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Biomedical subjects

E Bonifacio

Publications and source records attributed to E Bonifacio.

At least 109 records · Page 6Linked to original sources
PubMed1991

Novel considerations on the antibody/autoantigen system in type I (insulin-dependent) diabetes mellitus.

Insulin dependent diabetes (IDDM) has an autoimmune pathogenesis. Included is the presence of antibodies to pancreatic islet cells. The first identified were islet cell antibodies (ICA), detected by indirect immunofluorescence, and which react with all cells within islets. Importantly, the autoantibodies are found several years prior to disease and although a pathogenic role for the autoantibodies is unclear, they have become useful markers of prediabetes. A number of studies of twins discordant for IDDM and of first degree relatives of IDDM patients have established that there is an increased risk for disease in individuals who have ICA, especially when ICA levels are high. This high predictive value of ICA decreases in the general population where the incidence of IDDM is lower than in first degree relatives, and both ICA and the disease risk associated with ICA, appear to be influenced by a genetic susceptibility. This has been sustained in a study of patients with endocrine autoimmunity and ICA (Polyendocrine Study) where the predictive value of very high levels of ICA is less than 50% in patients without a first degree relative with IDDM. Hence, there remain a substantial number of patients with ICA who do not develop disease. From these patients, it was demonstrated that ICA include at least two distinct specificities, one of which is beta cell specific and is not associated with a high risk for IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes.

The sensitivity and predictive value of islet-cell antibodies (ICA) for the future onset of insulin-dependent diabetes mellitus (IDDM) were determined in 719 first-degree relatives of IDDM patients. ICA were quantified in Juvenile Diabetes Foundation (JDF) units, by indirect immunofluorescence in serum samples taken during prospective follow-up of up to 10.5 years. The threshold of ICA detection was 4 JDF units. ICA were detected in the first sample of 26 (3.3%) of the relatives, compared with 12 (2.2%) of 540 controls (298 blood donors and 242 healthy children). ICA were detected in follow-up samples from a further 14 relatives. IDDM developed in 14 (35%) of the 40 relatives with detectable ICA at any time and in 2 (0.3%) relatives without detectable ICA. In all 5 relatives with peak ICA levels above 80 JDF units IDDM developed within follow-up of 7 years; survival without IDDM at 10 years was 27% among relatives with peak ICA levels of 20-80 JDF units and 82% for peak ICA levels of 4-20. The predictive value for IDDM development within 10 years ranged from 40% (threshold 4 JDF units) to 100% (80 JDF units) and the sensitivity from 31% (80 JDF units) to 88% (4 JDF units).

Actuarial Analysis↗
PubMed1990

Assessment of precision, concordance, specificity, and sensitivity of islet cell antibody measurement in 41 assays.

Forty-one assays were analysed at the 3rd International Workshop on the standardisation of islet cell antibodies. Analysis of precision demonstrated assays consistently detecting blind duplicates within one doubling dilution and capable of discriminating one doubling dilution differences in islet cell antibody concentration. Some assays, however, reported duplicates discrepantly by more than seven doubling dilutions, and consequently could not distinguish even large quantities of islet cell antibodies. Precision was best in assays from laboratories which had participated in all three Standardisation Workshops and was not dependent upon methodology. The use of the Juvenile, Diabetes Foundation reference islet cell antibody standard and standard curves reduced the scatter of results, and was best amongst assays with better precision. Twenty-seven assays reported all ten blood donor sera as negative. However, 14 assays did not, and specificity (negativity in health) was less than 50% in three assays. Low specificity was strongly associated with poor precision. The detection limit of assays ranged from less than 5 to 50 JDF units and was partially dependent upon methodology. Assays incorporating extended incubation had the lowest detection limits without a decrease in the specificity of the ten blood donor sera. Precise quantification is fundamental for the standardisation and comparability of islet cell antibodies. Precise quantitative assays have been identified and reference standards and common units established.

Autoantibodies↗
PubMed1990

Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy.

