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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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.
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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

Gestational diabetes mellitus (GDM) is a risk factor for the development of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus postpartum. To evaluate whether there is any association of human leukocyte antigen (HLA) class II alleles (DR and DQ) with GDM and the postpartum development of IDDM, we analyzed 184 women with GDM from Germany for HLA class II alleles, islet autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), and protein tyrosine phosphatase IA-2 autoantibodies (IA-2A), and the postpartum development of diabetes. No elevation in the frequency of any HLA class II alleles was observed in GDM patients compared to 254 nondiabetic unrelated subjects. DR3 allele frequency was significantly increased in 43 women with islet autoantibodies [corrected P value (Pc) = 0.02], in particular in those with GADA (Pc = 0.002), or in the 24 women who developed IDDM postpartum (Pc = 0.005). In women with GADA, DR4 and DQB1*0302 were significantly elevated (Pc = 0.009). Twenty-five (59.5%) islet antibody-positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4-containing genotype. The cumulative risk to develop IDDM within 2 yr postpartum in GDM women with either DR3 or DR4 was 22% compared to 7% in women without those alleles (P = 0.02) and rose to 50% in the DR3- or DR4-positive women who had required insulin during pregnancy (P = 0.006). Combining the determination of susceptible HLA alleles (DR3, DR4) with islet autoantibody measurement increased the sensitivity of identifying GDM women developing postpartum IDDM to 92%, but did not improve risk assessment above that achieved using GADA measurement alone, which was the strongest predictor of IDDM. These results indicate that women with GDM who have islet autoantibodies at delivery or develop IDDM postpartum have HLA alleles typical of late-onset type 1 diabetes, and that both HLA typing and islet antibodies can predict the development of postpartum IDDM.
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PMID:Predictive value of human leukocyte antigen class II typing for the development of islet autoantibodies and insulin-dependent diabetes postpartum in women with gestational diabetes. 1040

Autoimmune (type 1) diabetes mellitus results from a progressive destruction of insulin secreting beta cells operated by T lymphocytes in pancreatic islets. Circulating autoreactive T cells to specific beta cell antigens are detected in patients with type 1 diabetes. To date, several beta cell autoantigens have been identified in this disease (GAD, IA-2, 38kD secretory protein, insulin, ICA69 etc.), however, it is possible that also other unidentified self molecules contribute to trigger beta cell autoimmunity. In this study we used the human insulinoma cell line CM as source of beta cell antigens to detect reactive T lymphocytes in patients with type 1 diabetes mellitus. This cell line has been previously shown to express a number of recognized beta cell antigens. Since the expression of several beta cell antigens is affected by glucose stimulation we tested two preparations of CM cells cultured under different conditions containing low (0.8 mM) and high glucose concentration (11 mM). T cell proliferation was measured using cells from 32 patients with type 1 diabetes (19 of recent onset and 13 at 3 to 22 months from diagnosis) and 27 age-matched control subjects. A significant increase in T cell proliferation to CM cells grown in high glucose conditions (11 mM) (p < 0.05) was found in type 1 diabetic patients compared to controls. No significant differences were observed when using CM cells cultured at the low glucose concentration. Furthermore, the response to both extracts of CM cells was independent of disease duration (p = 0.6 for both CM cells cultured at 0.8 and 11 mM glucose). These data indicate that T cell reactivity to homogenates of CM cells is detectable in patients with type 1 diabetes and suggest that this human insulinoma cell line is an interesting potential source of beta cell material for immunological studies of autoimmune diabetes.
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PMID:T cell reactivity to human insulinoma cell line (CM) antigens in patients with type 1 diabetes. 1043 97

It has been reported that there is a heterogeneity in the clinical course of Japanese patients with type 1 diabetes. To elucidate the associations of expression of autoantibodies to multiple islet antigens with age of onset and mode of diagnosis of diabetes in Japanese patients with type 1 diabetes, autoantibodies against the protein tyrosine phosphatase-like molecules ICA512 (IA-2) and phogrin (IA-2beta) (ICA512/phogrin-A), GAD (GADA), insulin (IAA), and islet cell cytoplasm (ICA) were determined in sera from 73 Japanese patients with type 1 diabetes obtained within 14 days of diagnosis. Patients were divided into groups based on the age of onset (</=10 years, n=24 and >10 years, n=49) or the mode of onset (abrupt onset, n=59 and urinary screening identified, n=14). Of 73 new-onset patients with type 1 diabetes, 43 (59%) and 32 (44%) had ICA512A and phogrin-A levels exceeding the 99th percentile of 184 normal control subjects, respectively. Forty-five patients (62%) were positive for either ICA512A or phogrin-A. The frequencies for other autoantibodies were 71% for GADA, 48% for IAA, and 62% for ICA. The frequency of ICA512/phogrin-A was significantly higher in patients with an age of onset less than 10 years (83%) than in patients aged >10 years (51%, P<0.01). The positivity of ICA512/phogrin-A was less in patients whose diabetes was diagnosed by the urine glucose screening test (21%, P<0.001) than in abrupt onset patients (71%). Combined analysis (>/=1 antibody) of GADA, IAA, and ICA512/phogrin-A detected 88% of abrupt onset and 93% of screening-positive patients vs. 70% and 29%, respectively, for ICA (P<0.0005). These results indicate that the expression of ICA512/phogrin-A and cytoplasmic ICA is less in patients identified by urinary glucose testing but indicate that with combined autoantibody testing 90% of patients can be identified independent of the mode of diagnosis.
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PMID:Autoantibodies to multiple islet autoantigens in patients with abrupt onset type 1 diabetes and diabetes diagnosed with urinary glucose screening. 1047 94

