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B M Dean

Publications and source records attributed to B M Dean.

At least 19 recordsLinked to original sources
PubMed1992

Distinct cytoplasmic islet cell antibodies with different risks for type 1 (insulin-dependent) diabetes mellitus.

The cytoplasmic islet cell antibody patterns of sera from islet cell antibody positive non-diabetic and diabetic endocrine autoimmune patients, and newly-diagnosed Type 1 (insulin-dependent) diabetic patients were characterised using four layer immunofluorescence with monoclonal anti-proinsulin or anti-glucagon antibodies. Two distinct islet cell antibody types were identified. One gave a diffuse cytoplasmic staining in both Beta and Alpha cells ('whole' islet pattern), and was not affected by pre-incubation with rat brain homogenate. The other had a granular appearance with staining restricted predominantly to Beta cells ('selective' islet pattern) and was completely inhibited by pre-incubation with rat brain homogenate. Some sera appeared to have a 'mixed' islet pattern, in which glucagon-positive cells gave a weaker cytoplasmic staining than proinsulin-positive cells. The granular 'selective' pattern was found in sera from 19 (79%) of 24 non-diabetic endocrine autoimmune patients, in two (22%) endocrine autoimmune patients who developed Type 1 diabetes (p less than 0.0001 vs non-diabetic endocrine autoimmune patients), and in none of 19 newly-diagnosed diabetic patients. The 'whole' islet pattern was found only in sera from patients who had, or who subsequently progressed to, Type 1 diabetes. This study has identified a novel islet cell antibody specificity and demonstrates that in islet cell antibody positive endocrine autoimmune patients, only islet cell antibodies which stain both Beta and Alpha cells are associated with progression to Type 1 diabetes.

Adult↗
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

Does exposure to rubella virus generate endocrine autoimmunity?

Rubella virus is a possible environmental agent which may be involved in triggering autoimmunity to pancreatic islet cells, leading to Type 1 diabetes. Autoantibody responses were determined in 239 10-year-old girls who received live attenuated rubella vaccine, of whom 61 (26%) had no pre-existing rubella immunity. Islet cell antibodies (ICA greater than 5 Juvenile Diabetes Foundation (JDF) units) were present in seven (2.9%) girls before vaccination, and they appeared in three more 6 weeks after vaccination (4.2%). However, the ICA levels were low in all cases and of the three girls who developed ICA greater than 5 JDF units 6 weeks post-vaccination, none had detectable ICA 18 months later. IgG-insulin autoantibodies were present in 17 (7.1%) girls before vaccination, and their prevalence decreased after vaccination (5.4%). Thyroid antibodies (thyroglobulin and microsomal) were present in 2% and 1%, respectively, of the girls before vaccination and none appeared afterwards. Thus, rubella vaccination did not elicit widespread endocrine autoantibody production and viral triggering of endocrine autoimmunity in susceptible subjects remains an open question.

Antigens, Viral↗
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

Islet cell antibodies and insulin autoantibodies in patients treated with oral hypoglycaemic agents.

Clinical and immunological features suggesting Type 1 diabetes were assessed in 202 patients treated with oral hypoglycaemic agents for presumed Type 2 diabetes. Islet cell antibodies (ICA) were detected at a level exceeding 5 JDF units in 5.9% of patients, and complement-fixing ICA were detected in 3.4%. IgG insulin autoantibodies were detected in 8.8% of insulin-naive patients, none of whom were ICA positive. ICA were detected more frequently in patients with shorter duration of diabetes (p = 0.02). Age and relative body weight were similar in ICA positive and negative groups. ICA positive patients were more likely to have lost weight (p less than 0.02) than ICA negative patients, although this may have been attributable to the differing duration of diabetes in the two groups. Other individual clinical features suggesting Type 1 diabetes were not significantly more frequent in ICA positive patients. However, a higher proportion of ICA positive than ICA negative patients had one or more features suggestive of Type 1 diabetes irrespective of the duration of diabetes. Clinical features suggesting Type 2 diabetes were present in a similar proportion of ICA positive and ICA negative patients. Fasting and glucagon stimulated C-peptide levels were similar in ICA positive and matched ICA negative patients.

Adult↗
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↗
PubMed1988

Predicting insulin-dependent diabetes.

