• autoimmunity
• hepatology
• immunology
• immunoregulation
• immunotolerance

• Humans
• Liver/immunology
• Liver/physiopathology
• Animals
• Liver Diseases/immunology
• Liver Diseases/physiopathology
• Immune System/physiology
• Immune Tolerance
• Autoimmunity

• European Association for the Study of the Liver (EASL)
• Sir Jules Thorn Charitable Trust (The Sir Jules Thorn Charitable Trust)
• GR-2018-12367794 Ministero della Salute (Italy Ministry of Health)
• PE-2016-02363915) Ministero della Salute (Italy Ministry of Health)

• Arthritis
• Asthma
• Colitis
• IL-10
• IL-24
• LAG3
• Psoriasis
• STAT6

• Humans
• T-Lymphocytes, Regulatory/immunology
• Animals
• B-Lymphocytes/immunology
• Immune System Diseases/immunology
• Immune System Diseases/therapy
• Disease Models, Animal
• Severity of Illness Index
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism

• Kv1.3
• immune system
• ion channels
• pharmacology
• therapeutics

• Humans
• Prospective Studies
• Potassium Channels, Voltage-Gated/therapeutic use
• Autoimmune Diseases/drug therapy
• Signal Transduction
• Kv1.3 Potassium Channel
• Potassium Channel Blockers/pharmacology

• Autoimmune diseases
• Immune deficiency diseases
• Ion channels
• Major organs
• Transporter

• Kupffer cells
• Kv1.3
• liver diseases
• macrophages
• margatoxin

• Animal models
• Autoimmune hepatitis
• Autoimmune liver disease
• IgG4-related sclerosing cholangitis
• Primary biliary cholangitis
• Primary sclerosing cholangitis

• TLR
• autoimmunity
• biliary epithelial cells
• primary biliary cholangitis

• Animals
• Autoimmunity
• Bile Ducts, Intrahepatic/immunology
• Bile Ducts, Intrahepatic/metabolism
• Bile Ducts, Intrahepatic/pathology
• Disease Susceptibility/immunology
• Epithelial Cells/immunology
• Epithelial Cells/metabolism
• Humans
• Immune System/immunology
• Immune System/metabolism
• Immune Tolerance
• Immunity, Innate
• Liver Cirrhosis, Biliary/etiology
• Liver Cirrhosis, Biliary/metabolism
• Liver Cirrhosis, Biliary/pathology
• Organ Specificity/immunology

• Fibrosis
• Inflammatory bowel disease
• Neuroinflammation
• Peptide
• Therapeutic development
• Toxin
• Voltage-gated potassium channel

• Bile acids
• Biliary epithelial cells
• Biomarkers
• Histology
• Personalized medicine
• Primary biliary cholangitis

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals. None have focused on the classic models of breaking tolerance, namely immunization with self-tissue. Here, we report a novel mouse model of autoimmune cholangitis via immunization with syngeneic bile duct protein (BDP). Our results demonstrate that syngeneic bile duct antigens efficiently break immune tolerance of recipient mice, capturing several key features of PBC, including liver-specific inflammation focused on portal tract areas, increased number and activation state of CD4 and CD8 T cells in the liver and spleen. Furthermore, the germinal center (GC) responses in the spleen were more enhanced in our mouse model. Finally, these mice were 100% positive for anti-mitochondrial antibodies (AMAs). In conclusion, we developed a novel mouse model of PBC that may help to elucidate the detailed mechanism of this complex disease.

Primary biliary cirrhosis (PBC) and primary Sjögren's syndrome (pSS) have been referred to as “generalized autoimmune epithelitis”. Indeed, the pathogenic mechanisms, clinical features, and optimal therapeutic approaches for them are not yet fully defined.

A retrospective analysis was carried out on clinical data obtained from 302 inpatients newly diagnosed with PBC, pSS, or the coexistence of PBC and SS between May 2011 and December 2014. Forty-two patients with abnormal hepatic function were divided into the PBC group (n = 17), the coexistent group (PBC accompanied by SS, n = 13), and the pSS group (n = 12). Their clinical symptoms, laboratory data, and pathological features were collected and analyzed when they were first diagnosed. The clinical and laboratory data were collected at 0, 1, and 3 months after treatment.

Of the 42 patients with abnormal liver function, 4 were male and 38 were female patients. Compared with the patients in the PBC group, the patients in the other 2 groups were more likely to have an elevated erythrocyte sedimentation rate (ESR) and serum immunoglobulin G (IgG) levels. Abnormal serum immunoglobulin M levels (IgM) were more frequent in the PBC group. Corticosteroids were effective in normalizing elevated liver enzyme levels in patients with SS and in those with coexistent conditions.

This pilot study suggests that patients with PBC, pSS, and PBC/SS coexistence and having liver function abnormality share similar symptoms, but have different pathogenesis and prognosis.

• Sjögren's syndrome
• autoimmune liver disease
• primary biliary cirrhosis

• anion exchanger 2
• fractalkine
• name change

• Autoantibody
• Autoimmunity
• Immune responses
• Ion channels

Primary biliary cirrhosis (PBC) is a chronic non-suppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient’s genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed.