The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range <5.5%), anti-GAD antibodies (<5.0 U), and anti-IA2 antibodies (<3.0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.
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PMID:Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity. 1053 47

In this article, we report the identification of a new autoantigen in type 1 diabetes originating from the exocrine pancreas. This antigen is a pancreatic enzyme termed bile salt-dependent lipase (BSDL). We show that antibodies present in the sera of newly diagnosed type 1 diabetic patients recognize BSDL and more specifically the COOH-terminal mucin-like region of the protein. Therefore, we engineered the COOH-terminal peptide of BSDL and demonstrated that autoreactivity was linked to specific glycosylation sites by at least two glycosyltransferases: the Core 2 beta(1-6)N-acetylglucosaminyltransferase and the alpha(1-3) fucosyltransferase FUT7. We next examined the prevalence of circulating anti-BSDL antibodies in type 1 diabetic patients and found 73.5% positivity (25 sera among 34 patients tested) at onset, whereas only 8.4% of normal individuals (7 of 83) were positive. Within a cohort of first-degree relatives of diabetic patients followed prospectively until development of diabetes, 6 of 19 (31.6%) were also positive. Interestingly, two prediabetic individuals were already positive for anti-BSDL antibodies (Abs), while islet cell cytoplasmic Abs and antibodies to GAD65, IA-2, and insulin were not detected. Anti-BSDL autoantibodies were weakly or not detected in patients suffering from pancreatitis or pancreatic adenocarcinoma or in patients with Graves' disease. Although autoreactivity to BSDL in prediabetic and newly diagnosed diabetic patients might reflect cross-reactivity, our results strongly suggest that in addition to pancreatic beta-cells, acinar cells may be also affected in type 1 diabetes.
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PMID:Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes. 1058 Apr 19

An immunoprecipitation assay for autoantibodies (Abs) to the human islet cell antigen IA-2 has been developed using 125I-labelled recombinant IA-2 expressed in E. coli. With this assay IA-2 Abs were detected in 103/217 (47%) of IDDM patients of different ages and with different disease duration. IA-2 Ab prevalence was higher in younger patients (at the age of 15 years or below) with the recent onset IDDM (64/113; 57%) compared to patients above the age of 15 years (11/25; 44%). One of 40 (2.5%) Graves' disease patients and five of 204 (2.5%) of NIDDM patients were also positive. IA-2 Abs were not detected in sera from patients with Hashimoto's thyroiditis (n=32), myasthenia gravis (n=20) or systemic lupus erythematosus (n=10). IA-2 Ab measurements based on 125I-labelled IA-2 showed a good correlation with the results of an immunoprecipitation assay based on 35S-labelled IA-2 produced in the in vitro transcription/translation system (r=0.78; n=113; p<0.001). Out of 217 IDDM sera which were tested for IA-2 Abs, 140 (65%) were positive for Abs to glutamic acid decarboxylase (GAD) and 166 (76%) were positive for Abs to IA-2 and/or Abs to GAD. In addition, Abs to IA-2, to GAD and to insulin were analysed in sera from recent onset IDDM patients who had not been treated with insulin (n=117). In all, 76/117 (65%) of these sera were positive for GAD Abs, 66/117 (56%) for IA-2 Abs, 45/117 (38%) for insulin Abs. However, 98/117 (84%) were positive for at least one of the three Abs confirming earlier observations on the complementarity of Ab testing in IDDM. Overall, the IA-2 Ab assay based on 125I-labelled recombinant IA-2 showed good sensitivity, precision and specificity which, combined with an easy and convenient protocol, makes it attractive for routine use.
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PMID:Autoantibodies to IA-2 in insulin-dependent diabetes mellitus. Measurements with a new immunoprecipitation assay. 1061 17

The relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with type 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles were characterized by lower frequencies of islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to HLA identity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences were observed in the levels of IA-2A, GADA, or insulin autoantibodies among siblings with different HLA risk markers. The DR2 or DQB1*0602-3 alleles were not related to the levels of any antibody specificity. A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progress to disease.
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PMID:Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group. 1061 49


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