Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes is associated with autoimmunity to insulin. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 locus which may regulate the expression of insulin in pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS VNTR-IDDM2 locus, peripheral blood T cell proliferation to human insulin and insulin autoantibodies (IAA) was measured in patients with new onset type 1 diabetes and control subjects. IAA were detected in 21 of 53 patients and in none of 25 control subjects, while T cell responses were low (stimulation index range 0.4-7.2) and similar in both groups. Both antibody and T cell responses were higher in younger subjects and IAA were more prevalent in patients with the HLA-DR4 allele. No relationship was observed between humoral and cellular responses to insulin. No association was found between the INS VNTR-IDDM2-susceptible allele and insulin autoimmunity. Increased T cell responses and IAA were found in patients with either the diabetes-susceptible or the diabetes-protective INS VNTR-IDDM2 locus genotypes, and increased T cell responses were also found in control subjects with either susceptible or protective INS VNTR-IDDM2 locus genotypes. This study confirms that primary T cell proliferative responses to insulin are low and detectable also in control subjects. The detection of T cell proliferation and autoantibodies to insulin in subjects with and without the protective INS VNTR-IDDM2 locus genotypes does not support the hypothesis of an allele-specific capacity for tolerance induction which could determine a susceptibility to develop autoimmunity against the insulin protein and subsequently diabetes.
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PMID:Autoimmune responses to the beta cell autoantigen, insulin, and the INS VNTR-IDDM2 locus. 984 45

We report on a 36-year-old patient suffering from chronic hepatitis C. Because of elevated liver enzymes and histology showing chronic inflammation and periportal fibrosis, interferon-alpha (IFN) therapy was started with a dosage of 5 Mio units three times a week. Four months later the patient hat to be hospitalized due to the typical clinical features of a recent onset type 1 diabetes (BG > 300 mg/dl, HbA1c 9.6%, ketonuria). In serum samples prior to and following interferon therapy, we analyzed titers of diabetes-related autoantibodies responding to GAD65 (glutamic acid decarboxylase), IA2c (tyrosine phosphatase) and ICA (islet cell autoantibodies). While ICA were negative before starting therapy, IA2c-antibodies were highly elevated. In contrast. GAD65-antibodies were elevated only slightly over the cut-off of the assay before therapy (controlled by a second different RIA assay) and increased 100 fold during IFN-alpha treatment. Additionally thyroid antibodies appeared. After the end of the IFN therapy, GAD65- and IA2c antibodies remained on high levels and also ICA could now be found. The patient was positive for HLA-DR4. This case supports the hypothesis that IFN-alpha therapy may lead to an augmented autoimmune reaction against islet cell antigens resulting in the development of diabetes mellitus type 1, especially if there are other predisposing factors before IFN treatment. We further discuss the possible involvement of interferon-alpha in the pathogenesis of autoimmune diabetes with reference to recent studies.
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PMID:[Augmentation of the immune response to islet cell antigens with development of diabetes mellitus caused by interferon-alpha therapy in chronic hepatitis C]. 1023 96

Insulin-dependent (Type 1) diabetes mellitus (IDDM) is a genetically controlled T-cell mediated autoimmune disease. Recently, subtyping of HLA-DRB1*04 identified the HLA-DRB1*0403 allele to be associated with protection in Caucasoids with the highest risk heterozygous genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201. Some studies confirmed this finding, but other reports were not consistent with a dominantly protective trait. We here report the frequency of HLA-DRB1*0403 in a large cohort (n=200) of Dutch patients with IDDM, their first-degree family members (n=370), and random controls (n=420) of the general population in The Netherlands. We found that HLA-DRB1*0403 is strongly associated with dominant protection against development of IDDM in unrelated subject, even in the context of the highest risk HLA-DQ phenotypes and HLA-DR4-DQB1*0302 (P < 0.0001).
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PMID:HLA-DRB1*0403 is associated with dominant protection against IDDM in the general Dutch population and subjects with high-risk DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype. 1045 27

Advanced glycation end products (AGEs) are believed to play an important role in the development of diabetic complications. AGEs increase in diabetes and modulate cellular functions through binding to a specific cell surface receptor (RAGE). The RAGE gene maps to chromosome 6p in the HLA class III area and is telomeric to the class II region at 250 kb from DRA. A recent report described the characterization of a major RAGE gene variant as a biallelic single base polymorphism (G/A 557) in the exon 3 sequence leading to a change of a glycine to a serine at position 82. Using DGGE and PCR-RFLP, we have investigated the distribution of this dimorphism in conjunction with HLA class II genes in large populations of type 1 diabetic patients and healthy subjects. Although no association of this RAGE gene polymorphism with disease susceptibility was found, we report a strong linkage disequilibrium between the variant carrying the serine amino acid at position 82 and two HLA-DR2 and HLA-DR4 specificities. In particular, we describe two major extensive HLA class II haplotypes associated with this serine variant and identified as DRB1*0401-DQA1*0301-DQB1*0301 in the diabetic group and DRB1*1501-DQA1*0102-DQB1*0602 in control individuals. These data were partially confirmed by family transmission analysis.
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PMID:Human RAGE GLY82SER dimorphism and HLA class II DRB1-DQA1-DQB1 haplotypes in type 1 diabetes. 1055

