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Query: UMLS:C0011849 (diabetes)
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The contribution of autoantibodies, HLA markers and age to long-term estimates of risk of type 1 diabetes were examined after a median of 11 years (range 7.5-14) during the follow-up in a cohort of 234 siblings (aged 2-29 years) of French children with recent-onset type 1 diabetes, of whom 12 (5.1%) developed diabetes. We evaluated islet cell antibodies (ICA) by indirect immunofluorescence and autoantibodies to insulin (IAA), to the 65 kDa isoform of glutamic acid decarboxylase (GADA) and to the IA-2 protein (IA-2A) by radioligand assay in sequential serum samples. Among the 234 siblings of type 1 diabetic patients screened, 27 were positive for at least one antibody, 11 of whom progressed to develop type 1 diabetes during the follow-up (sensitivity, 92%, predictive value, 41%). Among the four antibodies tested individually, ICA had the highest sensitivity (83%) but a poor predictive value (59%) and IA-2A the highest predictive value (70%). IAA and GADA both exhibited poor sensitivity and predictive value. Combinations of antibodies achieved better predictive values than antibodies tested individually. Satisfactory predictive values were obtained for the combination of GADA with IA-2A (83%), for any combination of at least two antibodies other than ICA (70%) and for the combination of ICA with at least one other antibody (69%). The risk estimates were highest in the presence of three or four antibodies, whether comprising ICA or not, but with a concomitant loss of sensitivity. For most antibody combinations, cumulative risks showed progression from approximately 50% after 5 years to 100% after 13 years. HLA-DR3/4 was significantly more frequent in siblings developing type 1 diabetes than in non-diabetic siblings (9/12 vs. 39/217, relative risk (RR)=14, P</=0.0001). The predictive value of HLA-DR3/4 was low (19%); however, taking into account the presence of HLA-DR3/4 in subjects who were positive for more than one antibody resulted in a higher predictive value (67%, vs. 20% in non-DR3/4 subjects, P</=0.02). In addition, siblings developing diabetes were younger at entry than those who did not (mean =7.5 +/-1.23 vs. 12.5 +/-0.39 years, respectively; P</=0.01). Ten of 12 were aged less than 10 years compared with 106/222 non-diabetic siblings (RR =5.4, P</=0.03). Moreover, younger age was associated with a more rapid development of type 1 diabetes. In conclusion, our results show that the combination of IAA, GADA and IA-2A autoantibodies in sequential serum samples is satisfactory for the identification of subjects at risk of developing type 1 diabetes. Additional factors such as younger age and HLA-DR3/4 as markers of progression to disease may contribute to more efficient prediction in antibody positive subjects.
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PMID:Young age and HLA markers enhance the risk of progression to type 1 diabetes in antibody-positive siblings of diabetic children. 987 86

The temporal development of autoantibodies was studied in 1,353 offspring of parents with type 1 diabetes. Islet cell antibodies (ICAs) and autoantibodies to insulin (IAAs), glutamic acid decarboxylase, and IA-2 were measured at birth, 9 months, 2 years, and 5 years of age. At birth, no offspring had islet autoimmunity other than maternally acquired antibodies, which were shown to influence antibody prevalence up to age 6 months. Antibodies detected thereafter were likely to represent a true de novo production, since prevalences were the same for offspring from mothers and fathers with diabetes, antibodies detected at 9 months were almost always confirmed in the 2-year sample and were associated with an increased likelihood of having or developing other antibodies. By 2 years of age, autoantibodies appeared in 11% of offspring, 3.5% having more than one autoantibody. IAAs were detected most frequently, and few had autoantibodies in the absence of IAAs. In 23 offspring with multiple islet autoantibodies, IAAs preceded other antibodies in 10 cases and were first detected concurrently with other antibodies in 12 and after detection of other antibodies in 1. Development of additional antibodies and changes in levels, including decline of IAAs at older age, was frequent. Nine children, all with IAAs and ICAs, developed diabetes. Overall cumulative risk for disease by 5 years of age was 1.8% (95% CI 0.2-3.4) and was 50% (95% CI 19-81) for offspring with more than one autoantibody in their 2-year sample. Autoimmunity associated with childhood diabetes is an early event and a dynamic process. Presence of IAAs is a consistent feature of this autoimmunity, and IAA detection can identify children at risk.
Diabetes 1999 Mar
PMID:Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. 1007 44