To determine whether organ-specific cardiac autoantibodies are present in dilated cardiomyopathy, indirect immunofluorescence on human heart and skeletal muscle was used to test sera from 200 normal subjects and from 65 patients with dilated cardiomyopathy, 41 with chronic heart failure due to myocardial infarction and 208 with other cardiac disease. Three immunofluorescence patterns were observed: diffuse cytoplasmic on cardiac tissue only (organ-specific), fine striational on cardiac and, to a lesser extent, skeletal muscle (cross-reactive 1) and broad striational on both cardiac and skeletal muscle (cross-reactive 2). Cardiac specificity of the cytoplasmic pattern was confirmed by absorption studies with homogenates of human atrium, skeletal muscle and rat liver. Organ-specific cardiac antibodies (IgG; titer range 1/10 to 1/80) were more frequent in patients with dilated cardiomyopathy (17 [26%] of 65) than in those with other cardiac disease (2 [1%] of 208, p less than 0.0001) or heart failure (0 [0%] of 41, p less than 0.001) or in normal subjects (7 [3.5%] of 200, p less than 0.0001). Organ-specific cardiac antibodies were more common in patients with dilated cardiomyopathy and in those with fewer symptoms (8 of 15 in New York Heart Association functional class I versus 9 of 50 in classes II to IV, p less than 0.01) and more recent (less than 2 years) onset of disease (9 of 19 versus 8 of 46, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Inappropriate major histocompatibility complex expression on cardiac tissue in dilated cardiomyopathy. Relevance for autoimmunity?

The inappropriate expression of major histocompatibility complex (MHC) molecules on epithelial and endothelial cells is a recognized marker of autoimmune disease. An autoimmune pathogenesis has been suspected in dilated cardiomyopathy (DCM). In the normal heart, MHC products are usually not detectable on myocytes using immunochemical techniques. MHC molecule expression has not, however, been assessed on cardiac endothelial cells. The aim of this study was to investigate possible autoimmune phenomena and MHC molecule expression in fresh endomyocardial biopsies from 29 patients with DCM. These were compared with those observed in surgical specimens from 63 patients with other acquired cardiac disease and from 22 with congenital heart disease (CHD) as normal controls. Conventional immunofluorescence (IFL) with monoclonal antibodies (MoAbs) to lymphocyte and macrophage markers and to MHC molecules was employed, and double IFL with antiserum to human Factor VIII was used for the identification of endothelial cells. Myocytes did not express MHC molecules in either DCM or controls. In normal hearts, Class II molecules were detected on endothelial and endocardial cells in only a few cases (3/22 and 2/22 respectively). By contrast, endothelial and endocardial cells inappropriately expressed Class II in a high proportion of DCM patients (28/29 and 22/29) but less frequently in other acquired cardiac diseases (19/63, P less than 0.001 and 11/63, P less than 0.001 respectively). In all the DCM biopsies examined there was a hierarchy of Class II subloci product expression (DR greater than DP greater than DQ); lymphocytic infiltration was a rare finding and macrophages/dendritic cells were not prominent. The finding of inappropriate MHC Class II molecule expression on cardiac endothelial and on endocardial cells suggests a possible pathogenic role for these cells in the initiation and/or perpetuation of DCM.

Adolescent↗
PubMed1990

On the pathogenesis of type 1 (insulin-dependent) diabetes mellitus: facts, areas still under development and new perspectives.

The observations emerged from the pancreatic transplant experiments in identical twins indicate that Type I diabetic patients maintain memory cytotoxic T cells for several years and these can be "re-awakened" when Class I identical beta cells are re-introduced into the diabetic melieu. In addition, these data have shown that these lymphocytes can (in a matter of a few weeks) cause rapid irreversible decompensation of beta cell function. From this, an important lesson is learnt: cytotoxic T cells, when generated in sufficient number against beta cells do not leave much "breathing space" for these cells. This has important implications for explaining the long latency period preceding the acute onset of Type I diabetes. ICA, when produced, seem unable to cause gross damage to beta cells. They persist for several years in the blood, but beta cell function remains apparently unaltered. It is only when cytotoxic T cells, with fine specificity for beta cells are generated that the 'killing cycle' is completed. Whether these cells are present all the time, and kept under tight control by active suppressor mechanisms or whether they appear only after an environmental trigger (e.g., retroviruses) is unknown. If the former is the case, this would give strong support to the suggested important role of suppressor T cells in the pathogenetic circuit. Some evidence for this has been produced (rev. in [116]) but, obviously, it requires confirmation (see debate which followed [116]). If, on the other hand, the latter is experimentally confirmed, one can return to the theory that cytotoxic T cells acquire the characteristics of autoreactivity by expressing receptors on their surface in a configuration which enables combination with self-autoantigens (rev. in [45]). In summary, the study of the etiopathogenesis of Type I diabetes and human autoimmunity in general has attracted a great deal of interest among immunologists. It is only by further dissecting the various limbs of the undesirable immune response against beta cells and, by trying to formulate novel hypotheses, sometimes against accepted dogmas [32], that the complete picture will be finally disclosed. At this stage it will be possible to design effective therapy trials, so that Type I diabetes and other related autoimmune disorders ultimately may be prevented.

