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D Vergani

Publications and source records attributed to D Vergani.

At least 37 records · Page 2Linked to original sources
PubMed2001

Autoimmune hepatitis.

Autoimmune liver disease encompasses several disorders (Table 1). Autoimmune hepatitis (AIH) affects mainly women and is characterized histologically by a portal tract mononuclear cell infiltrate disrupting the limiting plate and invading the parenchyma ("interface hepatitis") and serologically by the presence of autoantibodies and increased levels of immunoglobulin G (IgG), in the absence of a known cause. AIH responds to immunosuppressive treatment. It can present insidiously or as an acute hepatitis. The previously accepted requirement of 6-month duration of symptoms before diagnosis can be made has been abandoned and treatment should be instituted as soon as the disease is diagnosed. In this review, we concentrate on those reports that add to our knowledge in terms of pathogenesis, differential diagnosis, treatment, and clinical course. Special attention is given to overlap syndromes.

Journal Article↗
PubMed2001

Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity.

Pediatric autoimmune liver disease is mainly represented by two similar liver disorders: autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), both characterized by hypergammalobulinemia, interface hepatitis and the presence of a wide range of circulating autoantibodies. Although similar features are seen in AIH and inflammatory bowel disease, histological biliary changes are more common in ASC. In addition to their role as diagnostic markers, autoantibodies, such as anti-extractable nuclear antigen (ENA) antibodies and liver kidney microsomal antibody type 1 (LKM1) may be involved directly in inducing aggressive liver diseases. Although the cellular immune response in pediatric autoimmune liver disease has been less intensively investigated than humoral immunity, the importance of antigen specific T cells has been explored. Both alphabeta and gammadelta T cells derived from either peripheral blood and liver biopsies have highly heterogeneous TCR gene usage and cytolytic activity has been demonstrated. There have been attempts to seek triggers of liver autoimmunity and several sequences shared in common between autoantigens and hepatotropic viruses, namely hepatitis B, C and cytomegalovirus have been identified. The presence of cross-reactivity between homologous sequences, especially between HCV and cytochromes, supports the possibility that molecular mimicry plays a role in the induction of autoantibodies and autoreactive cytotoxic T cells.

Amino Acid Sequence↗
PubMed2000

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. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8(+) cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation. These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

CD8-Positive T-Lymphocytes↗
PubMed2000

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. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up-regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation.

Adult↗
PubMed2000

Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.

After hepatitis B virus (HBV) infection, liver injury and viral control have been thought to result from lysis of infected hepatocytes by virus-specific cytotoxic T cells. Patients are usually studied only after developing significant liver injury, and so the viral and immune events during the incubation phase of disease have not been defined. During a single-source outbreak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery. Although a rise in alanine transaminase (ALT) levels was present at the time of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury. Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) class I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepatitis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before symptomatic disease.

Acute Disease↗
PubMed2000

[Detection and assessment of myocardial stunning with perfusion tomographic scintigraphy using gated SPECT].

BACKGROUND: Gated-SPECT using 99mTc-labeled flow tracers provides the simultaneous assessment of global and regional myocardial perfusion and function. The aim of this study was to identify patients with stress-induced postischemic stunning, among those with reversible stress perfusion defects, and patients with artifactual defects among those with fixed defects, in order to assess the value of the functional data provided by gated acquisition of perfusion imaging in the characterization of ischemia. METHODS: We studied 221 consecutive patients who underwent conventional diagnostic dual day stress/rest gated-SPECT following injection of 925 MBq of 99mTc-tetrofosmin using a dual head SPECT camera, 115 of whom (52%) showed reversible perfusion defects, and 66 (30%) fixed defects. Perfusion was analyzed on ungated images using 20 segments scored on a 5-point scale (0 = normal, 4 = no uptake), while wall thickening was assessed visually on stress/rest end-systolic images using a 4-point score (0 = normal, 3 = absence of wall thickening). Left ventricular ejection fraction and volumes were calculated using an automatic algorithm (quantitative gated-SPECT). Fifty-two out of 221 (23.5%) patients underwent coronary angiography. RESULTS: In 40/115 (35%) patients with reversible perfusion defects, post-stress left ventricular ejection fraction was > 5% lower than that at rest (Group A: stunned), whereas in the remaining 75 patients, post-stress left ventricular ejection fraction was either +/- 5% or greater than that at rest (Group B: non-stunned). Peak exercise angina and ischemic electrocardiographic response to exercise were present in 79 and 58% respectively of Group A patients and in 33 and 39% of Group B patients. The number of patients with multivessel disease was significantly higher in Group A compared to Group B (58 vs 41%, p < 0.05). The total stress and rest perfusion scores were significantly higher in Group A than in Group B (p < 0.01); even the total stress wall thickening score was significantly higher in Group A (p < 0.001). As for global parameters, post-stress end-systolic volume was significantly higher in the stunned group (p < 0.05). In 40 out of 66 (60.5%) patients without reversible ischemia fixed defects were judged to be ischemic (Group C), while in 26/66 (39.5%) they were attributed to attenuation artifacts (Group D). Eighty percent of Group C patients had a previous myocardial infarction against none of Group D. Stress/rest perfusion and wall thickening scores were significantly higher in Group C than in Group D. CONCLUSIONS: Gated-SPECT myocardial perfusion evaluation allowed us to identify a subgroup of post-stress stunned coronary artery diseased patients. The post-stress left ventricular ejection fraction reduction in this population seems to be due to the increase in end-systolic volume. The stunned patients showed more severe perfusion defects and wall thickening abnormalities.

