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Biomedical subjects

D Vergani

Publications and source records attributed to D Vergani.

At least 109 records · Page 6Linked to original sources
PubMed1994

CD5+ B-cells at the onset of type I diabetes and in the prediabetic period.

OBJECTIVE: B-cells expressing CD5 are associated with the production of autoantibodies and are present at increased levels in several autoimmune diseases. The aim of this study was to investigate the relationship of these cells to the development of type I diabetes and the presence of organ and non-organ-specific autoantibodies. RESEARCH DESIGN AND METHODS: We measured percentage levels of CD5+ B-cells in patients with recent-onset (n = 34) and long-standing (n = 21) type I diabetes and in a cohort of 18 identical twins of patients with type I diabetes studied prospectively, 8 of whom became diabetic (prediabetic twins) during the study; the rest remained nondiabetic after at least 7 years and are now unlikely to develop the disease. Forty-seven healthy individuals were studied as control subjects. RESULTS: Percentage levels of total B-cells (CD20+) and the proportion expressing CD5 were increased in patients with recent-onset (P < 0.001 for both) but not long-standing type I diabetes compared with control subjects. Percentage levels of CD20+ B-cells were increased in prediabetic twins throughout the prediabetic period (P < 0.05), and there was an increased proportion of CD5-expressing B-cells that failed to reach statistical significance (P = 0.08). Percentage levels of CD20+ B-cells and the proportion expressing CD5 were normal throughout the study in twins remaining nondiabetic. No relationship between percentage levels of CD5+ B-cells and islet cell antibody, thyroid autoantibodies, or non-organ-specific autoantibodies was found. CONCLUSIONS: These results show an increase in B-cell percentage levels at the diagnosis of type I diabetes, which is because of an expansion of the CD5+ subset. These changes are also evident in twins throughout the prediabetic period, which suggests that they are related to the processes that lead to diabetes.

Adult↗
PubMed1994

Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis.

Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls (Pc < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%, Pc < 0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.

Adolescent↗
PubMed1994

T cell clones generated from patients with type 1 diabetes using interleukin-2 proliferate to human islet antigens.

T lymphocytes are implicated in the pathogenesis of Type 1 (insulin dependent) diabetes. Activated T lymphocytes expressing IL-2 receptors are found at increased levels in the peripheral blood in the prediabetic period, at diagnosis and for several months after the onset of the disease, but their role in the pathogenesis of the disease is not known. We have used co-culture of peripheral blood lymphocytes with IL-2 alone to selectively generate T cell clones from the in vivo activated T cell population, and examined the phenotype and antigen specificity of the clones derived. From 3 patients with newly-diagnosed Type 1 diabetes 184 clones were generated, the majority of which (39%) were CD4+TCR alpha beta+, whilst 31% were CD8+TCR alpha beta+. From 2 healthy control subjects 90 clones were obtained, of which 62% were CD4+TCR alpha beta+ and 33% were CD8+TCR alpha beta+. Antigen specificity was examined in 46 clones from the patients and 44 from the control subjects in proliferation assays, using as antigens homogenate of human islets of Langerhans, human islet membrane preparation and human liver membrane preparation. Three clones (all CD4+TCR alpha beta+) from the patients, but none from the control subjects, proliferated in a dose dependent fashion in response to stimulation with human islet homogenate presented by autologous APCs, but to neither of the other autoantigen preparations. Our results demonstrate that a relatively high proportion (7%) of T lymphocytes activated in vivo recognise human islet antigens, indicating that they may have a role in the pathogenesis of the disease.

Adult↗
PubMed1994

Effects of glibenclamide on ventricular fibrillation in non-insulin-dependent diabetics with acute myocardial infarction.