Autoantibodies↗
PubMed1989

Pathogenesis of type I (insulin-dependent) diabetes: possible mechanisms of autoimmune damage.

By definition, autoimmunity is a circumvention of self-tolerance. Considering the complex network of control mechanisms which initiate and regulate immune responses to foreign agents and maintain the natural state of self-tolerance, autoimmunity may result from a weakening of this delicate equilibrium at various levels. Several hypotheses have therefore been put forward to explain the 'active' immunization process against self-constituents which are normally tolerated.

Autoantigens↗
PubMed1989

Comparison of insulin autoantibodies in diabetes-related and healthy populations by precise displacement ELISA.

The second international workshop on insulin autoantibodies (IAAs) demonstrated improved concordance among laboratories with both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) when measurements were based on signals displaceable by preincubation with excess insulin. This feature has been incorporated into our original ELISA for IAAs, and the assay was used to compare IAAs in diabetes-related and healthy populations. The serum from a healthy islet cell antibody (ICA)+ and IAA+ subject was used to construct standard curves with and without preincubation with 1 U/ml human insulin. Reporting results in arbitrary displacement (delta +/- IAA) units derived from the standard curve improved precision and increased the specificity of the assay. Frequency analysis of the results from 200 control adults did not show a normal distribution, and cumulative frequency analysis demonstrated two populations: 10 of 200 (5%) control adults, 8 of 241 (3.3%) healthy schoolchildren, and 18 of 229 (7.9%) non-insulin-dependent diabetes mellitus (NIDDM) patients had IAAs greater than 12 delta +/- IAA units. On the same basis, we tested samples from 89 individuals in the prospective Bart's Windsor Family Study for insulin-dependent diabetes mellitus (IDDM), 31 of whom had ICAs greater than 5 Juvenile Diabetes Foundation (JDF) units. Of those with ICAs greater than 5 JDF units, 12 developed IDDM and 1 developed NIDDM in 10 yr of study. IAAs greater than 12 delta +/- IAA units were found in 6 of 12 (50%) who became diabetic and in 4 of 18 (22%) who remain healthy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Systematic variation and differences in insulin-autoantibody measurements.

Insulin autoantibodies (IAAs) are currently the subject of intensive investigation as potential markers for autoimmune insulitis. However, the results of different reports vary widely. In an attempt to elucidate the reasons for the discrepant reports and to initiate standardization procedures, the International Diabetes Workshop (IDW) undertook two studies in which 22 centers worldwide measured IAA in coded samples. The variance in binding signal from the 49 sera in study 1 was considerable, even when results were standardized, but was largely systematic and attributable to basic differences in assay type (liquid phase versus solid phase) and to differences in the ligand used (human vs. nonhuman insulin). In study 2, 5 sera were prepared and presented blindly to compare dilution curves, insulin-species specificity, interference from irrelevant serum proteins, precision, and dose-dependent displaceability. Many assays, both liquid and solid phase, were influenced by marked and unpredictable nonspecific binding, revealed by loss of parallelism between dilution curves in pooled normal serum and buffer, by variable binding signals with different normal sera, and by difficulty in distinguishing human insulin-specific from cross-reactive IAA sera. It was concluded from the experience of both studies that variance could probably be reduced by using a standard curve with derived common units, a single species of ligand, and methodology to minimize the effect of nonspecific binding. Variation related to assay type was probably due to liquid- versus solid-phase systems being differentially more sensitive to certain aspects of antigen-antibody binding; this issue will be addressed in future serum exchanges and workshops.