Exercise Test↗
PubMed1999

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. An indirect ELISA using eukaryotically expressed CYP2D6 was designed. Absorbance values obtained against a reference microsomal preparation were subtracted from those obtained against a microsomal preparation over-expressing CYP2D6, thus removing the non-CYP2D6-specific reaction. Sera from 51 LKM1 positive patients (21 autoimmune hepatitis and 30 with HCV infection), 111 LKM1 negative patients with chronic liver disease (including 20 with HCV infection) and 43 healthy controls were tested. Of 51 patients positive by immunofluorescence, 48 were also positive by ELISA while all the 154 LKM1 negative subjects were also negative by ELISA. There was a high degree of association between IFL and ELISA as demonstrated by a kappa reliability value of 0.96. The absorbance values by ELISA correlated with immunofluorescence LKM1 titres both in autoimmune hepatitis (r = 0.74, p < 0.001) and HCV infection (r = 0.67, p < 0.001). The simple, objective ELISA described has the potential to replace the standard immunofluorescence technique.

Adolescent↗
PubMed1999

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. Sixty-five children with chronic HBV infection, 104 patients with other chronic liver diseases (CLD), 36 patients with extrahepatic autoimmune diseases, and 24 healthy controls were investigated. Double reactivity to HBV-pol peptides and corresponding self homologues was observed in 40% of HBV-positive patients as compared with four (4%) with other chronic liver diseases, two (6%) with extrahepatic autoimmune diseases, and in none of the healthy controls (p < 0.001 for all). Double reactivity to myosin or caldesmon peptides and their HBV-pol homologues was associated with anti-smooth muscle Ab positivity by immunofluorescence (p < 0.05 for both). HBV-positive sera double reactive for myosin or caldesmon and their homologous HBV-pol peptides also reacted with the native proteins on immunoblot. Fifty to ninety percent Ab inhibition to individual HBV-pol and HBV-pol99-118 peptides was noted by preincubation with individual HBV-pol/self homologue peptide and native proteins, respectively, but not with control peptide. Our results show that cross-reactive immunity targeting homologous sequences of viral and self proteins may partly account for autoantibody production in HBV infection.

Adolescent↗
PubMed1999

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. The sequence similarity between a known T-cell epitope of glutamic acid decarboxylase-65, 509:VPPSLRTLED and the non-obese diabetic mouse class II major histocompatibility complex molecule I-Ag7 86:VPTSLRRLEQ is consistent with this. METHODS: We measured spontaneous proliferation of peripheral T-cells from non-obese diabetic mice and other, non-diabetes-prone strains, to the I-Ag7 86-101 and glutamic acid decarboxylase-65(509-524) peptides, binding of these peptides to intact I-Ag7 and assessed the effect of tolerance induction on diabetes development, by injecting young non-obese diabetic mice with high doses of peptide. RESULTS: T-cells from non-obese diabetic, but not other mice strains, spontaneously proliferate to the I-Ag7 86-101 and glutamic acid decarboxylase-65(509-524) peptides, but not control peptides. Both test peptides bind I-Ag7. Tolerance induction prolongs diabetes-free survival in non-obese diabetic mice when either the I-Ag7 86-101 or glutamic acid decarboxylase-65(509-524) peptide, but not control peptide, is used. CONCLUSION/INTERPRETATION: A peptide from the unique class II major histocompatibility complex, diabetes-susceptibility molecule, I-Ag7, presented by I-Ag7 is a target of T-cell responses in diabetes-prone nonobese diabetic mice and tolerance induction against the peptide offers appreciable protection against the development of diabetes.