T cell recognition of autoantigens is critical to progressive immune-mediated destruction of islet cells, which leads to autoimmune diabetes. We identified a naturally presented autoantigen from the human islet antigen glutamic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of chromatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent diabetes mellitus, IDDM)-associated HLA-DR4 molecule. Peptides encompassing this epitope-stimulated GAD65-specific T cells from diabetic patients and a DR4-positive individual at high risk for developing IDDM. T cell responses were antagonized by altered peptide ligands containing single amino acid modifications. This direct identification and manipulation of GAD65 epitope recognition provides an approach toward dissection of the complex CD4(+) T cell response in IDDM.
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PMID:Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65). 1117 25

The frequency of reticulin (ARA), endomysium (EmA), and gut epithelial cell (GECA) autoantibodies, and gliadin antibodies (AGA), was investigated in 86 Spanish diabetic patients by indirect immunofluorescence (IFI) and ELISA, along with their HLA phenotype. Four patients (5%) showed ARA-IgG (R1 pattern), eight (9%) showed AGA-IgG, and eight (9%) showed AGA-IgA. No EmA or GECA-positive patients were found. In diabetic patients, HLA-DR7 is increased in ARA-IgG+ vs. ARA-IgG- (though not significantly), and HLA-DR6 and HLA-DQ1 are significantly increased in the AGA-IgG+ group vs. the AGA-IgG- group. Comparison with a non-diabetic coeliac group showed that HLA-DR4 and HLA-DQ3 are significantly increased in the AGA-IgA+ group, whereas HLA-DQ2 shows a significant decrease in the AGA-IgG+ and AGA-IgA+ patients. Finally, when compared to the healthy group, HLA-DR7 frequency is decreased in the ARA-IgG- group, while HLA-DQ3 is significantly increased and HLA-DR6 and HLA-DQ1 significantly decreased in the AGA-IgG- group.Altogether, these data suggest that the genetic background leading to the appearance of coeliac-specific autoantibodies in Spanish diabetic patients differ depending on the autoantibody produced and is also different to the genetic background leading to diabetes in Spain.
J Diabetes Complications
PMID:Coeliac- and enteropathy-associated autoantibodies in Spanish insulin-dependent diabetes mellitus patients and their relation to HLA antigens. 1125 25

The IA-2 is a major autoantigen of type 1 diabetes belonging to the protein tyrosine phosphatase family. We report on the humoral autoimmunity to an alternatively-spliced variant of IA-2 (IA-2 variant) and autoimmune-mediated diabetes age of onset association with IA-2 autoantibody epitope specificities, in 144 recent-onset patients with type 1 diabetes and 54 GAD autoantibody-positive patients with type 2 diabetes. The cytoplasmic domain of IA-2 (IA-2ic) detected a somewhat greater proportion of patients expressing autoantibodies than IA-2 variant (56%vs. 52% of patients with type 1 diabetes and 17%vs. 9% of GAD autoantibody-positive patients with type 2 diabetes). Conversely, only 1% of IA-2 variant autoantibody-positive patients failed to react to IA-2ic construct. Among 80 patients with type 1 diabetes who were positive for autoantibodies to IA-2ic, 8% recognized the juxtamembrane region (JM, representing amino acids 601-629) only, 64% bound the protein tyrosine phosphatase (PTP)-like domain of IA-2 only, and 29% bound both JM and PTP epitopes. Autoantibodies to the PTP-like domain were prevalent in children and adolescents with type 1 diabetes. The age of disease onset in patients with IA-2JM autoantibodies only, was significantly higher than those in patients reacted with the PTP-like domain of IA-2 (P< 0.02). Among GAD autoantibody-positive patients with type 2 diabetes reacted with IA-2ic, 44% bound the JM region only, and 33% bound epitopes in the PTP-like domain only; 22% had autoantibodies to both regions. The frequency of GAD autoantibody-positive patients with type 2 diabetes positive for autoantibodies to the JM region only, was significantly higher than that in patients with type 1 diabetes (P< 0.01). IA-2PTP autoantibodies were significantly associated with HLA-DR4, while the additional reactivity to IA-2JM was associated with HLA-DR9 allele. These results suggest that autoantibody recognition of IA-2 epitopes in autoimmune diabetes is associated with age of disease onset, which may reflect the intensity of the beta-cell destruction process.
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PMID:Association between IA-2 autoantibody epitope specificities and age of onset in Japanese patients with autoimmune diabetes. 1177 57

