Complement-fixing Islet Cell Antibodies Research Articles

Epidemiologische Untersuchung zur Erkennung der präklinischen Phase des Typ-I-Diabetes bei Schulkindern*

Sera of 4208 schoolchildren in Ulm and surrounding areas (1916 boys, 2292 girls; mean age 13.9 [7-21] years) were analysed for the presence of cytoplasmatic islet-cell antibodies (ICA). ICA were demonstrated in 44 children (1.05%). Complement-fixing ICA (CF-ICA) were found in six of them, insulin autoantibodies (IAA) in seven. The early phase of insulin response in the intravenous glucose tolerance test was below the 1st percentile of normal controls in two of the ICA-positive children. In the course of the subsequent 6-9 months the ICA disappeared in half of the previously positive children. In the two with abnormal glucose tolerance tests ICA, CF-ICA and abnormal insulin secretion persisted during the observation period of 9 months. In another CF-ICA-positive schoolchild insulin response to the glucose tolerance test fell below the 1st percentile after 6 months. These results indicate that, even in an unselected group of children, persisting ICA and CF-ICA are high-risk markers for abnormal insulin secretion, which precedes the onset of type I diabetes.

Complement-Fixing Islet Cell Antibodies in Type-1 Diabetes Can Trigger the Assembly of the Terminal Complement Complex on Human Islet Cells and Are Potentially Cytotoxic

Forty-one sera of patients with IDDM (insulin-dependent diabetes mellitus) containing complement-fixing islet cell antibodies were analyzed for their ability to activate TCC (terminal complement complex). Eighteen sera were found to promote deposition of TCC on human islets of pancreatic cryostat sections with a nonhomogeneous pattern of distribution corresponding to that of insulin. Activation of TCC by IDDM serum and binding of this complex to islet cells was confirmed using purified islets. Flow cytometric analysis of islet cell treated with a TCC+IDDM serum showed IgG binding to the cell surface. The same serum had a cytotoxic effect on islet cells in the presence of human C. These results obtained with a homologous system of C activation by IDDM sera suggest that TCC may contribute, at least in part, to the pancreatic β cell damage.

The natural history of pre-Type 1 (insulin-dependent) diabetes mellitus in patients with autoimmune endocrine diseases

An 11-year prospective study was carried out in 180 non-diabetic patients with organ-specific autoimmune diseases to evaluate islet cell antibodies in predicting Type 1 (insulin-dependent) diabetes mellitus. Islet cell antibodies were characterised according to titres, persistence, complement-fixing ability, and pattern. During follow-up, 14 of 46 patients with islet cell antibodies persistently greater than 5 Juvenile Diabetes Foundation Units (JDF-U) (30.4%), none of 23 with islet cell antibodies between 2.5 and 5 JDF-U or fluctuating, and 3 of 109 without islet cell antibodies (2.7%), developed diabetes. The cumulative risk of developing diabetes was 70%, 0%, and 4%, respectively. All the patients who developed diabetes were females. Eight progressed to insulin-dependence acutely, four showed a transient period of non-insulin-dependence, while two were still insulin-free. No difference was found in titres of islet cell antibodies for the risk of diabetes. Complement-fixing islet cell antibodies enhanced the cumulative risk for the disease in patients with conventional islet cell antibodies at low-middle (> or = 2.5-40 JDF-U), but not at high (> or = 80 JDF-U) titres. Forty-two patients with islet cell antibodies were investigated for the whole or the selective pattern. In the presence of the whole pattern the cumulative risk for diabetes rose to 100%, while with the selective pattern it declined to 34%. The whole pattern was found in 83% of patients who developed Type 1 diabetes acutely. In patients with organ-specific autoimmune diseases, the whole islet cell antibody pattern greatly enhances the prediction for diabetes.

Antibodies to the M(r) 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired beta-cell function.

