The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection.

Background/aims: The chemokine receptor CX3CR1 and its specific ligand fractalkine (CX3CL1) are known to modulate inflammatory and fibroproliferative diseases. Here we investigate the role of CX3CR1/fractalkine in HCV-induced liver fibrosis.

Methods: A genotype analysis of CX3CR1 variants was performed in 211 HCV-infected patients.

Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis.

The CXC ligand (CXCL)12/CXC receptor (CXCR)4 chemokine-receptor axis controls hematopoiesis, organ development, and angiogenesis, but its role in the inflammatory pathogenesis of atherosclerosis is unknown. Here we show that interference with Cxcl12/Cxcr4 by a small-molecule antagonist, genetic Cxcr4 deficiency, or lentiviral transduction with Cxcr4 degrakine in bone marrow chimeras aggravated diet-induced atherosclerosis in apolipoprotein E-deficient (Apoe-/-) or LDL receptor-deficient (Ldlr-/-) mice. Chronic blockade of Cxcr4 caused leukocytosis and an expansion of neutrophils and increased neutrophil content in plaques, associated with apoptosis and a proinflammatory phenotype.

The role of chemokines and their receptors in dendritic cell biology.

Dendritic cells (DCs) are the chief inducers of adaptive immunity. Their normal life cycle begins with the generation of their precursors in the bone-marrow, followed by their release into the blood stream, continues with their entry into non-lymphoid tissues and commences with steady-state or infection-induced migration into draining lymph nodes. Each of these migration steps is controlled by distinct chemokine-chemokine receptor interactions, facilitated by dynamic changes in chemokine receptor expression.

Up-regulated eotaxin plasma levels in chronic liver disease patients indicate hepatic inflammation, advanced fibrosis and adverse clinical course.

Background And Aims: Recent studies highlight the role of chemokines for the attraction of inflammatory cells in liver injury and fibrogenesis. The CC chemokine ligand 11, eotaxin (CCL11), is up-regulated in senescent human hepatic stellate cells and crucial in animal models of T-cell mediated hepatitis. The aim of this study was to analyze the role of eotaxin in chronic liver disease.

Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells.

Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in liver fibrogenesis. The excessive synthesis of ECM proteins deteriorates hepatic architecture and results in liver fibrosis and cirrhosis. This study investigated the role of bone morphogenetic protein 7 (BMP7) as a member of the transforming growth factor (TGF)-beta superfamily in chronic liver disease.

A simple clinical score predicts high risk for upper gastrointestinal hemorrhages from varices in patients with chronic liver disease.

Objective: Upper gastrointestinal (GI) bleeding from esophageal or gastric fundus varices is a common complication of portal hypertension in liver cirrhosis and carries a high mortality rate of 20-35%. Stratifying high-risk patients for variceal bleeding is mainly based on endoscopic scoring. The purpose of this study was to develop a simple clinical score to assess the bleeding risk.

Insulin resistance in liver cirrhosis is not associated with circulating retinol-binding protein 4.

Objective: Retinol-binding protein 4 (RBP4) has been identified as a novel adipokine mediating systemic insulin resistance, and elevated serum RBP4 indicates overt or impending insulin resistance in lean, obese, and type 2 diabetic subjects. As insulin resistance is present in nearly all patients with liver cirrhosis, we evaluated RBP4 in patients with chronic liver disease (CLD).

Research Design And Methods: Serum RBP4 was measured in 111 CLD patients.

Acute hepatitis B virus infection by genotype F despite successful vaccination in an immune-competent German patient.

Background: Hepatitis B Virus (HBV) infection is a leading cause of chronic hepatitis and liver cirrhosis worldwide, and efficient protection can usually be achieved by vaccination that is based on recombinant HBsAg protein from HBV genotype A and D.

Results: Here we report the case of a fully immune-competent German patient that acquired a symptomatic acute HBV infection during adulthood despite a complete and formally successful vaccination, which had resulted in anti-HBs titers considered protective. Further phylogentic analysis identified an infection with the rare genotype F of HBV, possibly acquired in Spain, without apparent aberrations in the immunodominant 'a' determinant domain of the envelope gene.

Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.

Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques.

A novel model of demyelinating encephalomyelitis induced by monocytes and dendritic cells.

