UMLS:C0011854 - FACTA Search

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

The elimination of maternally acquired, diabetes-associated antibodies from the peripheral circulation of infants was studied in a population of 47 mothers and their newborn infants from families in which at least 1 first degree relative had type 1 diabetes. Blood samples were taken from the placental cord; from the infant at follow-up visits at the ages of 3, 6, 9, 12, 18, and 24 months; and from the mother at the time of delivery. The samples were analyzed for cytoplasmic islet cell antibodies (ICA), insulin antibodies (IA), autoantibodies to the 65-kDa isoform of glutamic acid decarboxylase (GADA), and autoantibodies to the protein tyrosine phosphatase-related IA-2 antigen (IA-2A). The mean elimination times for ICA, IA, GADA, and IA-2A were 3.1, 3.1, 4.5, and 4.3 months (P = NS), respectively. The initial levels of IA, GADA, and IA-2A in the cord blood correlated closely with the elimination time (r(s) = 0:84-0.91; P < 0.001). The mean proportions of ICA, IA, GADA, and IA-2A still detectable were 18%, 21%, 30%, and 20%, respectively, at 3 months; 2.2%, 14%, 10%, and 6% at 6 months; and 0.3%, 15%, 2.3%, and 5.1% at 9 months. One infant still tested positive for GADA at the age of 12 months, whereas all of the other antibodies had been eliminated by that age. When observing the natural history of beta-cell autoimmunity or when screening for secondary prevention in young children, cross-sectional autoantibody analyses do not provide sufficient information. Repeated testing is to be recommended in young children. In infancy, increasing antibody levels most likely reflect de novo synthesis of diabetes-associated autoantibodies.
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PMID:Postnatal elimination of transplacentally acquired disease-associated antibodies in infants born to families with type 1 diabetes. The Finnish TRIGR Study Group. Trial to Reduce IDDM in the Genetically at Risk. 1109 62

Although it is well known that patients with type 1 diabetes mellitus are susceptible to other autoimmune diseases, the simultaneous occurrence of clustered distinct autoimmune diseases is uncommon. We report a 16-year-old girl, previously diagnosed as having coeliac disease and IgA deficiency, who at 13 years of age developed a clustering of distinct autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis (RA) and euthyroid autoimmune thyroiditis, eventually resulting in a simultaneous long-term remission. The clinical picture was associated with a functional immunodeficiency characterized by a defect in proliferative responses to T cell predominant mitogens and a normal response to the B cell predominant mitogen. In addition, the T cell activation markers HLA-DR, IL-2 receptor and transferrin receptor) were not upregulated. The clinical course of this immunodeficiency paralleled the outcome of the autoimmune diseases. After the abrupt onset, spontaneous clinical remission of both diabetes mellitus and RA was observed. Insulin was first reduced in dose and then discontinued completely at 15 months, in the presence of normal C peptide secretion and normal metabolic control (HbA1c 5.8%). Anti-glutamate decarboxylase (GAD65) and anti-IA-2 antibodies remained persistently high. During the remission phase a normalization of the functional immune defect was observed. The gradual resolution of the multisystemic diseases as well as the normalization of immune function in our patient is unusual. This case may be of considerable value in furthering our knowledge of the immunological mechanisms implicated in these rare multireactive syndromes.
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PMID:Simultaneous peripubertal onset of multireactive autoimmune diseases with an unusual long-lasting remission of type 1 diabetes mellitus. 1110 28

Assays to detect autoantibodies to glutamic acid decarboxylase (GAD65) and the protein tyrosine phosphatase-like molecule IA-2, which are both present in pancreatic islets, have been used in the diagnosis and prediction of type 1 diabetes. In this study a novel fusion protein combining the entire GAD65 molecule with the 40 kDa intracellular domain of IA-2 (GAD-IA-2) was constructed to detect autoantibodies to both antigens by one single assay. For the same purpose a truncated version of this fusion protein which contained the entire GAD65 linked to the 203 carboxy-terminal amino acids of IA-2 (GAD-dIA-2) was made. A panel of 34 diabetic sera which represented unequivocally positive or negative antibody responses to GAD65 and/or IA-2 as well as 20 serum samples from healthy controls were tested in a radioligand binding assay with the constructed fusion proteins as antigens. Nine of the samples from patients with type 1 diabetes reacted with GAD65 while being negative for IA-2. Six sera were positive for IA-2 only, 11 were double positive, and 8 negative for both antibodies using the standard in vitro transcription translation assay with single antigens. The full-length, as well as the truncated fusion protein detected all samples positive for antibodies either to GAD65 or IA-2 or both, except for one GAD65 antibody positive sample. All samples from healthy controls tested negative in all assays. We conclude that the principle of a combinatorial molecule where a fusion protein expresses both GAD65 and IA-2 epitopes is feasible, and such a fusion protein can be used instead of the single antigens to reduce time and costs of large-scale screening for clinical purposes.
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PMID:Novel fusion proteins in the analysis of diabetes-associated autoantibodies to GAD65 and IA-2. 1112 50