Autoantibodies↗
PubMed1988

Serum exchange and use of dilutions have improved precision of measurement of islet cell antibodies.

In an attempt to improve the diagnostic value of measuring antibodies to islet cell cytoplasmic antigen, coded sera were distributed to 38 laboratories and results were returned for analysis. Comparison between laboratories revealed that results for some individual sera differed by up to nine doubling dilutions and even within laboratories duplicate samples could differ by six doubling dilutions. By including dilutions of sera it was possible to draw a standard curve for each laboratory and this revealed major variations in shape, slope and intercept. However, using each laboratory's standard curve and converting results to units, a substantial improvement was obtained. The approach described improves standardisation and will permit laboratories to identify poor precision and/or any systematic change in assay performance.

Animals↗
PubMed1988

Comparison and standardization of measurement of anti-acetylcholine receptor antibody between laboratories.

The presence of autoantibodies to the acetylcholine receptor (anti-AChR) is useful in the diagnosis of myasthenia gravis, and their titre correlates with severity of the disease. Standardization of their measurement is therefore clinically important. Six laboratories world-wide were asked to determine anti-AChR under local conditions in coded samples and to repeat the measurement on the same samples recorded. There was a high degree of consensus over rank order of the samples but a wide systematic variation in the titres obtained. Standardization of units is an important next step in improving the comparability of anti-AChR data between laboratories.

Autoantibodies↗
PubMed1987

SEAPAL quality control analysis of rheumatoid factor measurement in 29 diagnostic laboratories.

A programme for rheumatoid factor (RF) measurement was sponsored by the South East Asian Pacific League against Rheumatism (SEAPAL) and the Clinical Immunology Group (CIG) of the Australian Society for Immunology. Measurements in 29 laboratories in 12 countries showed: a large variety of methods were being used to measure RF, most using semiquantitative agglutination techniques; some laboratories have invalid techniques; the quoted upper normal limit varied considerably between assays, and false positives were identified in three laboratories; a wide range of intralaboratory precision within and between assays; and a reduction in discordance between laboratories by the inclusion of local standards. Before international standardisation of RF measurement can be achieved attention to many of these problems is required. In particular we recommend the wider use of reference standards and the regular participation in quality control programmes in order to monitor performance.

Asia, Southeastern↗
PubMed1987

Use of a standard curve improves precision and concordance of antinuclear antibody measurement.

An exchange of sera between 31 laboratories in Australia and 11 other countries has demonstrated problems in measurement of antinuclear antibody by immunofluorescence. Many laboratories lack precision and there is major discordance between laboratories. Four laboratories appeared unable to measure ANA in the concentration range from 2.5 to 20 IU/ml and only 13 out of 28 could discriminate between 7 IU/ml and 15 IU/ml. Incorporation of common standard sera to generate a standard curve for each assay led to improvements. Use of the standard curve to correct for variation between assays improved precision, and conversion of local titres to common units (IU/ml) improved concordance. This inexpensive and simple strategy should improve routine measurement of ANA and thereby increase its diagnostic value.

Autoantigens↗
PubMed1987

Western blot profiles, lymph node ultrastructure and viral expression in HIV-infected patients: a correlative study.

Sequential immunoblotting was performed on 64 patients infected with human immunodeficiency virus (HIV). Antibody profiles were related to immune function, T subsets and clinical features. In 20 patients, lymph node biopsy revealed a relationship between progressive follicular destruction, low antibody titres and ultrastructural evidence of viral replication and accumulation. Retroviral particles, including budding profiles, were confined to labyrinths formed from hypertrophied follicular dendritic (FD) cells; in some cases, including those with AIDS, the labyrinths showed degenerative changes. The demonstration of high antibody levels in asymptomatic patients with an intact FD cell network and low virion load suggests that antibody may have a protective role in vivo. Analysis of lymph node ultrastructure allows assessment of viral load and FD cell morphology. When combined with immunoblotting, it may be possible to improve prognostic stratification of patients with HIV infection.

AIDS-Related Complex↗