The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication.

Immunopathogenesis of hepatitis B virus recurrence after liver transplantation.

Background And Aims: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation.

Methods: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)-alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B.

Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection.

Background & Aims: Cytotoxic T cells have been suggested to be responsible for lysis of hepatitis B virus (HBV)-infected hepatocytes and control of virus infection. The frequency, kinetics, phenotype, and capacity for clonal expansion of circulating HBV-specific CD8 cells were analyzed directly in patients with acute HBV infection to clarify their pathogenetic role.

Methods: Three HLA-A2 peptide tetramers able to visualize HBV core, envelope, and polymerase epitope-specific cytotoxic T lymphocytes were synthesized and used for flow cytometric analysis of antigen-specific populations.

Prevalence of autoantibodies to autonomic nervous tissue structures in Type 1 diabetes mellitus.

Aims: The pathogenesis of diabetic autonomic neuropathy is multifactorial, but recent studies have suggested a link between the presence of autoantibodies to nervous tissue structures and severe, symptomatic autonomic neuropathy. The present study was designed to examine the true prevalence of these autoantibodies in a large clinic-based population of Type 1 diabetic patients compared to nondiabetic controls.

Methods: The presence of complement fixing autoantibodies to vagus nerve (CF-VN), sympathetic ganglion (CF-SG) and adrenal medulla (CF-ADM) was assessed by immunofluorescence in a large cohort of patients (n = 394) of varying duration of Type 1 DM (median 28 years, range 6 months to 73 years) and 160 age and sex-matched nondiabetic control subjects.

The role of HBV DNA quantitative PCR in monitoring the response to interferon treatment in chronic hepatitis B virus infection.

Background/aims: To investigate whether the measurement of HBV DNA by quantitative polymerase chain reaction (PCR) is helpful in monitoring response to interferon treatment in chronic hepatitis B virus infection, we have determined sequentially serum levels of HBV DNA during and up to 18 months after treatment, in 10 patients with a sustained response (all anti-HBe positive, five also HBsAg negative and anti-HBs positive) and, as controls, in 12 non-responders.

Methods: Serum HBV DNA was measured by standard hybrisation assay (Genostics, Abbott) and by quantitative PCR (Amplicor HBV Monitor test, Roche Diagnostic Systems).

Results: A clear difference in HBV viral load between responders and non-responders was observed from the fourth week of treatment and was maintained throughout the study period.

Spontaneous T-cell proliferation in the non-obese diabetic mouse to a peptide from the unique class II MHC molecule, I-Ag7, which is also protective against the development of autoimmune diabetes.

Aims/hypothesis: Major histocompatibility complex class II molecules present antigenic peptides to T-cells and have an important role in T-cell thymic education. The mechanism by which major histocompatibility complex alleles confer a high genetic risk for autoimmune diabetes is not known. One hypothesis is that during positive thymic selection, the peripheral T-cell repertoire is modelled by major histocompatibility complex-restricted presentation of self major histocompatibility complex molecule-derived peptides, some of which mimic tissue autoantigens.

[A comparison between attenuation-corrected and -uncorrected transmission-emission SPECT images obtained with Tl-201 in CAD patients].

Background: The aim of this study was to evaluate the impact of attenuation correction (AC) on the diagnostic accuracy of conventional stress/red thallium SPECT studies.

Methods: We studied 60 consecutive patients (36 males) who underwent conventional diagnostic stress/red study with and without AC (NAC) using a dual-head SPECT camera (Vertex ADAC) with a 153Gd source. The mean age of these patients was 60 years (30-80) and 29 of the subjects had a history of MI.

MHC restriction to T-cell autoaggression: an emerging understanding of IDDM pathogenesis.

The Nobel prize-winning discovery of MHC restriction by Zinkernagel and Doherty has led to some of the most exciting advances in immunology over the past two decades. The ongoing progress in our conceptual understanding of the processes governing the immunology to infection, tolerance to self and consequently the immune dysregulation in autoimmunity have all assimilated the laws of restriction as a central tenet. The focus of much of this research has been the T-cell and its interactions.

