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

In type 1 diabetes, a number of specific and non-specific antigens have been identified. The major autoantigens involved in the destructive process of beta-cells leading to the development of type 1 diabetes are proinsulin/insulin, glutamic acid decarboxylase (GAD) and the transmembrane protein tyrosine phosphatase (IA-2). These are the only autoantigens that partially satisfy the criteria by which an autoantigen or cross-reactive nonself antigen could be evaluated for a pathogenic role in autoimmune diseases. Antigens by definition induce antibody production and in type 1 diabetes, such (auto) antibodies are accepted as biochemical markers for the disease. Here we describe the main features and usefulness of these markers for disease prediction.
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PMID:Biochemical markers of type 1 diabetes: clinical use. 1171 91

Glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA-2 antibody levels were measured in 375 healthy children and adults and in 187 children with newly diagnosed type 1 diabetes mellitus (DM). GAD antibody levels were determined by radioimmunoassay, and IA-2 antibody levels by immunoprecipitation. Healthy children had higher GAD antibody levels than adults (p < 0.001). The 98th percentile was 1.60 U/ml in children and 1.16 U/ml in adults. IA-2 antibody levels did not differ between these two cohorts. Children with DM had higher GAD and IA-2 antibody levels than healthy children (p <0.001). Based on receiver operating characteristics (ROC) analysis, elevated levels of these antibodies showed high specificity rates (+/- SE) of 0.968 +/- 0.14 to 1.00 +/- 0.00. The sensitivity ranged between 0.439 +/- 0.037 (both antibodies elevated) and 0.850 +/- 0.027 (at least one antibody elevated). These data emphasize the importance of establishing age-specific reference values for DM-related antibodies in the background population before applying them for screening and intervention studies.
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PMID:Age-specific levels of diabetes-related GAD and IA-2 antibodies in healthy children and adults. 1182 79

ICA512/IA-2, a tyrosine phosphatase-like protein, is one of the major autoantigens in type 1 diabetes. Following phage display characterization of ICA512 autoantigenic epitopes, we developed fluid phase autoantibody radioimmunoassays for a series of ICA512 fragments (F1 [amino acids (aa): 761-964], F2A [aa 256-760], F2B [aa 761-928], and F2C [aa 929-979]). With the hypothesis that 'non-diabetes associated' ICA512 autoantibodies would differ from diabetes associated ICA512 autoantibodies in terms of epitopes recognized, we analyzed ten such serum samples (two from normal control individuals, one from a general population subject with transient ICA512 autoantibodies and seven from relatives of patients with type 1 diabetes who had single transient ICA512 positivity). All but one of the 'non-diabetes associated' ICA512 positive samples (9/10) did not react with Fragment 1 which contains the major antigenic epitopes of the molecule that were recognized by almost all (51/52) ICA512 positive new onset patient samples and pre-diabetic relatives (P< 10(-6)). The great majority of samples (44/52) from the new onset patients and pre-diabetic relatives reacted with at least two fragments and 60% (31/52) with three or more fragments. In contrast, only one sample of the ICA512 'non-diabetes associated' sera reacted with multiple fragments (P< 10(-4)). Our findings suggest that diabetes associated anti-ICA512 autoantibodies react with multiple ICA512 epitopes while non-diabetes associated ICA512 autoantibodies may usually represent reactivity of antibodies with determinants of ICA512 unrelated to type 1 diabetes. The ability to distinguish diabetes associated from non-diabetes associated anti-ICA512 autoantibodies should provide prognostic information and more importantly suggests that even with highly specific radioassays positivity may occur unrelated to type 1 diabetes.
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PMID:ICA512(IA-2) epitope specific assays distinguish transient from diabetes associated autoantibodies. 1190 51

The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2beta are autoantigens of type 1 diabetes in humans. Autoantibodies are predominantly against IA-2, and IA-2-specific epitopes are major autoantibody targets. We used the close homology of IA-2 and IA-2beta to design chimeras and mutants to identify humoral IA-2-specific epitopes. Two major IA-2 epitopes that are absent from the related autoantigens IA-2beta and IA-2Delta 13 splice variant ICA512.bdc were found contiguous to each other within IA-2 juxtamembrane amino acids 611-620 (epitope JM1) and 621-630 (epitope JM2). JM1 and JM2 are recognized by sera from 67% of patients with IA-2 Abs, and relatives of patients with type 1 diabetes having Abs to either JM epitope had a >50% risk for developing type 1 diabetes within 6 years, even in the absence of diabetes-associated HLA genotypes. Remarkably, the presence of Abs to one of these two epitopes was mutually exclusive of the other; JM2 Abs and not JM1 Abs were found in relatives with HLA DR3/4, DR4/13, or DR1/4 genotypes; and the binding of autoantibodies to the JM2 epitope, but not the JM1 epitope, markedly affected proteolysis of IA-2. This is a unique demonstration of HLA-associated B cell responses to epitopes within a single autoantigen in humans and is consistent with modification of Ag processing by specific Ab-influencing peptide presentation by HLA molecules.
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PMID:Two distinctly HLA-associated contiguous linear epitopes uniquely expressed within the islet antigen 2 molecule are major autoantibody epitopes of the diabetes-specific tyrosine phosphatase-like protein autoantigens. 1193 81