A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the M(r) 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p less than 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ beta chain (p less than 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin autoantibodies as determined by competitive radiobinding assay are positively correlated with impaired beta-cell function — The Ulm-Frankfurt population study

Out of a random population of 4208 non-diabetic pupils without a family history of Type I diabetes 44 (1.05%) individuals had islet cell antibody (ICA) levels greater or equal to 5 Juvenile Diabetes Foundation (JDF) units. 39 of these ICA-positives could be repeatedly tested for circulating insulin autoantibodies (CIAA) using a competitive radiobinding assay. The results were compared with the insulin responses in the intravenous glucose tolerance tests (IVGTT) and with HLA types. Six pupils were positive for CIAA. All of them had complement-fixing ICA, and 5 of them were HLA-DR4 positive. Three of the 6 showed a first-phase insulin response below the first percentile of normal controls. Our data indicate that in population-based studies CIAA can be considered as a high risk marker for impaired beta-cell function in non-diabetic ICA-positive individuals.

Five-year follow-up of islet cell antibodies in Type 2 (non-insulin-dependent) diabetes mellitus

The aim was to study the frequency and appearance of cytoplasmic islet cell antibodies in relation to impairment of insulin secretory capacity and some clinical characteristics in a representative group of middle-aged (45-64 years) patients with Type 2 (non-insulin-dependent) diabetes mellitus (70 male, 63 female) at the time of diagnosis and at five-year follow-up. Non-diabetic control subjects (62 male, 82 female) were similarly examined at five-year intervals. At the baseline five out of 133 (3.8%) diabetic patients were positive for conventional and four (3.0%) for complement-fixing islet cell antibodies. Ten patients had become positive by the second screening for conventional antibodies and six for complement-fixing antibodies, but none showed negative conversion. Two non-diabetic subjects (1.5%) became antibody positive during the follow-up. Insulin treatment was started during the follow-up for four out of 15 (27%) conventional antibody positive and for one out of 121 (0.8%) antibody negative diabetic patients (p = 0.001). The sensitivity of the positive conventional and complement-fixing antibody for identifying patients who developed an impairment of insulin secretory capacity (post-glucagon C-peptide less than or equal to 0.60 nmol/l at 5-year) was 75%. The respective specificity was 90% and the positive predictive values were highest in the case of high positivity (50%). The negative predictive value of antibody positivity was close to 100%. In conclusion, islet cell antibody positivity in patients classified as Type 2 was persistent during the follow-up and predicted the future development of insulin deficiency especially in those patients with high or increasing antibody titres.

Glucose Tolerance and Incidence of Pancreatic Islet Cell Antibodies in Pregnancy in Women with Thyroid Autoantibodies

The prevalence of pancreatic islet cell antibodies (ICA) and complement fixing ICA (CF-ICA) and the effect of pregnancy of glucose tolerance was studied in 3 groups of women. One group had thyroid autoantibodies in serum detected in early pregnancy and subsequent development of postpartum thyroiditis (PPT), another group had thyroid autoantibodies without signs of PPT and the third group did not have thyroid autoantibodies or PPT. In the women with thyroid autoantibodies and PPT, ICA were found in one of 12 women (8%, 95% confidence limits 0-38%). In the group with thyroid autoantibodies without PPT, ICA were found in three of 27 women (11%, 2-29%), whereas two of 20 women without thyroid autoantibodies had ICA (10%, 1-32%), N.S. Where present, serum ICA levels were very low and similar in early pregnancy and 6 months postpartum. CF-ICA were only found in two women with thyroid autoantibodies without signs of PPT. In all groups glucose tolerance was impaired in pregnancy when compared to postpartum despite an increased insulin response to glucose ingestion. In pregnancy, however, glucose tolerance was more impaired in the women with thyroid autoantibodies and subsequent PPT, than in the women without thyroid autoantibodies. Postpartum glucose tolerance was similar in all groups. It is concluded, that the presence of thyroid autoantibodies in early pregnancy or development of PPT is not accompanied by an increased prevalence of islet cell antibodies, but women with thyroid autoantibodies and subsequent PPT have a significantly more reduced glucose tolerance in late pregnancy than women without thyroid autoantibodies.