A novel assay for detecting antibodies to cytochrome P4502D6, the molecular target of liver kidney microsomal antibody type 1.

Liver Kidney Microsomal type 1 (LKM1) antibody, the diagnostic marker of autoimmune hepatitis type 2, is also found in a proportion of patients with hepatitis C virus infection (HCV). It is detected conventionally by the subjective immunofluorescence technique. Our aim was to establish a simple and objective enzyme-linked immunosorbent assay (ELISA) that measures antibodies to cytochrome P4502D6 (CYP2D6), the target of LKM1.

[Myocardial scintigraphy by the gated SPECT method in coronary disease patients with postischemic stunning].

Unlabelled: Gated SPECT using Tc-99m-labeled flow tracers provides simultaneous assessment of global and regional myocardial perfusion and function. The aim of this study was to evaluate whether regional wall thickening (WT) obtained after stress and at rest makes it possible to identify and analyze a subgroup of post-ischemic stunned patients.

Methods: We studied 20 patients (18 males) who underwent conventional diagnostic dual-day stress/rest Gated SPECT following injection of 925 MBq of 99mTc-tetrofosmin using a dual-head SPECT camera (Vertex ADAC).

Carcinoid heart disease from ovarian primary presenting with acute pericarditis and biventricular failure.

A case is described of a 54 year old woman who had acute pericarditis with large exudative effusion accompanied by severe right and left ventricular failure. The patient was finally diagnosed with carcinoid heart disease from an ovarian carcinoid teratoma. She was treated with octreotide--a somatostatin analogue--followed by radical surgical resection of the neoplasm.

Mimicry between the hepatitis B virus DNA polymerase and the antigenic targets of nuclear and smooth muscle antibodies in chronic hepatitis B virus infection.

Autoantibodies to nuclear and smooth muscle are common in hepatitis B virus (HBV) infection. To understand their origin, we scanned protein databases and found that HBV-DNA polymerase (HBV-pol) shares 7-9 amino acid sequences with nuclear (MHC II trans-activator, nuclear pore core protein, nuclear mitotic apparatus, and polymyositis sclerosis Ag) and smooth muscle proteins (caldesmon and myosin). Twenty-mer peptides with relevant homologues and an irrelevant control peptide were constructed and ELISAs were established.

Argininosuccinate lyase: a new autoantigen in liver disease.

Anti-liver cytosol 1 autoantibody (LC1) characterizes a severe form of autoimmune hepatitis (AIH), staining the cytoplasm of periportal hepatocytes and targeting an unidentified 60-kD liver cytosolic antigen. To identify its target, we used high-titre anti-LCI+ sera from two patients with AIH to screen 18 cytoplasm enzymes with periportal location by double immunodiffusion (DDI). Both sera gave a broad precipitin line against human liver cytosol, suggesting that they may recognize two distinct antigens, a possibility confirmed by the appearance of two precipitin lines when DDI conditions were optimized (0.

Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis.

We describe two patients with liver kidney microsomal antibody type 1 (LKM1)-positive autoimmune hepatitis (AIH) with associated endocrinopathies. The first patient had insulin-dependent diabetes (IDDM), and the second patient had Addison's disease and hypoparathyroidism, and is also positive for islet cell antibodies, without overt diabetes. To account for the existence of multiple endocrinopathy in these patients, we investigated whether there is sequence similarity between the target of LKM1 antibodies, cytochrome P4502D6 (CYP2D6), and other human proteins, and if so, whether this structural similarity produces a detectable cross-reactive immune response.

Immunological liver diseases in children.