Amino Acid Sequence↗
PubMed1999

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. RESULTS: Tetramer-positive cells specific for the core 18-27 epitope were found at a higher frequency than those specific for polymerase 575-583 and envelope 335-343 epitopes in most patients with acute HBV. The number of HBV-specific CD8 cells was highest during the clinically acute stage of infection and decreased after recovery. These cells expressed an activated phenotype and had an impaired capacity to expand in vitro and to display cytolytic activity in response to peptide stimulation. Recovery of these functions was observed when the frequency of specific CD8 cells decreased, coincident with a progressive decrease in their expression of activation markers. CONCLUSIONS: This study provides the first ex vivo evidence that the highest frequency of circulating HBV-specific CD8 cells coincides with the clinically acute phase of hepatitis B. These cells exhibit an activated phenotype with limited further proliferative capacity that is restored during recovery.

Adult↗
PubMed1999

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. At the last follow up 16-26 (median 21) months after starting treatment, all the 10 responders were HBV DNA negative by hybridisation. By PCR, however, five (one anti-HBs and four anti-HBe positive) were still HBV DNA positive. In addition, one anti-HBs positive patient HBV DNA negative by PCR at last follow up, had fluctuating levels of HBV DNA by PCR during the observation period, only intermittently falling below the threshold of the assay. CONCLUSIONS: The measurement of HBV DNA by quantitative PCR provides early prediction of response to interferon, allowing prompt modification of treatment. With this technique, HBV DNA is detected in a high proportion of sustained responders, suggesting that HBV may never be completely eliminated by interferon treatment, even after anti-HBs seroconversion.

Adolescent↗
PubMed1999

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. RESULTS: All three autoantibodies were frequently detected in Type 1 DM (CF-VN, 22.1%; CF-SG, 30.7%; CF-ADM, 13.2%) but only rarely in healthy control subjects (4.4%, 4.4% and 3.1%, respectively; P < 0.0005 for all). There was no association between any of the autoantibodies and retinopathy (fundoscopy), peripheral somatic neuropathy (biothesiometry) or nephropathy (urinary albumin-creatinine ratio). CONCLUSIONS: Our results on this large cohort establish the extensive presence of autonomic nervous tissue autoantibodies in Type 1 DM. Their role in reflecting, causing or predicting autonomic neuropathy remains to be determined.

Adolescent↗
PubMed1999

[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). The mean age of these patients was 59 years (38-71) and 10 of them had a history of previous acute myocardial infarction (AMI). Perfusion was analyzed on ungated images using 20 segments scored on a 5-point scale (0 = normal, 4 = no uptake), while WT and motion were assessed visually on stress/rest end-systolic images using a 4-point score (0 = normal, 3 = absence of WT/motion). Left ventricular ejection fraction (LVEF) and volumes were calculated. All patients underwent coronary angiography. RESULTS: All patients showed at least one reversible defect with post-stress WT reduction and normal rest WT. The stunned group showed a significant post-stress reduction of LVEF and a statistically non-significant increase of end systolic volume (ESV). A good correlation was observed between global perfusion and WT score both at stress and rest conditions; LVEF showed a significant inverse correlation with global post-stress and rest perfusion and WT score. ESV and the global perfusion stress/rest score showed a good correlation, while end-diastolic volume did not correlate. In 44% of the segments with fixed defects, there was a normal WT and normal coronary-related vessel (false positives); 28% of reversible segments showed a post-stress pathological WT and five of them a rest pathological WT. CONCLUSIONS: The gated SPECT myocardial perfusion evaluation allowed us to analyze a subgroup of post-stress stunned coronary artery disease patients. The post-stress LVEF reduction in this population seems to be due to the increase of end-systolic volume caused by endocardial ischemia. The stunned segments showed severe perfusion defects.

Adult↗
PubMed1999

[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. Reconstructed images were visually analyzed using 20 segments scored on a 5-point scale (0 = normal, 4 = no uptake). Diagnostic accuracy was evaluated in 24 consecutive patients who underwent coronary angiography. Polar plots from each of the four reconstructed data sets per patient were normalized on the maximum and quantified using a nine segment model. RESULTS: The comparison between the segmental stress score obtained with and without AC showed agreement in 1057 out of 1200 (88%) segments analyzed, K statistic value = 0.67. The number of fixed defects was significantly lower after AC. The diagnostic accuracy, evaluated in 24 patients (480 segs), was not significantly different between AC and NAC analysis (80 vs 84% respectively). CONCLUSIONS: AC seems to reduce the number of fixed defects due to attenuation artefacts without improving diagnostic accuracy, probably because of the low number of subjects submitted to angiography and of the interpreting bias due to the expertise of the operators. In fact, in the rather small group of patients evaluated, no improvement in diagnostic accuracy was observed, probably because several attenuation defects were not considered pathological due to operator expertise.

Adult↗