BACKGROUND: Glibenclamide, a hypoglycemic sulfonylurea, has shown antiarrhythmic effects in acutely ischemic myocardium. The aim of the present study was to evaluate the effectiveness of the drug in preventing ventricular fibrillation in diabetic patients with acute myocardial infarction. METHODS: We studied 232 patients with non-insulin-dependent diabetes mellitus (106 on glibenclamide, group A1; 126 treated with another hypoglycemic drug or with diet only, group A2) and 830 non-diabetic people. All the patients were admitted to our coronary care unit with their first myocardial infarction. RESULTS: Ventricular fibrillation occurred in 1.9% of group A1, 7.9% of group A2, and 9.9% of the non-diabetic (A1 versus A2, P < 0.05; A2 versus the non-diabetic group, NS; A1 versus the non-diabetic group, P < 0.01). Sustained ventricular tachycardia was not significantly different among the groups. CONCLUSIONS: The antiarrhythmic effectiveness of glibenclamide might be related to its blocking action on the ATP-dependent potassium channel, with consequent attenuation of the efflux of potassium induced by ischemia. We also observed a higher mortality rate resulting from heart failure in group A2 than in group A1 or the non-diabetic group. Since glibenclamide has never shown significant effects on myocardial contractility, this finding remains to be elucidated. Glibenclamide therefore appears to have an antifibrillatory effect in acute myocardial infarction; with respect to acute coronary events, the drug might be able to prevent ventricular fibrillation, which is most often fatal when it occurs before hospitalization.

Adult↗
PubMed1993

Analysis of peripheral blood mononuclear cells in rodents by three-colour flow cytometry using a small-volume lysed whole blood technique.

Techniques were adapted to permit phenotypic analysis of peripheral blood leucocytes in rats and mice using small volumes of lysed whole blood and single, dual- or triple-colour immunofluorescence staining with flow cytometry. Red cell lysis using proprietary lysing solutions provides populations of lymphocytes, monocytes and granulocytes clearly differentiable by their light scatter properties. In the present study, measurement of functional and activation T lymphocyte subsets was performed by single- and dual-colour flow cytometry in both species and in excess of 5000 lymphocytes could be counted using as little as 10 microliters of whole blood. Triple-colour fluorescence, using antibodies labelled with fluorescein, phycoerythrin and biotin permitted simultaneous detection of three phenotypic markers. This novel technique has two major advantages, maximising the phenotypic information which may be obtained and using volumes of blood which are sufficiently small that they can be drawn regularly from the same animal.

Animals↗
PubMed1993

Methods for assessing complement activation in the clinical immunology laboratory.

Complement activation is a key component of the pathogenesis of immune-mediated tissue damage in many diseases. Assessment of complement activation in current practice is largely based on the measurement of intact C3 and C4 or the determination of complement haemolytic function. These parameters reflect activation only indirectly, are insensitive and open to influence by factors other than complement conversion. New approaches to evaluate complement activation directly using sensitive techniques have been developed, and several could be adopted easily in most laboratories. These concentrate on the detection of activation fragments, neoantigens or complexes that only arise as a direct result of complement activation. The wide application of these techniques in research and clinical practice would enhance our understanding of the pathogenesis of a range of inflammatory and infectious diseases.

Anaphylatoxins↗
PubMed1993

Autoantibodies to nervous tissue structures are associated with autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus.

There is evidence that the immune system may play a role in the pathogenesis of autonomic neuropathy in Type 1 (insulin-dependent) diabetes mellitus. In the present study, we investigated the presence of autoantibodies to sympathetic and parasympathetic nervous structures and their correlation with other conventional autoantibodies in well-characterised diabetic populations, with or without diabetic neuropathy, and normal subjects. An indirect immunofluorescent complement-fixation technique was used, with monkey adrenal gland, rabbit cervical ganglia and vagus nerve as substrates. Of the patients with symptomatic autonomic neuropathy 33% were positive for at least one autoantibody (20% anti-sympathetic ganglia, 10% anti-vagus nerve and 13% anti-adrenal medulla). The frequency of having one or more antibodies to nervous tissues and the prevalence of anti-cervical ganglia antibodies were significantly higher in the neuropathic patients than in the diabetic control subjects with disease of similar duration and in the normal subjects (p < 0.05). Of the patients without complications with diabetes of shorter duration 33% were also positive for at least one autoantibody (13% anti-ganglia, 13% anti-vagus nerve and 13% anti-adrenal medulla). No correlation was found with other tissue autoantibodies, including islet cell antibodies. Our data indicate that nervous tissue autoantibodies are associated with symptomatic autonomic neuropathy. Anti-sympathetic ganglia and anti-vagus nerve antibodies seem to be more disease-specific. Patients with diabetes of shorter duration who were positive for these autoantibodies may represent pre-neuropathic patients.