Local inflammation may be a precipitating event in autoimmune processes. In this study, we demonstrate that regulated influx of monocytes and dendritic cells (DC) into the CNS causes an acute neurological syndrome that results in a demyelinating encephalomyelitis. Expansion of monocytes and DC by conditional expression of Flt3 ligand in animals expressing CCL2 in the CNS promoted parenchymal cell infiltration and ascending paralysis in 100% of the mice within 9 days of Flt3 ligand induction.

Migratory fate and differentiation of blood monocyte subsets.

Monocytes are established circulating precursors for tissue macrophages and dendritic cells (DCs). Monocyte-derived macrophages and DCs fulfill critical roles in innate and adaptive immunity during inflammation, and it is believed that monocytes also maintain these populations in peripheral tissues during homeostasis. However, the continuous replenishment of any DC pool by blood monocytes in the steady state remains to be established, and some macrophage populations may be self-renewing in the steady state.

Resistin serum levels are associated with insulin resistance, disease severity, clinical complications, and prognosis in patients with chronic liver diseases.

Objectives: Hyperinsulinemia and insulin resistance are present in nearly all patients with liver cirrhosis. Resistin, a mainly adipose-derived peptide hormone, reduces insulin sensitivity in adipocytes, skeletal muscles, and hepatocytes. In experimental cirrhosis models, resistin expression is upregulated.

Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts.

The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. Here we identify plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes.

Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice.

Atherosclerosis regression is an important clinical goal. In previous studies of regression in mice, the rapid loss of plaque foam cells was explained by emigration to lymph nodes, a process reminiscent of dendritic cells. In the present study, plaque-containing arterial segments from apoE-/- mice were transplanted into WT recipient normolipidemic mice or apoE-/- mice.

Modulation of dendritic cell trafficking to and from the airways.

We investigated the fate of latex (LX) particles that were introduced into mice intranasally. Macrophages acquired the vast majority of particles and outnumbered LX particle-bearing airway dendritic cells (DCs) by at least two orders of magnitude. Yet alveolar macrophages were refractory to migration to the draining lymph node (DLN), and all transport to the DLN could be ascribed to the few LX(+) airway DCs.

Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery.

Monocytes are circulating precursors for tissue macrophages and dendritic cells (DCs) but are not recognized to directly participate in antigen presentation. We developed techniques to label mouse monocyte subsets with particulate tracers in vivo. Gr-1lo but not Gr-1hi monocytes were stably labeled by intravenous injection of 0.

Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6-year survival in patients with chronic liver disease.

Background/aims: Alterations of plasma coagulation factor XIII may contribute to bleeding disorders in patients with liver cirrhosis. As standard clotting tests such as prothrombin time or activated thromboplastin time (aPTT) cannot detect factor XIII deficiency, this may often be overlooked in clinical practice. We aimed to define factor XIII's clinical and prognostic role in chronic liver disease.

Langerhans cells arise from monocytes in vivo.

Langerhans cells (LCs) are the only dendritic cells of the epidermis and constitute the first immunological barrier against pathogens and environmental insults. The factors regulating LC homeostasis remain elusive and the direct circulating LC precursor has not yet been identified in vivo. Here we report an absence of LCs in mice deficient in the receptor for colony-stimulating factor 1 (CSF-1) in steady-state conditions.

Elevation of Nepsilon-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis.

Objectives: Progression of liver fibrosis to cirrhosis is a dire consequence of chronic liver diseases (CLD). Nepsilon-(carboxymethyl)lysine (CML)-modified advanced glycation end products (AGEs) in patients with CLD could reflect the degree of severity of the disease.

Design And Methods: In 110 patients with CLD and 124 healthy controls, CML serum levels and their diagnostic sensitivity and specificity were determined and compared to hyaluronan (HA).

Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.

Background: Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection. It also shows activity against hepatitis B virus (HBV) in patients with or without lamivudine (LAM)-associated mutations. Development of clinical or virological HBV breakthrough during TDF therapy has not been reported so far.

High adiponectin in chronic liver disease and cholestasis suggests biliary route of adiponectin excretion in vivo.

Background/aims: Models of fatty liver diseases and fibrosis suggest a hepatoprotective effect of adiponectin, an adipocyte-derived hormone with antidiabetic, antiobesity, antiatherogenic and anti-inflammatory effects.

Methods: We studied adiponectin serum levels in 111 chronic liver disease (CLD) patients and 226 healthy controls and the impact of cholestasis on adiponectin by bile duct ligation experiments in mice.

Results: Adiponectin was significantly elevated in CLD, and correlated with stage of liver cirrhosis, liver cell injury, e.