The occurrence of type I diabetes is associated with autoimmunity against insulin, glutamate decarboxylase (GAD65) and the transmembrane protein IA-2. Experiments in the spontaneously diabetic NOD mouse and the BB rat have shown early autoantigen treatment to confer protection from diabetes. The question remains of whether human type I diabetes can be prevented by autoantigen 'vaccination'.
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PMID:[Vaccination against type 1 diabetes at the clinical trial stage]. 1019 8

We analyzed 747 children, younger than 15 yr of age, with newly diagnosed diabetes, for antibodies to glutamic acid decarboxylase (GADA), the IA-2 protein (IA-2A), insulin (IAA), and islet cells, to evaluate the influence of positivity for GADA, IA-2A, IAA, or multiple (> or = 3) autoantibodies at diagnosis, on the clinical presentation and natural course of the disease over the first 2 yr and to characterize autoantibody-negative patients. At diagnosis, 73.2% of the children tested positive for GADA, 85.7% for IA-2A, 54.2% for IAA, and 72.6% for multiple autoantibodies. Only 17 subjects (2.3%) had no detectable autoantibodies. The patients testing positive for multiple autoantibodies were younger than the remaining children (P < 0.001). A similar age difference was seen when comparing IAA-positive and -negative patients (P < 0.001). There was no significant difference between the GADA-positive and -negative subjects in the degree of metabolic decompensation at diagnosis, whereas those testing positive for IA-2A had reduced serum C-peptide concentrations (P = 0.003), and those positive for IAA had lower glycated hemoglobin values. The patients with no detectable autoantibodies had higher serum C-peptide levels (P = 0.007) at diagnosis than did the other subjects. The children initially positive for IA-2A had decreased serum C-peptide concentrations at 24 months (P = 0.045), and their daily insulin dose was higher at 18 (P = 0.005) and 24 months (P < 0.001). The patients who tested positive for multiple autoantibodies at diagnosis had decreased serum C-peptide levels (P < 0.001) and higher insulin doses (P = 0.005) at 12, 18, and 24 months. A lower proportion of them were also in clinical remission at 12 and 18 months (P = 0.01). Autoantibody-negative subjects needed less exogenous insulin at 6 and 18 (P = 0.01) and at 24 months (P < 0.001) than the other subjects, and a higher proportion of them were in clinical remission at 18 months (P < 0.001). We conclude that positivity for multiple diabetes-related autoantibodies is associated with accelerated beta-cell destruction and an increased requirement for exogenous insulin over the second year of clinical disease, indicating that multiple autoantibodies reflect an aggressive progression to total beta-cell destruction. Patients testing negative for diabetes-associated autoantibodies at diagnosis seem to have a milder degree of beta-cell destruction, but their metabolic decompensation is similar to that seen in other affected children, suggesting that they do represent classical type 1 diabetes.
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PMID:Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. 1032 75

GAD65 (glutamic acid decarboxylase) is an important autoantigen in both type 1 (insulin-dependent) diabetes mellitus (IDDM) and the neurological autoimmune disease stiff-man syndrome (SMS), and is expressed in pancreatic islets as well as the nervous system. Still, only 30% of SMS patients also have type 1 diabetes. To study regulation of T cell responsiveness to GAD65, we investigated a non-diabetic SMS patient with HLA-DR3/7 (predisposing to type 1 diabetes) and high levels of type 1 diabetes-associated autoantibodies against GAD65 and islet cells, and compared the results with those of her diabetic son and two other SMS patients. T cell responses to GAD65 were repeatedly absent in primary stimulation, whereas IA-2, islet antigen and tetanus toxoid induced significant T cell proliferation. However, after in vitro restimulation, GAD65 reactive T cell lines and clones were obtained that were HLA-DR3 restricted, and cross-reactive with a homogenate of purified human pancreatic islets. These T cells produced the immunoregulatory cytokine IL-10 in combination with IFN-gamma and IL-4 (Th0). The dominant T cell epitope was mapped to the central region of GAD65. Although no primary response to whole GAD65 was detectable, the naturally processed GAD65 peptide epitope was recognized vigorously in the primary stimulation assay. The lack of detectable primary T cell responses to GAD65, together with the GAD65-specific cytokine production of restimulated T cells, suggest that GAD65-specific cellular autoimmunity in this patient is suppressed and may be related to the absence of diabetes despite humoral autoreactivity and genetic predisposition.
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PMID:GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient. 1033 Mar

Investigations of humans and nonobese diabetic mice suggest that proinsulin and/or a fragment of the region spanning C-peptide and the B-chain of insulin (i.e., proinsulin peptide) may serve as key autoantigens in IDDM. Therefore, we analyzed cellular immune reactivities against these molecules in people with or at varying risks for the disease to clarify their role in the pathogenesis of IDDM. In vitro peripheral blood mononuclear cell (PBMC) responses against these antigens, a control antigen (tetanus toxoid), and phytohemaglutinin were determined in 60 individuals with newly diagnosed IDDM (< or = 1 day from diagnosis) in 34 islet cell cytoplasmic autoantibody- and/or insulin autoantibody-negative first-degree relatives of the IDDM subjects, and in 28 autoantibody-negative control subjects. Unlike previous reports suggesting diabetes-associated elevations in cellular immunity to other beta-cell antigens (e.g., GAD, IA-2, etc.), we observed equivalent levels of phytohemaglutinin stimulation and cellular proliferation in all groups against these antigens (all P values were not significant). The mean stimulation index +/- SD and frequency of reactivity to proinsulin for healthy control subjects and IDDM patients, respectively, were as follows: 1 microg/ml (1.5 +/- 1.0, 1 out of 17 [6%]; 1.9 +/- 1.4, 4 out of 33 [12%]); 10 microg/ml (1.7 +/- 1.3, 1 out of 17 [6%]; 1.2 +/- 0.6, 0 out of 28 [0%]); and 50 microg/ml (1.2 +/- 0.6, 1 out of 16 [6%]; 1.1 +/- 0.6, 1 out of 27 [4%]). The response in healthy control subjects, autoantibody-negative relatives, and IDDM patients, respectively, against the proinsulin peptide fragment were as follows: 1 microg/ml (0.9 +/- 0.4, 1 out of 12 [8%]; 1.3 +/- 1.1, 4 out of 34 [11%]; 1.1 +/- 0.3, 2 out of 28 [7%]); 10 microg/ml (0.9 +/- 0.6, 1 out of 12 [8%]; 1.2 +/- 0.6, 3 out of 34 [9%] 1.4 +/- 1.7, 2 out of 28 [7%]); and 50 microg/ml (1.0 +/- 0.7, 1 out of 12 [8%]; 1.2 +/- 0.5, 2 out of 34 [6%]; 1.3 +/- 0.5, 2 out of 28 [7%]). Taken together with previous studies reporting relatively infrequent occurrences of autoantibodies to proinsulin, the role of immunity to this molecule in the pathogenesis of IDDM in humans remains unclear.
Diabetes 1999 Feb
PMID:Cellular immune responses against proinsulin: no evidence for enhanced reactivity in individuals with IDDM. 1033 5

The prevalence and levels of islet-cell antibodies (ICA) decrease in the years following diabetes onset but may persist, particularly in patients with concomitant autoimmune disease. The aim of this cross-sectional study was to investigate the frequencies, associations and levels of the major anti-beta-cell antibodies in long-standing diabetic patients (median duration: 14 years; range 5-47 years) with and without autoimmune thyroid disease (ATD) in order to consider the specific antipancreatic immunologic features associated with endocrine autoimmunity. Both ICA and glutamic acid decarboxylase (GAD) antibody (GAD-A) frequencies were increased in diabetic patients with ATD (38 vs 23%, p = 0.03 and 70 vs 21%, p < 10(-4) respectively). Although IA2-A frequency tended to be higher in diabetic patients with ATD, no significant difference was seen (37 vs 26%, p = 0.14). GAD median level was significantly higher in the diabetic group with ATD (15 vs 5 units, p < 10(-4)). IA2-A and ICA median levels were similar in both groups. Regardless of the combined analysis performed (ICA/GAD-A, ICA/IA2-A or GAD-A/IA2-A), the prevalence of combined antibody positivity was higher in diabetic patients with than without ATD. In both diabetic populations, ICA and GA-DA were significantly associated (p < 10(-4), and their levels were correlated (r = 0.42, p < 10(-4) and r = 0.584, p < 10(-4) respectively). No significant correlation was seen between IA2-A levels and either ICA or GAD-A titres. It is concluded that Type 1 diabetes mellitus with ATD is characterised by increased persistent humoral islet-related reactivity, particularly directed towards GAD.
Diabetes Metab 1999 Mar
PMID:Combined analysis of long-term anti-beta-cell humoral reactivity in type 1 diabetes with and without thyroid disease. 1033 21