Adolescent↗
PubMed1993

T cell activation and disease severity in HIV infection.

In vitro studies have indicated that T lymphocyte activation may be of importance in the pathogenesis of HIV infection. In order to define the role of immune activation in vivo, we assessed the expression of the T cell activation markers HLA-DR and CD25 by flow cytometry in peripheral blood in relation to disease severity and the surrogate markers CD4 and beta 2-microglobulin in 157 patients with HIV infection and 53 healthy seronegative blood donors. Percentage levels of CD3+HLA-DR+ T lymphocytes were significantly higher (P < 0.0001) and percentage levels of CD3+CD25+ T lymphocytes significantly lower (P < 0.0001) in all HIV+ patients compared with controls. A significant correlation was observed between increasing percentage levels of CD3+HLA-DR+ T lymphocytes and both declining CD4 counts (r = 0.52; P < 0.001) and increasing beta 2-microglobulin levels (r = 0.56; P < 0.001). Percentage levels of CD4+HLA-DR+ and CD4+ CD25+ lymphocytes were significantly higher in all HIV+ patients compared with controls (P < 0.001). Levels of activated (HLA-DR+ and CD25+) CD4+ lymphocytes showed a significant step-wise linear increase with increasing disease severity (P < 0.001). High levels of CD3+HLA-DR+ T lymphocytes were found in a greater proportion (81.8%) of asymptomatic HIV+ patients (Centres for Disease Control (CDC) group II) than low CD4 counts (51.5%) (P < 0.001). Compared with controls, HIV+ patients had higher percentage levels of CD8+HLA-DR+ lymphocytes (P < 0.001), but similar levels of CD8+CD25+ lymphocytes. These results indicate that T cell activation is not only a consistent but also an early feature in HIV infection. Monitoring levels of activated T cells and their subsets is of value in assessing progression of HIV-related disease.

Adult↗
PubMed1993

Serum interleukin-1 alpha and soluble interleukin-2 receptor concentrations in cystic fibrosis.

Interleukin (IL)-1 and IL-2 may participate in the systemic inflammatory response and hypergammaglobulinaemia observed in patients with cystic fibrosis. Thirty seven patients with cystic fibrosis were compared with 25 normal controls. High IgG and IgM concentrations were associated with more severe pulmonary disease. IL-1 alpha and soluble IL-2 receptor concentrations were higher in the cystic fibrosis group than in the controls and also correlated with concentrations of IgG and IgM. These results suggest that these cytokines may contribute to enhanced immunoglobulin synthesis and silent inflammatory activity in clinically stable patients with cystic fibrosis.

Adolescent↗
PubMed1993

Immunological studies on type 1 diabetes in identical twins.

Diabetes is a multifactorial disease, the pathogenesis of which involves participation of the host immune system in beta cell destruction. Studies on identical twins offer the opportunity to define genetic and non-genetic factors which may contribute to susceptibility to the disease. Our own work indicates that the number and nature, as well as the intensity and persistence of immune abnormalities of cellular and humoral immune responses can be powerful predictors of the disease and also identify twins who have a degree of protection from the disease.

Antibody Formation↗
PubMed1993

Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM.