Aspartic acid at position 57 of the HLA-DQβ chain is protective against future development of insulin-dependent (Type 1) diabetes mellitus

Insulin-dependent (Type I) diabetes mellitus is a chronic autoimmune disease. From studies in discordant twins and multiplex families a long prediabetic period has been reported. In a population-based program started in 1983, fifteen individuals at possible risk for future Type I diabetes were followed for up to 74 months. Two individuals (13%) developed Type I diabetes. These probands were characterized by the presence of high-level cytoplasmic islet cell antibodies (ICA), complement-fixing ICA, and an impaired first-phase insulin response after intravenous glucose load. Both were homozygous for a high-risk immunogenetic marker of Type I diabetes, i.e., non-Asp at codon 57 of the HLA-DQ beta chain. In all other subjects studied, the immunogenetic marker that confers "dominant resistance", aspartic acid at codon 57, was found. On the basis of our data we conclude that a combination of assays which determine ICA, first-phase insulin release, and HLA-DQB1 polymorphisms will identify individuals with a high probability of developing Type I diabetes at the population level. Conversely, HLA haplotypes positive for aspartic acid seem to confer resistance to the disease.

Islet Cell Antibodies as Predictive Markers for IDDM in Children With High Background Incidence of Disease

To determine the prevalence and predictive value of islet cell antibodies (ICAs) for the development of insulin-dependent diabetes mellitus (IDDM) in 1212 Finnish children aged 3-18 yr, samples for ICA determination were taken in 1980, and subsequent analyses were performed in originally ICA+ children and in 296 initially ICA- children in 1983 and 1986. All 1212 subjects were followed for 8 yr for the development of IDDM. Fifty children (4.1%) were positive for conventional ICAs (IF-ICAs) in 1980 (range 3-80 Juvenile Diabetes Foundation units [JDF U]; median 30 JDF U), of which 12 (1.0%) had complement-fixing ICAs (CF-ICAs) in their serums (range 3-30 JDF U; median 8 JDF U). None were exclusively CF-ICA+. Boys were CF-ICA+ more often than girls (9 of 563 [1.6%] vs. 3 of 649 [0.5%], respectively; P less than 0.05). Over the next 6 yr, 4 of 39 subjects lost their IF-ICAs, and 4 of 12 lost their CF-ICAs without progressing to diabetes. The initial IF-ICA levels in these subjects were lower (range 3-8 JDF U; median 7 JDF U; P less than 0.05) than those in the persistent cases. In the initially ICA- subgroup (n = 296), 7 subjects (2.4%) later became IF-ICA+, and 4 (1.4%) became CF-ICA+. The levels of ICA in these subjects were lower than in the originally ICA+ ones (P less than 0.05), and 3 IF-ICA+ and 2 CF-ICA+ subjects again became ICA- before 1986.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA antigens in spanish type 1 diabetic population. correlations with clinical, biological and autoimmune markers

The HLA haplotype and its relationships with clinical, biological and immunological parameters were analyzed in a group of 87 Spanish type 1 diabetic patients at the clinical onset of the disease. The frequency of HLA-B18, DR3 and DR4 antigens was significantly increased whereas DR2, DR5 and DR7 were decreased in comparison with 189 healthy unrelated controls without family history of diabetes. DR3 showed a maximum relative risk for diabetes (5.5) whereas DR4 had a lower one (4.0). HLA-DR4 patients were younger at the time of diagnosis than DR4 negative (16.7 vs 21.4 years). We found no statistically significant relationship between HLA antigens and the other variables studied including the presence of islet cell antibodies, complement fixing islet cell antibodies, insulin autoantibodies, organ-specific antibodies, fasting and maximal glucagon stimulated C-peptide levels, initial glycemia and glycosylated hemoglobin.

Frequency of Islet Cell Antibodies in Adult Newly Diagnosed Diabetic Patients

The sera of 138 Saudi patients with newly diagnosed diabetes (age, 24 to 75 years) were tested for islet-cell autoantibody (ICA), complement-fixing islet cell antibody (CF-ICA), and thyroid, stomac...

Transplacental passage of autoantibodies from a mother with diabetes and Graves' disease to her infant.

Antibodies to islet cells and thyroid gland were examined in a mother with insulin-dependent diabetes mellitus and Graves' disease and in her infant. Islet cell antibodies (ICA), complement-fixing ICA, islet cell surface antibodies (ICSA) and anti-microsomal antibodies (MAb) persisted in the mother during pregnancy. At birth, ICA, ICSA and MAb could be detected in the infant. ICSA and ICA in the infant disappeared by the 3rd and 7th months, respectively. There was no clinical or laboratory evidence of diabetes in the infant. These data suggest that anti-islet cell antibodies themselves may have no significant effect on islet cells.

B-cell responses to intravenous glucose and glucagon in non-diabetic twins of patients with type 1 (insulin-dependent) diabetes mellitus.

The B-cells of patients with recently diagnosed Type 1 (insulin-dependent) diabetes may have no response to glucose when the response to glucagon is present but attenuated. This observation suggests that the recognition of glucose is more severely affected than that for non-glucose stimulants. To determine whether a similar selective decrease in glucose response was present before the onset of diabetes we studied two groups of non-diabetic identical twins of patients with recently diagnosed Type 1 diabetes: one group with complement-fixing islet cell antibodies who were at high risk of developing diabetes (four of the five have already developed diabetes) and a group without such antibodies at low risk of developing diabetes. In addition, a group of patients with chronic pancreatitis were studied to control for non-specific damage to the B-cell. Responses to i.v. glucose and i.v. glucagon were compared. Patients with chronic pancreatitis has similar responses to both glucose and glucagon and the responses did not differ from control subjects. The B-cells of the immune positive group showed evidence of pathology because the insulin and C-peptide responses to both stimuli were reduced when compared to either their control subjects or the immune negative twin group. However, the B-cell response to both glucose and glucagon in the immune positive twins was similar. Because the B-cell response to glucose was not less than that to glucagon, a selective destruction of the glucose recognition system cannot be a characteristic of all twins throughout the period before they develop Type 1 diabetes.

Correlation between residual beta-cell function and islet cell antibodies in newly diagnosed type I diabetes. Follow-up study.

To establish whether there is a correlation between the autoimmune response to the islets and beta-cell function during the initial stages of type I (insulin-dependent) diabetes, and islet cell antibody (ICA) titer and C-peptide levels (fasting and glucagon stimulated) were determined in 39 newly diagnosed patients at onset of diabetes and every 3-6 mo for 2 yr. ICAs were detected in 74% of the patients, and beta-cell function was detected in 84% of the patients at onset. The ICA+ and ICA- groups had similar C-peptide values at diagnosis and at 3 mo, but from 6 mo on, the ICA+ group consistently showed a tendency to lose C-peptide secretory capacity more quickly when assessed by fasting and glucagon-stimulated C-peptide levels (ICA+ vs. ICA- fasting C-peptide levels at 18 and 24 mo, P = .013 and .017, respectively; ICA+ vs. ICA- glucagon-stimulated C-peptide levels at 6, 18, and 24 mo, P = .023, .007, and .028, respectively). The initial ICA titer had the highest predictive value on the outcome of beta-cell function (P = .04), and patients with complement-fixing ICAs did not behave differently from the general ICA+ group. This correlation between beta-cell function and ICA titer supports the role of autoimmunity in the pathogenesis of type I diabetes and has important implications for the design of immunotherapy trials.

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.

Islet-cell antibodies as predictors of the later development of type 1 (insulin-dependent) diabetes. A study in identical twins.

To determine the value of islet-cell antibodies, both complement-fixing and non-complement-fixing, in predicting the later development of Type 1 (insulin-dependent) diabetes, we studied different groups of identical twins. Twelve twins have developed diabetes and 11 of these had non-complement-fixing islet-cell antibodies before diagnosis, and eight out of nine tested had complement-fixing islet-cell antibodies. Of the twins who have remained non-diabetic for many years and are now unlikely to develop diabetes, twelve have had non-complement-fixing islet-cell antibodies at some stage but only four have ever had complement-fixing antibodies. In 29 non-diabetic co-twins tested within 5 years of the diagnosis of diabetes in the affected twin the presence of islet-cell antibodies, especially complement-fixing, predicted the progression to frank diabetes with a high specificity (100%), sensitivity (88%) and predictive value (100%). In pairs remaining discordant the antibodies were found more frequently in the diabetic than the non-diabetic twin. We conclude that the presence of islet-cell antibodies is not genetically determined and can occur without progression to diabetes. However, the presence of islet-cell antibodies, especially complement-fixing, in non-diabetic twins tested soon after the diagnosis of their co-twin, indicates a high risk for the development of diabetes.