• Primary biliary cirrhosis
• Innate immunity
• Adaptive immunity
• Ursodeoxycholate
• Chemokines
• Macrophages
• Cytokines

• Biliary Epithelium
• Primary Biliary Cirrhosis
• Primary Sclerosing Cholangitis

• CRAC
• KCa3.1
• KV1.3
• ORAI
• STIM
• TRP, T cells, B cells, macrophages, mast cells, DC, disease, therapy
• calcium
• chloride
• ion channels
• magnesium
• potassium
• sodium
• transporters
• zinc

• Adaptive Immunity/physiology
• Animals
• Calcium Channels/genetics
• Calcium Channels/metabolism
• Cation Transport Proteins/genetics
• Cation Transport Proteins/metabolism
• Humans
• Hypersensitivity/genetics
• Hypersensitivity/immunology
• Hypersensitivity/metabolism
• Immunity, Innate/physiology
• Immunologic Deficiency Syndromes/drug therapy
• Immunologic Deficiency Syndromes/genetics
• Immunologic Deficiency Syndromes/immunology
• Immunologic Deficiency Syndromes/metabolism
• Immunotherapy/methods
• Ion Channels/genetics
• Ion Channels/metabolism
• Lymphocytes/cytology
• Lymphocytes/immunology
• Lymphocytes/metabolism
• Mast Cells/immunology
• Mast Cells/metabolism
• Molecular Targeted Therapy
• Mutation
• Signal Transduction

• R01 GM099873 NIGMS NIH HHS
• R01 AI097302 NIAID NIH HHS
• GM076063 NIGMS NIH HHS
• AI097302 NIAID NIH HHS
• GM099873 NIGMS NIH HHS
• AI080583 NIAID NIH HHS
• R01 GM076063 NIGMS NIH HHS
• R01 AI080583 NIAID NIH HHS

• Gut–liver axis
• Inflammatory bowel disease
• Intestinal microbiota
• Mucosal immunity
• Primary biliary cirrhosis
• Primary sclerosing cholangitis

It has been well established that numerous kinds of autoantibodies have been detected in liver disease. Some kinds of autoantibodies may be helpful in the diagnosis of autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis or primary sclerosing cholangitis. However, these autoantibodies are present even in sera of patients with viral hepatitis, drug-induced hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease and hepatocelluar carcinoma as well as in sera of patients with autoimmune liver diseases. Other kinds of autoantibodies are recognized as predictive hallmarks for disease activity or prognosis in liver diseases. On the other hand, treatment with interferon initiates the production of several types of autoantibodies in patients with chronic hepatitis C virus infection. Some of autoantibodies induced by interferon may postulate the treatment outcome in those patients. Recent studies also revealed the close correlation between oxidative stress and the production of autoantibodies in liver diseases. This article primarily reviews the recent advances of autoantibodies in the liver diseases and discusses the clinical significance of these autoantibodies.

• Autoantibodies
• Autoimmune liver diseases
• Diagnosis
• Disease activity
• Prognosis

• Animals
• Cytokines/biosynthesis
• Fatty Liver/etiology
• Humans
• Immunity, Innate
• Liver Diseases/etiology
• Liver Diseases, Alcoholic/etiology
• Non-alcoholic Fatty Liver Disease
• Signal Transduction
• Toll-Like Receptors/physiology

• R01 AA017729 NIAAA NIH HHS
• R01 DK075635 NIDDK NIH HHS
• R37 AA014372 NIAAA NIH HHS

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of serum autoantibodies and chronic nonsuppurative destructive cholangitis. The pathogenesis of PBC involves environmental factors, genetic predisposition and loss of immune tolerance. In recent years, it has become univocally accepted that an inappropriately activated immune response is one of the most important factors in PBC. In this study, the role of autoimmunity in PBC is summarized and a feasible research orientation is recommended.

• Primary biliary cirrhosis
• Autoimmunity
• Humoral immunity
• Cellular immunity
• Nonspecific immunity

• alcoholic liver disease
• cystic fibrosis
• hepatitis C
• non-alcoholic steatohepatitis
• primary biliary cirrhosis
• toll-like receptors

• Animal models
• Apoptosis
• Autoantibodies
• Cholestasis
• Genetics
• Immunopathogenesis
• Molecular mimicry

The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure in the pathogenesis of primary biliary cirrhosis (PBC) and autoimmune pancreatitis (AIP), both of which are broadly categorized as autoimmune disorders involving hepatobiliary-pancreatic lesions. Avirulent and/or commensal bacteria, which may have important role(s) as initiating factors in the pathogenesis of autoimmune disorders such as PBC and AIP, will be emphasized.

• liver disease
• immunology
• innate immunity
• bacterial dna

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMA) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility, and a plethora of candidate environmental factors to trigger the disease onset. For these reasons PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre-existing conditions (mostly genetic, as recently illustrated by genome-wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features demonstrated for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA thus turning the non traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments.