as a result of primary damage may contribute to the persistence of chronic inflammation through autoimmunity. Myocarditis can occur as a result of exposure to various infectious and noninfectious insults, but does not generally lead to a fatal outcome (ie, most affected individuals can recover spontaneously). However, a proportion of those affected can develop dilated cardiomyopathy (DCM). Estimates indicate that approximately half of DCM patients undergo heart transplantation because of a lack of alternative therapeutic options.1e3 Furthermore, several clinical studies suggest that DCM patients can have autoantibodies to several cardiac antigens, including adenine nucleotide translocator (ANT).4e6 Because DCM can arise as a sequel to myocarditis, it has been postulated that autoimmune response may be an underlying mechanism in its pathogenesis. 7ANT exists in multiple isoforms, all four of which are expressed in humans (ANT 1 , ANT 2 , ANT 3 , and ANT 4 ), but only three in mice (ANT 1 , ANT 2 , and ANT 4 ). ANT 1 is expressed in muscle tissues (heart and skeletal) and the brain, ANT 2 can be expressed in liver, kidney, and heart, and ANT 4 expression is restricted to the testes in mice.

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Primary biliary cirrhosis: lessons learned from an organic-specific disease

Cited by 3 publications

References 81 publications

Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible

Xenobiotic-Induced Loss of Tolerance in Rabbits to the Mitochondrial Autoantigen of Primary Biliary Cirrhosis Is Reversible

Pluripotent plasticity of stem cells and liver repopulation

Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

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