The monoclonal antibodies 2H4 (anti-CD45RA) and UCHL1 (anti-CD45RO) were used to subdivide the CD4 and CD8 T-cell subsets into naive and memory cells. The peripheral blood lymphocytes of 34 patients with recent-onset IDDM, 21 patients with long-standing IDDM, and healthy control subjects of similar age and sex were analyzed by a three-color immunofluorescence technique. CD4 and CD8 lymphocytes expressed the CD45 isoforms alone (CD45RA+ or CD45RO+) or in combination CD45RA+RO+). Simultaneous coexpression of both CD45RA and CD45RO (CD45RA+RO+) on CD4 and CD8 lymphocytes in patients with recent-onset IDDM was higher than in control subjects (P < 0.001). The proportion of CD4 lymphocytes expressing CD45RA alone (CD45RA+RO-) was similar in these groups, but the percentage of CD8 lymphocytes that were CD45RA+RO- was significantly higher in the patients with recent-onset IDDM (P < 0.05). The result of these changes is a significant increase in expression of naive phenotypes (CD45RA+ and CD45RA+RO+) on CD4 and CD8 lymphocytes in recent-onset IDDM (P < 0.005 and P < 0.0001). In long-standing IDDM, total CD45RA+ expression on CD4 and CD8 lymphocytes was reduced compared with control subjects (P < 0.05) as a result of a tendency of CD45RA+RO- and CD45RA+RO+ subsets to be lower. This increase in total naive (CD45RA+) lymphocytes and in coexpression of naive (CD45RA) and memory (CD45RO) markers on CD4 and CD8 lymphocytes subsets in patients with recent-onset IDDM suggests that abnormal regulation of T-cell activation and maturation is important in the pathogenesis of the disease.

Adult↗
PubMed1993

Lymphocyte vaccination prevents spontaneous diabetes in the non-obese diabetic mouse.

The aim of this study was to investigate whether lymphocyte vaccination can prevent diabetes occurring in the non-obese diabetic (NOD) mouse, an animal model of human insulin-dependent diabetes mellitus (IDDM). The lymphocyte vaccine was composed of lymphocytes isolated from the spleens of diabetic NOD mice, activated in vitro using concanavalin A (Con A) and rendered immunogenic using glutaraldehyde treatment. These cells were used to vaccinate mice at 6 weeks with boosters at weeks 10, 14 and 18. The animals were then monitored for signs of diabetes until week 30. Twenty-eight NOD mice (11 male, 17 female) were T-lymphocyte vaccinated while 35 littermates (14 male, 21 female) were sham vaccinated with the vaccine carrier, as control mice. The percentage of mice remaining non-diabetic was 50% in the T-lymphocyte-vaccinated group compared with 20% in control mice (P < 0.05). When the results were divided according to sex of the mouse the percentage of female NOD mice remaining non-diabetic was 47.1% in the T-lymphocyte-vaccinated group compared to only 9.4% in the controls (P < 0.01), while in the males there was no significant difference between the groups. These results suggest that T-lymphocyte vaccination can prevent diabetes in NOD mice and that it has its greatest effect in females. The therapy is apparently safe and its efficacy indicates that it may be of value in prediabetes in man.

Animals↗
PubMed1992

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese.

OBJECTIVE: To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. METHODS: Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. RESULTS: HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P less than 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). CONCLUSION: Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.

China↗
PubMed1992

Naturally occurring soluble CD4 in patients with human immunodeficiency virus infection.

To investigate its use as a marker of disease severity, serum soluble CD4 (sCD4) was measured by ELISA in patients with human immunodeficiency virus (HIV) infection. Levels of sCD4 were higher in patients than in controls (P less than .001) but did not increase with disease severity. sCD4 release per CD4 lymphocyte showed a linear increase with disease severity and performed as well as beta 2-microglobulin, a widely used marker. To study the role of sCD4 in the pathogenesis of HIV infection, an ELISA to detect sCD4 complexed with glycoprotein 120 (gp120) HIV envelope protein was developed. Preformed sCD4-gp120 complexes were not detectable in patient serum, but addition of recombinant gp120 showed that circulating sCD4 is capable of binding HIV envelope proteins. This study indicates that the sCD4-to-CD4 lymphocyte ratio increases linearly with disease severity and may be a useful marker of CD4 lymphocyte damage. In addition, serum sCD4 can bind viral particles, which may have implications for the use of recombinant sCD4 as a therapy in HIV infection.

AIDS-Related Complex↗