Type 1 diabetes is thought to be an autoimmune disease mediated by T lymphocytes recognizing critical islet cell antigens. Recently, the tyrosine phosphatase like protein IA-2 was suggested as a putative autoantigen in type 1 diabetes since autoantibodies are detected in sera of diabetic patients and prediabetic subjects. Similarly, T cell responses of peripheral blood lymphocytes of type 1 diabetic patients to this protein have been described. Only very few data is available about immunodominant epitopes of IA-2 recognized by T cells. We have studied T cell responses in type 1 diabetic patients and age and partly HLA matched controls to IA-2 peptides designed to bind HLA risk alleles of IDDM as DR*0401 and DQ*0302. Both diabetic patients and controls responded to IA-2ic and some of the peptides. Three peptides of the C-terminal region of IA-2 were recognised by T cells of a fraction of diabetic patients but at least two of these peptides triggered also T cell responses in DR*0401/DQ*0302-matched controls. Most peptides bound to different HLA alleles ("promiscous binders"). The identification of autoantigenic epitopes may offer clues to related sequences e.g. of viral origin what relates to models of diabetes pathogenesis ("molecular mimicry"). Secondly, the design of antigen- or even epitope-specific immune intervention strategies aiming at tolerization of disease specific T cells in type 1 diabetes may profit from the knowledge of immunodominant T cell epitopes of a putative autoantigen.
Exp Clin Endocrinol Diabetes 1999
PMID:T cell reactivity to DR*0401- and DQ*0302-binding peptides of the putative autoantigen IA-2 in type 1 diabetes. 1037 40

The islet autoimmunity of preclinical type 1 diabetes remains poorly characterized in humans. In this paper, the IgG subclass response to the islet autoantigens insulin, glutamic acid decarboxylase, and IA-2 was studied sequentially from birth to diabetes onset or current follow-up in 26 autoantibody positive offspring of parents with diabetes. Islet autoantibody appearance was characterized by an early IgG1 peak response to one or more Ags, most commonly to insulin, at a median age of 2.2 yr (interquartile range, 2-2.9 yr). In five offspring, an acute fulminant beta-cell destruction and diabetes onset occurred during this initial Ab response. In the remainder, early Ab levels declined markedly, and Ab peaks against other beta cell Ags arose sequentially over several years suggesting regulation and spreading of autoimmunity. Second peak Ab responses to the same Ag were observed in only two offspring, both developing diabetes at this time. Two others developed diabetes with declining Ab levels. Abs of IgG1 subclass dominated against each Ag, and other subclasses, were usually only detected during peak IgG1 responses. The IgG4 response to insulin was exceptional, being dominant over IgG1 in four offspring and in five others appeared and/or persisted after IgG1 levels declined. These Th2-associated IgG4 responses were not correlated with protection from diabetes. The presence of IgG1-restricted responses to DA2 were associated with diabetes development. These findings suggest that type 1 diabetes has an early acute destructive phase of beta cell autoimmunity, which may be regulated and which spreads chronically until diabetes onset.
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PMID:Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. 1038 57

Islet cell antibodies (ICA) are a specific marker for Type 1 (insulin-dependent) diabetes mellitus. ICA are found in the serum of over 80% of newly diagnosed patients and the levels of ICA are directly of prognostic value. Standardisation of ICA and the uniform reporting of ICA levels in international units is critical to preclinical/clinical research and the development of assays for ICA as diagnostics, in particular for the differential diagnosis of late onset Type 1 and Type 2 diabetes. Proficiency studies carried out by the Immunology of Diabetes Workshops on Standardization have clearly shown that a single reference material, serum sample 673, obtained by Dr J. Ludvigsson, has significantly reduced inter- and intra-assay variability in the reporting of ICA levels. Nevertheless, this material is a frozen serum of limited shelf-life and is difficult to distribute on a worldwide and routine basis. Therefore, the Immunology of Diabetes Workshop Standardization Committee and the Juvenile Diabetes Foundation International requested that the National Institute for Biological Standards and Control (NIBSC) organise an international collaborative study to compare the activities of lyophilised, stable ICA preparations. In addition, the purpose was to investigate if sample 673 could also serve as a standard for GAD65 and IA-2 antibodies. Twenty participants in eight countries have been recruited to the study.
Diabetes Metab Res Rev
PMID:The development of a World Health Organisation international standard for islet cell antibodies: the aims and design of an international collaborative study. 1039 50


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