Complex protein antigens contain multiple potential T cell recognition epitopes, which are generated through a processing pathway involving partial antigen degradation via proteases, binding to MHC molecules, and display on the APC surface, followed by recognition via the T cell receptor. We have investigated recognition of the GAD65 protein, one of the well-characterized autoantigens in type I diabetes, among individuals carrying the HLA-DR4 haplotypes characteristic of susceptibility to IDDM. Using sets of 20-mer peptides spanning the GAD65 molecule, multiple immunostimulatory epitopes were identified, with diverse class II DR molecules functioning as the restriction element. The majority of T cell responses were restricted by DRB1 molecules; however, DRB4 restricted responses were also observed. Antigen-specific T cell clones and lines were derived from peripheral blood samples of pre-diabetic and IDDM patients and T cell recognition and response were measured. Highly variable proliferative and cytokine release profiles were observed, even among T cells specific for a single GAD65 epitope.
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PMID:Complexity of human immune response profiles for CD4+ T cell epitopes from the diabetes autoantigen GAD65. 1190 49

HLA-DR4 has been implicated in several diseases including rheumatoid arthritis (RA) and type I diabetes, the strength of associations being ethnically variable. Unusually high level of heterogeneity in DR4-DQB1 haplotypes has been reported in the Indian population. The present study is an attempt to determine the genetic diversity of the HLA-DR4 allelic family and its associated DQA1-DQBI haplotypic combinations in the healthy North Indian population. Using PCR-SSP and PCR-SSOP techniques, nine subtypes of DR4 were encountered of which DRB1*0403 was the most predominant allele (34.8%) followed by *0404 (27%), *0401 (14.6%), and *0405 (11%). No examples of *0402, *0409, *0411, *0413-*0417, and *0419-23 were encountered, although a few other subtypes, *0410 (three examples), *0406 and *0418 (two examples each), and *0407, *0408, and *0412 (single example each) occurred infrequently in a cohort of 85 HLA-DR4 positive samples studied. Most of these subtypes occurred in combination with DQA1*03-DQB1*0302 (69.5%). DRB1*0403 and *0404 exhibited maximum heterogeneity of DQB1 combinations. Haplotype data revealed the presence of 15 different DR4-DQ haplotypes, four of which were found to be "unique" to Asian Indians, not reported in any other population. These results help to explain the observed variability in DR4 associations in autoimmune diseases in Asian Indians and provide support for scientific and historical documentation of extensive admixture in the Indian subcontinent.
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PMID:Heterogeneity of HLA-DRB1*04 and its associated haplotypes in the North Indian population. 1191 67

Type 1 diabetes is characterized by T-cell infiltration of the islets of Langerhans and abundant HLA class II molecule expression on islet endothelial cells (ECs). The specificity of infiltrating T-cells for islet autoantigens has been amply demonstrated in animal models, and is implicit in human diabetes, but the processes regulating endothelial transmigration of islet autoantigen-specific T-cells into islets are not known. We examined the ability of ECs expressing HLA class II molecules to process and present the islet autoantigen GAD65 and examined the effects of presentation on transmigration of GAD65-specific T-cells. Primary cultures of human vascular ECs expressing the DRB1*0401 (VEC1) and DRB1*0301 (VEC2) genotypes were established and de novo expression of HLA class II molecules induced with interferon-gamma. Under these conditions, VEC1 efficiently processed and presented whole GAD65 to the HLA-DR4-restricted murine T-cell hybridoma T33.1 that recognizes the 274-286 epitope of GAD65. Using a transwell system, we examined the effect of GAD65 presentation on migration of GAD65-specific T-cells across EC monolayers. Migration of T33.1 hybridoma cells and of the human T-cell clone, PM1#11 (recognizes GAD65 epitope 339-352 presented by HLA-DR3) across VEC1 and VEC2, respectively, were greatly enhanced in the presence of GAD65, commencing more rapidly and achieving a higher peak migration at 3 h. Migrated PM1#11 cells retained full proliferative capacity. These results support the hypothesis that presentation of autoantigens by islet endothelium in vivo could promote transmigration of circulating islet autoantigen-specific T-cells primed in regional lymph nodes against islet autoantigens.
Diabetes 2003 Mar
PMID:Processing and presentation of the islet autoantigen GAD by vascular endothelial cells promotes transmigration of autoreactive T-cells. 1260 13


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