719 first-degree relatives of diabetic children were followed up to assess the value of HLA haplotype sharing and of islet-cell antibodies (ICA) for prediction of insulin-dependent diabetes (IDDM). Within a maximum of 8 years' follow-up (3384 patient-years of observation) 16 unaffected relatives (5 parents and 11 siblings) became insulin dependent. The cumulative risk of becoming insulin dependent by age 25 was 16% for siblings sharing two HLA haplotypes with the proband, 9% for those sharing one haplotype, and zero for those sharing none. 13 of 24 (54%) subjects positive for complement-fixing ICA on three or more occasions became insulin dependent, as against 1 of 30 (3%) with noncomplement-fixing ICA alone and 2 of 665 (0.3%) ICA-negative subjects; by life-table analysis the risks after 8 years of known ICA status are 76%, 3%, and 0.6%, respectively. In terms of total time at risk ICA-positive family members had a relative risk of 75.2 compared with ICA-negative individuals. With positivity for complement-fixing ICA the relative risk was 188.5.

Actuarial Analysis↗
PubMed1988

Interferon-gamma induces class II MHC antigens on RINm5F cells.

The ability of recombinant interferon-gamma (rIFN-gamma) to induce major histocompatibility complex (MHC) antigen expression in the rat insulinoma cell line RINm5F was investigated. The cells were stained with monoclonal antibodies specific for rat class I and class II MHC antigens. RINm5F cells endogenously expressed class I antigens; this was enhanced by rIFN-gamma. Class II antigens could not be detected on RINm5F cells, but both I-A and I-E were induced by rIFN-gamma.

Adenoma, Islet Cell↗
PubMed1988

Insulin responses and lymphocyte subclasses in children with newly diagnosed insulin-dependent diabetes.

Children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) had increased numbers of CD25 positive lymphocytes in peripheral blood and peripheral blood mononuclear cells responded to insulin antigens by proliferation. The CD25 positivity and insulin proliferation were associated to the duration of symptoms before the diagnosis of IDDM. Thus increased numbers of CD25 positive cells were found in 89% and insulin induced proliferation in 100% of patients with symptoms of diabetes of less than 1 week's duration before diagnosis, while CD25 positivity and insulin-induced proliferation were observed in 36% and 29% of children who had had symptoms for 4 weeks or more before diagnosis. Children with IDDM also had increased numbers of CD4 positive T cells in peripheral blood. The frequency of HLA-DR4 and HLA-DR3/4 in diabetic children was higher and that of HLA-DR2 lower than in the normal population. Insulin, islet cell, gastric-parietal cell, thyroid and antinuclear antibodies did not correlate to the duration of symptoms before diagnosis.

Adolescent↗
PubMed1987

Pre-diabetes in the spontaneously diabetic BB/E rat: pancreatic infiltration and islet cell proliferation.

A cohort of BB/E rats derived from litters with a high and low incidence of IDDM was studied prospectively to examine the relationship between circulating autoantibodies, islet insulin secretion, pancreatic infiltration, and islet cell replication during the pre-diabetic period. Although a higher incidence of islet cell surface (ICSA) and insulin autoantibodies (IAA) was detected in the diabetes-prone than in the low diabetic-incidence BB/E rats there was no correlation between the two antibodies in individual animals. Moreover, ICSA, but not IAA, were associated with loss of first phase islet insulin release. Between 75 and 105 days of age the number of diabetes-prone rats with ICSA and impaired islet insulin secretory function increased. Over the same period, there was a concomitant increase in the proportion of diabetes-prone animals with pancreatic infiltration, and increased islet endocrine cell proliferation. All these interrelated phenomena were observed in diabetes-prone BB/E rats at a time when the animals were normoglycaemic.

Animals↗
PubMed1987

Insulin autoantibodies, islet cell surface antibodies and the development of spontaneous diabetes in the BB/Edinburgh rat.

The presence of insulin autoantibodies (IAA) and islet cell surface antibodies (ICSA) was sought in two longitudinal studies, involving BB/Edinburgh rats of high (BB/E/H, n = 157) and low (BB/E/L, n = 61) susceptibility to diabetes development. Both studies were designed to correlate pancreatic morphology with cellular and humoral immunity. In Study I, groups of eight male and eight female non-diabetic rats of the BB/E/H line were killed at 15 day intervals from 30-105 days and plasma samples were obtained by cardiac puncture. In study II, 61 BB/E/H and 41 BB/E/L rats underwent pancreatic biopsy 1-3 times from 30 days of age until onset of diabetes or 150 days, plasma samples being taken from the tail vein at biopsy. Both studies revealed a higher prevalence for ICSA than IAA in BB/E rats. Whereas a highly significant association of ICSA with diabetes development was observed in study II (chi 2 = 8.30, P less than 0.005), IAA were associated with diabetes development only weakly (P less than 0.03, Mann-Witney U-rank test). No correlation between the presence of ICSA and IAA in individual rats was observed and IAA were not significantly associated with BB/E/H in preference to BB/E/L rats, although positive IAA values were significantly elevated in the former compared with the latter (P less than 0.01). These observations support the concept that IAA form part of a background of heightened autoimmunity against which frank diabetes develops in some animals.

