Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8(+)/I-Abo transgenic mice expressing functional HLA-DQ8 molecules and devoid of endogenous mouse class II. DQ8(+)/I-Abo mice produced antigen-specific antibodies and formed germinal centers after immunization with GAD65 peptides. Two GAD peptide-specific (247-266 and 509-528), DQ8 restricted Th1 CD4(+) T cell lines, were generated from immunized DQ8(+)/I-Abo mice. They induced severe insulitis after adoptive transfer into transgene positive (but not negative) mice who were treated with a very low dose of streptozotocin that alone caused no apparent islet pathology. In addition to CD4, islet mRNA from these mice also showed expression of CD8, IFNgamma, TNFalpha, Fas, and Fas ligand. Our data suggest that a mild islet insult in the presence of HLA-DQ8 bearing antigen-presenting cells promotes infiltration of GAD peptide reactive T cells into the islet.
 ...
PMID:Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice. 972 63

Autoimmunity precedes clinical type 1 diabetes, and indicators of maturing autoimmune responses may be useful markers for disease prediction. To study this, epitope maturation of autoantibodies to the related protein tyrosine phosphatase (PTP)-like autoantigens IA-2 and IA-2beta was examined in sequential samples from birth in a cohort of 21 offspring developing multiple islet autoantibodies and a similar cohort of 48 relatives of patients with type 1 diabetes recruited at an older age. Initial reactivity in offspring was heterogeneous against the IA-2 juxtamembrane region (10/21) and PTP domains (13/21), and both specificity and extent of initial IA-2/IA-2beta autoantibodies were associated with HLA class II genotype. Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2beta epitopes were observed in seven offspring. In contrast, in older relatives, IA-2/IA-2beta Ab reactivity was stable and spreading rare. Development of diabetes in children was associated with the presence of Abs to the IA-2 juxtamembrane region (risk by age 5 yr, 52% vs 0% in those with PTP domain Abs only; p < 0.02), and 5 of 26 relatives who developed diabetes had IA-2 Abs only against the juxtamembrane region. The findings show that autoantibody reactivity to IA-2/IA-2beta is dynamic in the young, show that the juxtamembrane region of IA-2 is an early IA-2 autoantibody target, and suggest that these Abs are a risk factor for development of type 1 diabetes in infancy.
 ...
PMID:Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes. 986 31

Continuing progress has been made in elucidating the genetic factors involved in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]) in the past year. Two genome scans suggested additional susceptibility intervals and provided supporting evidence for several previously reported linkages. Other studies focused on the confirmation of linkage using multipoint sibpair analyses with densely spaced markers and multiethnic collections of families. Although significant and consistent linkage evidence was reported for the susceptibility intervals IDDM8 (on human chromosome 6q27), IDDM4 (on 11q) and IDDM5 (on 6q25), evidence for most other intervals varies in different data sets -probably due to a weak effect of the disease genes, genetic heterogeneity or random variation. Linkage disequilibrium mapping has become an increasingly important tool for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations. Functional studies indicate, firstly, that the susceptible and protective HLA class II molecules HLA-DR and -DQ bind and present nonoverlapping peptides and, secondly, that the variable number of tandem repeats at the 5' end of the insulin gene (susceptibility interval IDDM2) regulates insulin expression in the thymus.
 ...
PMID:Genetic susceptibility factors in type 1 diabetes: linkage, disequilibrium and functional analyses. 991 16

The common autoimmune disease type 1 diabetes provides a paradigm for the genetic analysis of multifactorial disease. Disease occurrence is attributable to the interaction with the environment of alleles at many loci interspersed throughout the genome. Their mapping and identification is difficult because the disease-associated alleles occur almost as commonly in patients as in healthy individuals; even the highest-risk genotypes bestow only modest risks of disease. The identification of common quantitative trait loci (QTL) in autoimmune disease and in other common disorders, therefore, requires a very close marriage of genetics and biology. Two QTLs have been identified in human type 1 diabetes: the major histocompatibility complex HLA class II loci and a promoter polymorphism of the insulin gene. The evidence for their primary roles in disease aetiology demonstrates the necessity of combined studies of genetics and biology. Their functions and interaction underpin an emerging picture of the basic causes of the disease and direct analyses towards other candidate genes and pathways. The genetic tools used for QTL identification include transgenesis and gene knockouts, whole genome scanning for linkage, mouse congenic strains, linkage disequilibrium mapping, and the establishment of ancestral haplotypes among disease-associated chromosomes.
 ...
PMID:From genome to aetiology in a multifactorial disease, type 1 diabetes. 1019 89

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.
 ...
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

In this study, we report type 1 diabetes age-of-onset association with HLA class II (DRB1, DQB1, and DPB1) and class I (A) genes in 222 multiplex families from the Human Biological Data Interchange. Linear regression showed a small (R2 = 0.26) but significant correlation in the ages of onset among sib pairs. A strong association in age of onset between members of sib pairs was observed when the analysis was performed using contingency tables that split sibs into three age-at-onset ranges (0-10, 11-20, and 21-36 years). The association is strongest for sib pairs that share both haplotypes and is nonsignificant for sib pairs that do not share any DR-DQ haplotypes. A goodness-of-fit test revealed that DR-DQ haplotype sharing cannot account for all the association in age of onset among sib pairs. The age-of-onset distribution of DR-DQ haplotypes is affected by the DPB1 and A alleles present. The strongest associations were found with the A locus: DR3/DR4 genotype frequency decreases with age of onset in this data set only among A*0101- individuals, and A*2402 is strongly associated with younger age of onset in many DR-DQ haplotypes.
 ...
PMID:Association between type 1 diabetes age of onset and HLA among sibling pairs. 1042 87