Persistent reduction of CD4/CD8 lymphocyte ratio amd cell activation before the onset of Type 1 (insulin-dependent) diabetes

Over a period of 5 years, lymphocyte subpopulations and their markers of activation were studied prospectively in 56 first degree relatives of Type 1 (insulin-dependent) diabetic probands. Lymphocytes were phenotyped using a panel of monoclonal antibodies which recognise CD3, CD4, CD8 lymphocytes, K/NK cells, HLA Class II products and IL-2 receptors (IL-2r). Twenty-six subjects were negative for islet cell antibody (ICA), 18 had complement fixing ICA (CF-ICA) and 12 only conventional ICA (ICA-IgG). The total number of observations (blood samples collected) was 386. Overall, changes in T cell data were observed in the three groups of first degree relatives compared to 70 normal subjects without a family history of diabetes. Six individuals developed Type 1 diabetes in the course of the study. They all possessed CF-ICA and five out of six showed a persistent reduction (less than 1.5) of the CD4/CD8 lymphocyte ratio before the clinical onset of the disease. Activated lymphocytes were found on two occasions in two of these subjects. We conclude that imbalance of lymphocyte immunoregulatory subsets is present before the onset of Type 1 diabetes in susceptible individuals; the persistence of a reduced CD4/CD8 lymphocyte ratio may reflect the ongoing process leading to B-cell destruction.

Islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation.

The aim of this study was to investigate a possible reenhancement of islet cell autoimmunity in type I (insulin-dependent) diabetic patients who received HLA-mismatched pancreas transplants from cadaveric donors and who underwent generalized immunosuppression. Circulating islet cell antibodies (ICA) and complement-fixing ICAs (CF-ICAs) have been tested at 1, 2, 3, 6, and 12 mo and at least once a year posttransplantation in 23 recipients of 25 transplants (22 simultaneous with kidney, 2 retransplants, 1 isolated; 23 segmental neoprene injected, 2 whole with enteric drainage). Patients were aged 35.3 +/- 1.9 yr with a duration of diabetes of 20.6 +/- 1.1 yr. Immunosuppression consisted of double or triple association of azathioprine, cyclosporin, and prednisone with or without temporary antilymphocyte globulins. The number of HLA-A and HLA-B compatibilities was none in 8 patients, one in 12 patients, two in 4 patients, and three in 1 patient. The mean follow-up was 4.0 +/- 0.4 yr/patient (range 0.4-7.2). ICAs were positive pretransplantation in 2 of 25 patients and reappeared 1-42 mo posttransplantation in another 7. In 6 patients, CF-ICAs were also positive. In 7 of 9 ICA+ patients the pancreas transplant failed; in 1 patient this occurred 4 mo before ICA reappearance, and in 6 patients it occurred 2-35 mo after the first detection of ICAs. Pancreas-transplant failure was significantly associated with the positivity for ICAs (P less than .05) and particularly for CF-ICAs (P less than .005). ICA positivity was transitory in 4 patients (2-27 mo) and persistent in the remaining 5 (up to 61 mo).(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective analysis of islet cell antibodies in children with type 1 (insulin-dependent) diabetes.

The prevalence of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes was determined in a cohort of 678 children. The natural course of islet cell antibodies was followed in 375 children at 1 year, 252 and 135 children after 2 and 3 years respectively. Islet cell antibodies were determined by indirect immunofluorescence on cryostat sections of human pancreas. At diagnosis of diabetes 85% of the children had detectable islet cell antibodies (mean titre 10.4). After 3 years 62% of the children were still islet cell antibody positive (mean titre 2.9) indicating a greater persistence of islet cell antibodies than described in earlier studies. In this large cohort a significant correlation between islet cell antibody prevalence or persistence and sex, age or HLA-DR type was not observed except for a faster loss of islet cell antibodies in very young boys and in patients lacking HLA-DR types 3 and 4. Complement fixing islet cell antibodies correlated with high titre islet cell antibodies. Greater persistence of islet cell antibodies was seen for cases with high antibody titre and in children with diagnosis of diabetes during the first half of the year.

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 non-complement-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.