Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis.

Unlabelled: Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T-cell (Treg) impairments. Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. Here, we describe multiple CD39(pos) Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH.

Polymorphisms in ABCB11 and ATP8B1 Associated with Development of Severe Intrahepatic Cholestasis in Hodgkin's Lymphoma.

We report a young man presenting with jaundice and severe debilitating intrahepatic cholestasis 7 months before the diagnosis of Hodgkin's lymphoma. Serum gamma-glutamyl transferase (GGT) activity was not raised. Liver biopsy demonstrated deficiency of canalicular GGT and bile salt export pump expression, which suggested "benign" recurrent intrahepatic cholestasis.

Liver immunology.

The liver is the largest organ in the body and is generally regarded by nonimmunologists as having little or no lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ.

Tracing environmental markers of autoimmunity: introducing the infectome.

We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease.

Inflammation and hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with both acute and chronic liver dysfunction, spanning a spectrum that ranges from mild neuropsychological disturbances to coma. The central role of ammonia in the pathogenesis of HE remains incontrovertible however, there is a robust evidence base indicating the important role of inflammation in exacerbating the neurological effects of HE. Inflammation can arise directly within the brain itself as a result of deranged nitrogen and energy homeostasis, with resultant neuronal, astrocyte and microglial dysfunction.

Ex vivo magnetic resonance imaging of transplanted hepatocytes in a rat model of acute liver failure.

Hepatocyte transplantation is being evaluated as an alternative to liver transplantation. However, the fate of hepatocytes after transplantation is not well defined. The aims of the study were to improve hepatocyte labeling in vitro using superparamagnetic iron oxide nanoparticles (SPIOs) and to perform in vivo experiments on tracking labeled cells by magnetic resonance imaging (MRI).

Biological functions of ecto-enzymes in regulating extracellular adenosine levels in neoplastic and inflammatory disease states.

When present in the extracellular environment, the nucleoside adenosine protects cells and tissues from excessive inflammation and immune-mediated damage while promoting healing processes. This role has been highlighted experimentally using distinct disease models, including those of colitis, diabetes, asthma, sepsis, and ischemic injury. Adenosine also suppresses immune responses, as in the tumor microenvironment, assisting immune evasion while promoting angiogenesis.

T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile.

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects.

Infectome: a platform to trace infectious triggers of autoimmunity.

The "exposome" is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases.

Systemic inflammation and ammonia in hepatic encephalopathy.

Infection and inflammation have been associated with the development of delirium for many centuries and there is a rapidly growing evidence base supporting the role of inflammation in exacerbating the neurological manifestations of both acute and chronic liver failure. Inflammation in the context of hepatic encephalopathy (HE) can arise directly within the brain itself resulting in astrocytic, microglial and neuronal dysfunction, impacting on the development of 'brain failure'. Inflammation may also develop systemically and indirectly influence brain function.

Autoimmune hepatitis: a comprehensive review.

Autoimmune hepatitis (AIH) is an immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. Overlap/variant forms of the disease, presenting with concomitant features of primary biliary cirrhosis or primary sclerosing cholangitis are increasingly recognised.

Acute liver failure and the brain: a look through the crystal ball.

Over the past 35 years, the outlook for a patient presenting with acute liver failure (ALF) has changed beyond all recognition. A patient presenting in 1984 had an 80 % likelihood of succumbing to intracranial hypertension. Today due to dramatic improvements in intensive care in dedicated liver transplant units, this has been reduced to just 20 %.

p38 mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: lessons to learn from ANCA vasculitis and pemphigus vulgaris.

Evidence is beginning to accumulate that p38 mitogen activated protein kinase (p38 MAPK) signaling pathway plays an important role in the regulation of cellular and humoral autoimmune responses. The exact mechanisms and the degree by which the p38 MAPK pathway participates in the immune-mediated induction of diseases have started to emerge. This review discusses the recent advances in the molecular dissection of the p38 MAPK pathway and the findings generated by reports investigating its role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and autoimmune hepatitis.

The X-factor in primary biliary cirrhosis: monosomy X and xenobiotics.

Primary biliary cirrhosis (PBC) is a chronic, cholestatic, autoimmune liver disease characterised by the destruction of small- and medium-sized bile ducts. The serological hallmark of PBC includes antimitochondrial antibodies (AMA). The disease has a striking female predominance, and primarily affects women of middle-age.