We have recently shown that an as yet unidentified gene within or in the vicinity of the HLA complex, in linkage disequilibrium with microsatellite D6S2223, modifies the risk to develop type 1 diabetes independently of HLA-DR and -DQ genes. This microsatellite is located 2.5 Mb telomeric to HLA-F and particular alleles at this microsatellite modifies the risk encoded by the high-risk DRB1*03-DQA1*0501-DQB1*0201 (hereafter called DR3) haplotype. Coeliac disease and type 1 diabetes share some susceptibility HLA class II haplotypes, in Scandinavia particularly the DR3 haplotype. We therefore investigated whether the marker D6S2223 might also be associated with coeliac disease. In order to keep the contributions from the DRB1-DQA1-DQB1 genes constant (i.e., eliminate the effects of linkage disequilibrium to disease associated DR and/or DQ alleles), we only used cases and controls being homozygous for DR3. We found the frequency of allele 3 at D6S2223 to be reduced among patients with coeliac disease compared to controls, to a similar extent as seen in type 1 diabetes, which could not be explained by a different distribution of HLA-B alleles (as ascertained by typing for the MIB microsatellite). This negatively associated allele 3 at D6S2223 occurred in a homozygous combination at a significantly lower frequency among patients than controls. Thus, allele 3 at D6S2223 on DR3 haplotypes is associated with reduced susceptibility for development of both type 1 diabetes and coeliac disease. This suggests that a gene(s) in the vicinity of D6S2223 is involved in the pathogenesis of both of these immune-mediated diseases.
 ...
PMID:A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease. 1048 43

Type 1 diabetes is a T-cell-mediated disease in which presentation of autoantigens to CD4+ T-cells is thought to play a crucial role. Polymorphism of HLA class II genes accounts for 50% of the genetic risk of contracting type 1 diabetes. HLA-DQ and -DR molecules predisposing to or protecting from type 1 diabetes have been identified, but the molecular basis controlling these associations is as yet undefined. Apart from distinct thymic selection of autoreactive T-cells by susceptible and protective HLA molecules, exclusive presentation of autoantigenic peptides by type 1 diabetes-predisposing HLA molecules or, alternatively, induction of regulatory T-cells by protective alleles are potential mechanisms for modification of type 1 diabetes risk by HLA polymorphism. As a first step in exploring the role of HLA molecules in autoantigen-specific cellular responses in type 1 diabetes, we have screened peptides covering the sequence of two major autoantigens targeted by humoral and cellular immune responses, GAD65 and islet associated-2 (IA-2), for binding to class II molecules. We developed a sensitive novel competition binding assay allowing us to measure peptide binding on intact cells to 10 HLA-DR and 4 HLA-DQ molecules. For all tested alleles, multiple peptides binding with high affinity were identified. We report clustering of binding peptides in the COOH-terminal regions of GAD65 and IA-2, as well as highly promiscuous binding patterns of some peptides. Our results demonstrate that most peptides derived from the GAD and IA-2 autoantigens can bind to both type 1 diabetes-predisposing and type 1 diabetes-protective HLA molecules, although some exceptions were observed. The binding inventory presented here for GAD and IA-2 peptides can be useful for mapping natural epitopes and predicting peptide-specific responses induced by preventive immunization.
 ...
PMID:Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes. 1051 57

The HLA-DMA and HLA-DMB genes are located in the HLA-D region between DQ and DP. Four variants of DMA (DMA*0101-0104) and five of the DMB (DMB*0101-0105) have so far been identified. HLA-DM molecules are required in the process of peptide loading to HLA class II antigens, both regulating the dissociation of class II-associated invariant chain peptides (CLIP) and the subsequent binding of exogenous peptides to HLA class II molecules. In order to investigate the immunogenetic heterogeneity within the HLA-D susceptibility region, we analysed the distribution of DMA alleles in 125 patients with type 1 diabetes mellitus and 90 healthy controls, and of DMB alleles in 102 patients and 89 healthy controls. Patients and controls were all from central Germany. The polymerase chain reaction (PCR) amplified products were purified and separated on a 10% polyacrylamide gel electrophoresis. Among the four recognized DMA alleles, DMA*0102 was significantly less frequent (12% vs. 28.9%, P<0.01) in patients with type 1 diabetes mellitus. DMB*0101 (70.6% vs. 97.8%, P<5.5x10(-3)) was also reduced in frequency compared to controls. Comparing patients and controls positive for the type 1 diabetes high-risk markers we found a significant association between DMA*0102 and DQA*0501 (9.5% vs. 39.1%, P<0.02), as well as DMB*0101 and DQA*0501 (62.5% vs. 96.2%, P<0.03). In conclusion, DMA*0102 and DMB*0101 contribute to genetic protection to type 1 diabetes mellitus in individuals with high-risk DQA markers in the German population.
 ...
PMID:HLA-DMA and HLA-DMB alleles in German patients with type 1 diabetes mellitus. 1051 69

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.
 ...
PMID:Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a german population. 1052 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>