Aging↗
PubMed1987

Immunological responses of the BB rat colony in Edinburgh.

Several immunological responses of the spontaneously diabetic BB rat colony in Edinburgh designated (BB/E) have been studied. The proliferative responses to Con A and LPS, ability to make IL-2 and to show NK activity have been studied using diabetic and non-diabetic BB/E rats and normal Wistar rats. Our data suggest that the diabetic animals in the BB/E colony do not have marked deficiencies in any of these parameters. Lymphopenia and depressed T-cell responses do not appear to be a prerequisite for the development of diabetes in the BB/E colony.

Animals↗
PubMed1986

Islet-cell antibodies and insulin autoantibodies in association with common viral infections.

The appearance of islet-cell antibodies (ICA) and insulin autoantibodies (IAA) was sought in a prospective study of subjects with acute infections (mumps, rubella, chickenpox, and measles) followed for 6 months. IAA appeared in many patients' serum samples after these acute infections, IgM-IAA being more prevalent than IgG-IAA; there was a particularly high incidence (81%) after chickenpox. ICA were detected in 2 subjects--in 1 after rubella and in the other after measles, but this patient had evidence of previous rubella and a strong autoimmune family history. ICA did not appear after mumps. It is postulated that viral infections may trigger the production of IgM-IAA by a common mechanism involving polyclonal immunocyte activation.

Acute Disease↗
PubMed1986

Insulin autoantibodies in the pre-diabetic period: correlation with islet cell antibodies and development of diabetes.

IgG and IgM class insulin autoantibodies were measured by an enzyme-linked immunosorbent assay in sera from members of the Barts-Windsor-Middlesex prospective family study for Type 1 (insulin-dependent) diabetes. One hundred and twelve individuals from 28 families were selected for study on the basis of a clearly defined islet cell antibody status. IgG insulin autoantibodies were found to be significantly associated with islet cell antibody positive (n = 30) versus islet cell antibody negative (n = 57) first degree family relatives (p = 0.002), with increased significance (p = 0.0003) if complement-fixing (CF)-islet cell antibody individuals (n = 20) only were considered. In addition, a significant association of IgG insulin autoantibodies with subsequent development of diabetes was observed within the CF-islet cell antibody positive group (p less than 0.0003). No such associations were found for IgM insulin autoantibodies, but a higher prevalence of these autoantibodies was observed in islet cell antibody negative first degree relatives (n = 57) compared with a control group of 73 Blood Bank donors (p = 0.00007), and they were significantly associated with siblings (n = 48) rather than parents (n = 39), (p = 0.001). We conclude that the presence of IgG insulin autoantibodies and CF-islet cell antibodies confer more risk for future development of diabetes than the presence of either marker alone.

Autoantibodies↗
PubMed1986

Induction of class II MHC antigens in vitro on pancreatic B cells isolated from BB/E rats.

The ability of recombinant Interferon-gamma to induce class II expression in vitro on pancreatic islet B cells has been investigated by exposing islets isolated from BB/E and normal Wistar rats to Interferon-gamma and then staining successively with monoclonal antibodies specific for rat class II MHC antigens and insulin. Induction of class II expression was never observed on islet cells obtained from either normal Wistar rats or rats from the BB/E low diabetes incidence (less than 2%) subline. In contrast, pancreatic B cells from rats from the BB/E high diabetes incidence (60-70%) subline expressed class II antigen following culture with Interferon-gamma.

Animals↗
PubMed1985

In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis.

After the death of a 12-year old girl with newly discovered insulin-dependent diabetes mellitus, we used monoclonal antibodies in an effort to identify the cells invading the pancreas. The majority of infiltrating lymphocytes were of the T cytotoxic/suppressor phenotype, but other T-cell subpopulations were present. Some of the T cells were "activated" (positive for HLA-DR antigen, and the interleukin-2 receptor). Immunocytes bearing IgG were scattered in the gland, and complement-fixing IgG antibodies were deposited in some islets. Increased expression of Class I (HLA-A, B, and C) molecules was observed in the affected islet cells, and in damaged islets showing scant lymphocytic infiltration, some beta cells (still producing insulin), but not glucagon or somatostatin cells, were HLA-DR positive. The capillary endothelium was markedly dilated and strongly HLA-DR positive. These findings may contribute to an understanding of the sequence of events leading to the destruction of beta cells in classic Type I diabetes mellitus.

Antibodies, Monoclonal↗