Autoimmune liver diseases comprise a number of disorders in which inflammatory damage to the liver is believed to derive from an autoimmune attack. These include autoimmune hepatitis (AIH), characterised by positive smooth muscle and/or nuclear (SMA/ANA) or liver kidney microsomal type 1 (LKM1) antibodies, autoimmune sclerosing cholangitis (ASC), usually SMA/ANA positive, and AIH after liver transplantation, which is positive for SMA, ANA, or atypical LKM. These disorders often present with symptoms indistinguishable from prolonged acute hepatitis.

Autoantibody prevalence in children with liver disease due to chronic hepatitis C virus (HCV) infection.

HCV infection and interferon-alpha (IFN-alpha) therapy have been associated with autoimmunity. To assess whether chronic liver disease (CLD) due to HCV infection or its treatment with IFN-alpha cause autoimmune manifestations, the prevalence of tissue autoantibodies in 51 children with chronic HCV infection and 84 with other CLD was analysed by standard techniques. Sixty-five percent of patients with chronic HCV infection, 66% with chronic hepatitis B infection and 60% with Wilson's disease were positive for at least one autoantibody.

Cytokine overproduction in healthy first degree relatives of patients with IDDM.

Healthy family members of patients with insulin-dependent diabetes mellitus (IDDM) are known to share a number of immunological abnormalities with their affected relatives. Since monocyte and type 1 T-cell-derived cytokines contribute to the pathogenesis of IDDM, we studied the production of these cytokines in the healthy first degree relatives of 29 children with IDDM. We report that circulating tumour necrosis factor-alpha (TNF-alpha) and soluble interleukin-2 (sIL-2) receptor were present in increased amounts in non-diabetic family members at levels similar to those found in the diabetic children (duration of disease 3 months-5 years).

De-novo autoimmune hepatitis after liver transplantation.

Background: Late graft dysfunction that does not result from recognised causes, such as rejection, infection, or vascular or biliary complications, can occur after liver transplantation. We investigated a particular type of unexplained graft dysfunction that is associated with autoimmune features in children who underwent transplantation at our unit between 1991 and 1996.

Methods: Seven (4%) of 180 liver-transplant recipients developed an unexplained but characteristic form of graft dysfunction (five boys, two girls; median age at presentation 10.

Lymphocyte vaccination protects prediabetic non-obese diabetic mice from developing diabetes mellitus.

In the therapeutic manoeuvre termed "lymphocyte vaccination", activated lymphocytes capable of transferring an autoimmune disease are instead attenuated and given in vaccine form. We have previously shown that such a therapy administered to non-obese diabetic (NOD) mice at 6 weeks of age prevents diabetes mellitus. To assess whether this therapy has potential clinical relevance, in the present study lymphocyte vaccination was applied in NOD mice in 3 weekly doses commencing in the immediate prediabetic period (age 12 weeks), when insulitis is advanced and diabetes incipient.

Autonomic nervous dysfunction in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA): possible pathogenic role of autoantibodies to autonomic nervous structures.

Autonomic nervous dysfunction has been previously reported in SLE, RA and systemic sclerosis, but the pathogenesis of such a complication is poorly understood. In the present study, four standard cardiovascular autonomic function tests were performed in 34 female patients with connective tissue diseases and in 25 healthy control subjects, and results expressed as cardiovascular (CV) test scores. Moreover, in each subject the presence of circulating complement-fixing autoantibodies directed against sympathetic and parasympathetic nervous structures, represented by superior cervical ganglia and vagus nerve, respectively, was simultaneously assessed by an indirect immunofluorescent complement-fixation technique, using rabbit tissue as substrate.

A 12-year-old girl with antimitochondrial antibody-positive autoimmune hepatitis.

Autoimmune hepatitis is rare and, in childhood, is typically associated with either the nuclear and/or smooth muscle antibody or with the liver kidney microsomal type 1 antibody. Antimitochondrial antibodies, which are considered diagnostic of primary biliary cirrhosis, have not been described in the paediatric age. We report for the first time a 12-year-old girl with antimitochondrial-antibody-positive autoimmune hepatitis.