Autoantigenic epitope mapping represents a critical issue in autoimmune diseases. The islet tyrosine phosphatase-like protein IA-2/ICA512bdc is a major autoantigen in type 1 diabetes (IDDM), but the epitopes responsible for autoantibody binding have been only partially defined. The aim of our study was to identify ICA512bdc epitopes, and in particular mini-epitopes, utilizing a novel strategy for autoimmune diseases. The study was performed in three sequential steps: (1) construction of a lambda-phage surface-displayed ICA512bdc cDNA library with the methodology of tagged random priming with peptides displayed as a fusion to the C terminus of the capsid protein D; (2) affinity selection of the resulting library, followed by immunoscreening, enzyme-linked immunosorbent assay and sequence analysis of positive clones, and (3) radioimmunoprecipitation to detect autoantibodies to the selected clones. This strategy resulted in the identification of two epitopes (IA-2 residues 761 - 964 and 929 - 979), which were recognized by 100 % and 62.9 % ICA512bdc-positive IDDM patients, respectively. Interestingly, the larger clone was detected also by a proportion (16.7 %) of new onset ICA512bdc-negative patients, thus suggesting that this region contains not only the main autoantigenic repertoire of ICA512bdc molecule, but is able to detect IA-2 autoantibodies in even higher percentages of patients. In addition, this study showed the existence of multiple epitopes located in the C-terminal domain of the IA-2 protein, one of which is formed by the 50 C-terminal amino acids, and provided evidence that the strategy used represents a valid tool for identification of epitopes within autoantigenic molecules.
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PMID:Application of phage display peptide library to autoimmune diabetes: identification of IA-2/ICA512bdc dominant autoantigenic epitopes. 1198 30

The tyrosine phosphatase-like protein IA-2 is a major target antigen for autoantibodies in the preclinical period of type 1 diabetes. In this study, we examined whether immunoglobulin isotypes and IgG subclass specific autoantibodies directed at IA-2 discriminate between children at risk of type 1 diabetes who progressed to diabetes vs. those who remained diabetes-free. IgG1-4, IgA and the IgE-specific IA-2 antibody (IA-2A) were measured by radioligand assays in 50 patients with type 1 diabetes and 41 ICA-positive siblings of patients with type 1 diabetes who were followed for diabetes development. Of 41 siblings, 32 were positive for IA-2A; of these, 59 % had IA-2 IgG1, 59 % IgG4, 16 % IgG3, 9 % IgG2, 16 % IgA and 13 % IgE antibodies. IA-2 IgG1 was the dominant isotype in prediabetic children (n = 14, 86 % positive) and patients with type 1 diabetes (98 % positive) whereas only 7 of 18 (39 %) non-progressors had antibodies of this isotype. In subjects that remained diabetes-free, a significantly higher frequency of IA-2 IgG4 in the absence of IgG1 was observed (50 %) compared to progressors (7 %) and patients with type 1 diabetes (0 %). Life-table analysis revealed that IA-2A restricted to IgG4 correlated with protection from type 1 diabetes (p < 0.003). In contrast, IA-2 IgG2, IgG3, IgE and IgA did not differ significantly between study groups. Our findings suggest that the measurement of IA-2 IgG1 and IgG4 subclass antibodies can serve as surrogate marker to discriminate between antibody positive subjects at high or low risk for rapid development of diabetes.
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PMID:IA-2 autoantibodies restricted to the IgG4 subclass are associated with protection from type 1 diabetes. 1198 27

This article aims to estimate the prevalence of SOX13 antibodies in Swedish patients with type 1 diabetes and healthy controls. The patients (n = 102; median age 35 years [range, 9-89]) were newly diagnosed with type 1 diabetes in a defined area in southern Sweden during 1995-1998. Islet cell antibodies (ICA) were analyzed with immunofluorescence, while glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase antibodies (IA-2A), and antibodies against the transcription factor SOX13 (SOX13Ab) were analyzed with radioimmunoprecipitating assays. SOX13Ab were found in 9.8% (10/102) of type 1 patients compared to 2.0% (2/99) in healthy controls (P = 0.033). At least one of the four autoantibodies (ICA, GADA, IA-2A or SOX13Ab) were identified in 67% (68/102) of the patients. Samples positive for IA-2A were only in one case positive also for SOX13Ab. IA-2A-positive patients were often positive also for ICA and GADA (19/27), and the same combination was also common for SOX13Ab-positive patients (6/10). Only 2.0% (2/102) were positive for SOX13Ab alone. ICA, GADA and IA-2A were more frequent in younger patients (<or= 35 years of age) than in older patients, while SOX13Ab showed similar frequency in both groups. We concluded that the frequency of SOX13Ab was significantly increased in Swedish patients with type 1 diabetes, but that the addition of SOX13Ab to the combination of GADA and IA2-A only increased the sensitivity by 2% for autoimmune diabetes. Therefore, SOX13 could be a minor autoantigen involved in the pathogenesis of type 1 diabetes.
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PMID:Increased autoantibodies to SOX13 in Swedish patients with type 1 diabetes. 1202 Nov 10