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.
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PMID:ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. 1113 89

We measured the concentrations of the soluble forms of the intercellular adhesion molecule-1 (sICAM-1) and L-selectin in 95 autoantibody-positive siblings of children with type 1 diabetes and 95 sex- and age-matched siblings testing negative for diabetes-associated autoantibodies to assess the possible role of soluble adhesion molecules as markers of progressive ss-cell destruction in preclinical diabetes and their ability to discriminate between those siblings who progress to clinical disease and those who remain nondiabetic. We observed an inverse correlation between age and the levels of both sICAM-1 (r = -0.31, p < 0.001) and sL-selectin (r = -0.27, p < 0.001) in the control siblings but no association with HLA-DR phenotypes. There was no difference in the circulating levels of soluble adhesion molecules between the antibody-positive and negative siblings. Among the antibody-positive siblings, those with at least three autoantibodies had higher sICAM-1 levels (p < 0.01) than those testing positive for only one, and siblings with three autoantibodies or more had higher concentrations of sL-selectin (p < 0.01) than those with two autoantibodies. Siblings with an islet cell antibody level of 20 Juvenile Diabetes Foundation units or more had higher sICAM-1 concentrations than those with a level below 20 (p < 0.001), and those testing positive for antibodies to the protein tyrosine phosphatase-related IA-2 antigen had increased levels of both sICAM-1 (p = 0.03) and sL-selectin (p = 0.02) compared with siblings who tested negative. The antibody-positive siblings who progressed to clinical type 1 diabetes were significantly younger than the nonprogressors (p < 0.001) and had higher levels of sICAM-1 initially (p < 0.001). The difference in sICAM-1 concentrations remained significant (p = 0.03) after age adjustment. Our results indicate that concentrations of soluble adhesion molecules are increased in the autoantibody-positive siblings who have the highest risk of developing clinical diabetes, suggesting that ss-cell destruction is reflected in increased circulating levels of these molecules. This is supported by the observation of elevated sICAM-1 concentrations in the 29 siblings who actually progressed to clinical type 1 diabetes. Peripheral levels of soluble adhesion molecules are not able to discriminate between progressors and nonprogressors, however, due to substantial overlapping between these two groups.
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PMID:Soluble adhesion molecules in preclinical type 1 diabetes. The Childhood Diabetes in Finland Study Group. 1113 83

Type 1 diabetes mellitus is an autoimmune disease in which the presence of different autoantigens can often be found. The aim of our study was to evaluate the prevalence of antibodies against insulin (IA) and autoantibodies against glutamic acid decarboxylase (anti-GAD), tyrosine phosphatase IA-2 (anti-IA-2), thyroid microsomal peroxidase (anti-TPO) and thyroglobulin (anti-TG) in 55 randomly selected Type 1 diabetic patients (34 males, 21 females). Mean age of these patients was 39 +/- 12 yrs, mean duration of diabetes 18 +/- 13 yrs. Positivity of anti-GAD was found in 29 (58%) patients, anti-IA-2 in 13 (25%) patients, IA in 46 (85%) patients, anti-TPO in 10 (21%) and anti-TG in 11 (23%) patients. Simultaneous positivity of thyroid and islet autoantibodies was found in 6 (11%) patients whereas the positivity at least one of them was in 38 (69%) patients. No relationship between glycated hemoglobin and autoantibody concentration was found in the whole group of patients. The autoimmune thyroid disease was newly detected in 4 patients from high concentration of thyroid autoantibodies together with impaired TSH and T4 values and ultrasonography finding. No clinical evidence of thyroid disease was previously found in these patients. Positivity of anti-GAD or anti-IA-2 was found in almost 65% and of any thyroid autoantibody in almost 30% of our patients. Four patients with autoimmune thyroid disease were newly identified. We conclude that the evaluation of thyroid autoantibodies in Type 1 diabetic patients may improve the diagnosis of thyroid disease in very early stage and thus prevent consequent complications.
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PMID:The evaluation of thyroid and islet autoantibodies in type 1 diabetes mellitus. 1122 67