Asialoglycoprotein receptor (ASGPR): a peculiar target of liver-specific autoimmunity.

Asialoglycoprotein receptor (ASGPR) autoantibodies have been considered specific markers of autoimmune hepatitis (AIH). The exact mechanisms responsible for the development of these autoantibodies and leading to autoimmunity to this peculiar liver receptor remain elusive. Furthermore, loss of T cell tolerance to ASGPR has been demonstrated in patients with AIH, but it is poorly understood whether such liver-specific T cell responses bear a pathogenic potential and/or participate in the precipitation of AIH.

Potential Roles for Infectious Agents in the Pathophysiology of Primary Biliary Cirrhosis: What's New?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease serologically characterized by the presence of high-titer antimitochondrial antibodies and, histologically by chronic nonsuppurative cholangitis and granulomata. The aetiology of the disease remains elusive, although genetic, epigenetic, environmental, and infectious factors have been considered important for the induction of the disease in genetically prone individuals. The disease shows a striking female predominance and becomes clinically overt at the fourth to sixth decade.

Ileal inflammation may trigger the development of GP2-specific pancreatic autoantibodies in patients with Crohn's disease.

Why zymogen glycoprotein 2 (GP2), the Crohn's disease (CD)-specific pancreatic autoantigen, is the major target of humoral autoimmunity in inflammatory bowel diseases (IBD) is uknown. Recent evidence demonstrates that GP2 is also present on the apical surface of microfold (M) intestinal cells. As the colon lacks GP2-rich M cells, we assumed that patients with colonic CD are seronegative for anti-GP2.

What is new in primary biliary cirrhosis?

Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts. The disease mainly affects middle-aged women who frequently suffer from concomitant autoimmune diseases. This review discusses the most recent findings in the epidemiology, natural history and approaches used for the accurate diagnosis of the disease.

Circulating neutrophil dysfunction in acute liver failure.

Unlabelled: Systemic inflammation and susceptibility to developing sepsis is common in acute liver failure (ALF) resulting in tissue damage and organ failure. This study characterized the function of circulating neutrophils in 25 patients with ALF and subacute liver failure (SALF). ALF (n=15)/SALF (n=10) patients were prospectively studied and compared with 11 healthy (HC) and 6 septic controls (SC).

Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterized by circulating antimitochondrial antibodies (AMAs) as well as disease-specific antinuclear antibodies, cholestatic liver function tests, and characteristic histological features, including granulomas. A variety of organisms are involved in granuloma formation, of which mycobacteria are the most commonly associated.

Sclerosing cholangitis with granulocytic epithelial lesion: a benign form of sclerosing cholangiopathy.

The association between autoimmune pancreatitis and sclerosing cholangitis has attracted considerable attention. In contrast to type 1 (IgG4-related) autoimmune pancreatitis, bile duct involvement is uncommon in type 2 autoimmune pancreatitis, a more benign condition characterized histologically by granulocytic epithelial lesions (GELs). Following our recent report on a child with GEL-positive sclerosing cholangitis and excellent response to steroids, we retrospectively reviewed the liver histology of a large number of patients with sclerosing cholangitis to investigate the possible role of type 2 autoimmune pancreatitis in this pathology.

Transient elastography is a useful noninvasive tool for the evaluation of fibrosis in paediatric chronic liver disease.

Background: Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort.

Familial primary biliary cirrhosis: like mother, like daughter?

The reasons underlying why autoimmune diseases overwhelmingly affect women more than men are not clear. Nor are the reasons why autoimmune disease is more prevalent in families. This review uses primary biliary cirrhosis (PBC) as a model autoimmune disease to discuss the familial risk, focusing mainly on mother-daughter pairs.

Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn's disease.

Background: Glycoprotein 2 (GP2) was discovered as the major autoantigen of Crohn's disease (CD)-specific pancreatic autoantibodies (PAB). We investigated anti-GP2 IgA and IgG antibodies as novel serological parameters in CD and assessed their association with distinct disease phenotypes.

Methods: Anti-GP2 and anti-Saccharomyces cerevisiae (ASCA) IgA and IgG were detected by ELISA employing recombinant human GP2 and phosphopeptidomannan, respectively and PAB by indirect immunofluorescence (IIF) in 271 sera, 169 with CD and 102 with ulcerative colitis (UC).