Antibodies to tyrosine phosphatase (IA2-Ab) and glutamate decarboxylase 65 (GAD65-Ab) are major markers for IDDM in Caucasians. TTG-Ab is specific for celiac disease. Celiac disease is caused by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Ten to twenty percent of celiac disease patients also have IDDM. The aim of the study was to estimate the prevalence of TTG-Ab in MMDM (n = 71), IDDM (n = 74), and NIDDM (n = 216) and 122 controls from Cuttack in eastern India. MMDM patients are typically young at onset with low body mass index, require insulin for glycemic control, have insulin resistance, and do not develop ketosis on withdrawal of insulin. TTG-Ab was evaluated by radioimmunoassay using in vitro translated recombinant human 35S-TTG. In controls, TTG-Ab was present in 3/122 (2%); in MMDM, TTG-Ab was present in 14/71 (20%); 11/74 (15%) IDDM (P < 0.05 vs. controls) and 23/216 (11%) NIDDM (P < 0.05 vs. controls) were also positive for TTG-Ab. We conclude that MMDM, IDDM, and NIDDM patients from Cuttack have a significantly high proportion of TTG-Ab compared to healthy controls. The highest significance is seen with MMDM patients. It is important to note that subclinical celiac disease must be considered in the differential diagnosis of MMDM.
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PMID:Autoantibodies to tissue transglutaminase in patients from eastern India with malnutrition-modulated diabetes mellitus, insulin-dependent diabetes mellitus, and non-insulin-dependent diabetes mellitus. 1202 Nov 13

The tyrosine phosphatase-like protein IA-2 is an important islet autoantigen in type 1 diabetes. Although the radioligand binding assay with in vitro synthesized (35)S-labeled antigen has been used extensively for measuring autoantibodies to IA-2, disadvantages of both assays with respect to synthesis and handling of the radioactive antigen limit their use in routine laboratories. Therefore, we attempted to develop a nonradioactive ELISA for the simple detection of IA-2 autoantibodies. The biotinylated cytoplasmic domain of IA-2 expressed in Escherichia coli was used as an antigen. We evaluated two kinds of ELISA: ELISA with biotin-IA-2 directly captured on streptavidine-coated plates (solid phase) and ELISA with antigen-antibody preincubation in solution in which serum samples were reacted first with biotin-IA-2 and the mixture was transferred to streptavidine-coated plates (liquid phase). We compared their disease sensitivity and specificity with a conventional radioligand binding assay in 52 patients with recent-onset type 1 diabetes and 138 normal individuals. The radioligand binding assay had 61.5% sensitivity and 99.3% specificity. The liquid-phase ELISA showed relatively higher sensitivity (55.8%) and specificity (99.3%) than the solid-phase ELISA (sensitivity 53.8% and specificity 97.1%). Furthermore, the mean SD score in IA-2 autoantibody-positive serum samples measured by liquid-phase ELISA was significantly higher than the SD score obtained by solid-phase ELISA (P < 0.0001). We concluded that this liquid-phase ELISA is suitable for detecting IA-2 autoantibodies in patients with type 1 diabetes with a similar sensitivity and specificity to those of conventional radioligand binding assay.
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PMID:Autoantibodies to IA-2 in type 1 diabetes: measurements with a new enzyme-linked immunosorbent assay. 1202 Nov 15

Women with gestational diabetes mellitus (GDM) have considerable risk for developing both type 1 and type 2 diabetes in life. Autoantibodies against glutamic acid decarboxylase (GAD65) and tyrosine phosphatase (IA-2) are strongly associated with autoimmune diabetes and can be useful in early identification of the development of type 1 diabetes in women with GDM. On the other hand antibodies against minor islet antigens in adults can be predictors for autoimmune polyendocrine syndrome. The aim of our study was to estimate the prevalence of autoantibodies against minor antigens-tissue transglutaminase (TTG), ICA12, and 21-hydroxylase (21-0H)-in GDM patients from southern India. Eighty-six serum samples from GDM subjects and 114 samples from healthy controls were tested for the presence of GAD65 and IA-2Ab as well as for the presence of 21-OH, TTG, and ICA12Ab by radiobinding assay with in vitro translated recombinant human 35S-GAD65, IA-2, TTG, ICA12, and 21-OH antigens. We observed the presence of GAD65 or IA-2 autoantibodies in 41% (35/86) of GDM patients, while none of the patients tested positive for any of the minor autoantibodies. Our results demonstrate that there is a high prevalence of autoantibodies in GDM subjects that are at higher risk of developing autoimmune diabetes later, but none of the patients carries antibodies against minor antigens, which could predict autoimmune polyendocrine syndrome in adults.
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PMID:Women diagnosed with gestational diabetes mellitus do not carry antibodies against minor islet cell antigens. 1202 Nov 24


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