Recent reports indicate that genes with tissue-restricted expression, including those encoding the type 1 diabetes autoantigens insulin, glutamic acid decarboxylase (GAD), and the tyrosine-phosphatase-like protein IA-2 (or ICA512), are transcribed in the thymus. The reported modulation of diabetes susceptibility by genetically determined differences in thymic insulin levels and studies in transgenic mice provide correlative and functional evidence that thymic expression of peripheral proteins is crucial for immunological self-tolerance. However, there are no specific data about the existence, tissue distribution, phenotype, and function of those cells that express insulin and other self-antigens in the human thymus. We find that the human thymus harbors specialized cells synthesizing (pro)insulin, GAD, and IA-2, mainly localized in the medulla, and we demonstrate such cells also in peripheral lymphoid organs (spleen and lymph nodes). Phenotypic analysis qualifies these cells as antigen-presenting cells (APCs), including both dendritic cells and macrophages. These cells often appear surrounded by apoptotic lymphocytes, both in thymus and spleen, and may therefore be involved in the deletion of autoreactive lymphocytes. Our findings demonstrate the existence of, and define the tissue distribution and phenotype of, a novel subset of APCs expressing self-antigens in human lymphoid organs that appear to be involved in the regulation of self-tolerance throughout life.
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PMID:Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. 1123 56

Type 1 diabetes results from the autoimmune destruction of pancreatic beta-cells in genetically susceptible individuals. Growing evidence suggests that genetically determined variation in the expression of self-antigens in thymus may affect the shaping of the T-cell repertoire and susceptibility to autoimmunity. For example, both allelic variation and parent-of-origin effects influence the thymic expression of insulin (a known type 1 diabetes autoantigen), and insulin gene transcription levels in thymus inversely correlate with susceptibility in both humans and transgenic models. It is unclear why patients lose tolerance to IA-2 (insulinoma-associated tyrosine phosphatase-like protein, or islet cell antigen 512 [ICA512]), especially because IA-2 polymorphisms are not associated with type 1 diabetes. We report that alternative splicing determines differential IA-2 expression in islets compared with thymus and spleen. Islets express full-length mRNA and two alternatively spliced transcripts, whereas thymus and spleen exclusively express an alternatively spliced transcript lacking exon 13. This encodes for the transmembrane (TM) and juxta-membrane (JM) domains that comprise several type 1 diabetes target epitopes, supporting the concept that tolerance to IA-2 epitopes not expressed in lymphoid organs may not be achieved. We propose differential splicing as a regulatory mechanism of gene expression playing a permissive role in the development of autoimmune responses to IA-2. Our findings also show that candidate gene expression studies can help in dissecting the complex genetic determinants of a multifactorial disease such as type 1 diabetes.
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PMID:Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen. 1128 59

Autoantibodies against IA-2 have been detected in up to 86% of newly diagnosed patients with type 1 diabetes and appear to identify a subgroup of prediabetic subjects who rapidly progress to type 1 diabetes. We examined the association of IA-2 gene polymorphism with type 1 diabetes in Japanese subjects. A total of 276 Japanese subjects were studied for disease association and, in addition, another 53 patients were studied for association with the autoantibody status to IA-2. A microsatellite marker D2S1753E, located in the intron of the IA-2 gene, was used as a genetic marker in this study. In Japanese, two alleles (161mu and 165mu) were more frequent, and the 163mu allele was less frequent than in Caucasians (p = 0.0001). There was no significant difference in frequencies of alleles between diabetic patients and control subjects. The frequency of IA-2 gene polymorphism was not significantly different between patients stratified by age-at-onset, or between patients with and without susceptible HLA, DRB1*0405, DRB1*0802 and DRB1*0901. There was no significant difference in allele frequency of the IA-2 gene polymorphism between patients with and without autoantibody to IA-2. In conclusion, IA-2 gene polymorphism is not associated with either susceptibility to, or heterogeneity in type 1 diabetes in Japanese subjects.
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PMID:Polymorphism in gene for islet autoantigen, IA-2, and type 1 diabetes in Japanese subjects. 1133 76

Cytotoxic CD8 T lymphocytes (CTL) are effectors of pancreatic islet beta-cell destruction in type 1 diabetes but, with the exception of a single report, CTL to islet antigen peptides have not been identified. We used autologous blood monocyte-derived dendritic cells to elicit HLA-A2-restricted CTL to a peptide, MVWESGCTV (aa 797-805), that is contiguous with a dominant CD4 T-cell epitope in the islet antigen tyrosine phosphatase IA-2. IA-2 peptide-specific CTL activity measured as 51Cr release from autologous lymphoblasts was detected in 2/6 islet antibody-positive relatives at high risk for type 1 diabetes but also in 2/6 closely HLA-matched controls. All subjects had CTL activity to an HLA-A2-restricted Epstein-Barr virus peptide. CTL to the IA-2 self-peptide were therefore not disease-specific, consistent with other evidence that autoreactive T cells are present in healthy individuals.
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PMID:Cytotoxic T cells to an epitope in the islet autoantigen IA-2 are not disease-specific. 1135 32

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