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)

Coeliac disease is a common enteropathy with a strong inherited risk characterised by dietary wheat, rye and barley induced T-cell activation. Although there is replicated linkage to 2q33, results are inconsistent from association studies of the most promising candidate genes: the CD28/CTLA4/ICOS cluster. CTLA4 plays a key role in regulating T lymphocyte mediated inflammatory responses, and variants in the 3' region influence development of diabetes and thyroid disease. We genotyped CTLA4 variants (-1722 C/T, -658 T/C, -318 C/T, +49 A/G, +1822 C/T, CT60 A/G) to tag all common haplotypes (>5% frequency) and an ICOS variant (IVS+173 C/T) in 340 white UK Caucasian coeliac disease cases. Strict ascertainment criteria for coeliac cases required both villous atrophy at diagnosis and positive serology. In total, 973 healthy controls were available for SNP, and 705 for CTLA4 haplotype, based association analyses. Coeliac disease showed weak association with the CTLA4 +1822T (P=0.019) and CT60 G (P=0.047) alleles. Strong association was seen with a common CTLA4 haplotype (P=0.00067, odds ratio 1.41) of frequency 32.7% in coeliac disease and 25.5% in healthy controls. A common CTLA4 haplotype shows strong association with coeliac disease, and contains multiple alleles reported to affect immunological function. Loss of tolerance to dietary antigens in coeliac disease may be mediated in part by heritable variants in co-signalling genes regulating T-cell responses.
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PMID:A common CTLA4 haplotype associated with coeliac disease. 1565 18

Recent success in pancreatic islet allotransplantation has raised expectations but has equally highlighted the acute shortage of donor tissue. The use of xenogeneic tissue would help to address this shortage; however, strong cellular immunity limits the application of this approach. T-cell responses to xenogeneic tissues involve recognition of intact species-mismatched major histocompatibility complex (MHC) molecules, the direct pathway, and xenogeneic proteins presented as peptides by responder-type MHC molecules, the indirect pathway. In this study, we exploited the species difference to selectively and sequentially inhibit direct and indirect xenoresponses after transplantation of porcine islets into mice. Selective inhibition of the direct response was achieved using porcine CTLA4-Ig, which binds preferentially to pig versus mouse B7 molecules. Selective inhibition of the indirect response was achieved using murine CTLA4-Ig, which binds preferentially to mouse B7 molecules. Administration of porcine CTLA4-Ig alone caused modest prolongation of islet survival. Injection of murine CTLA4-Ig alone had a minimal effect. However, the injection of the porcine fusion protein early and the murine homolog late after grafting led to permanent survival of the porcine islets, in the absence of any other immunosuppression. These results suggest that a similar approach could have clinical utility in porcine islet xenotransplantation.
Diabetes 2005 Apr
PMID:Achieving permanent survival of islet xenografts by independent manipulation of direct and indirect T-cell responses. 1579 43

Type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, could be attributed to many defects in nonobese diabetic (NOD) mice, including deficient expressions of costimulatory molecules that impair antigen presentation. Thus, this deficient antigen presentation may result in a reduced ability to induce a tolerogenic response through negative selection/regulation of autoreactive T cells. Improperly activated T cells seem to be able to induce autoimmune responses causing diabetes. To re-establish tolerance to autoantigens by modulating costimulation, we constructed and tested a new type of DNA vaccine encoding a membrane-bound preproinsulin (mbPPI) and a chimeric gene vector encoding mutant B7.1/CD40L (mB7.1/CD40L) fusion protein. This mutant B7.1 binds CTLA4 but not CD28. We report that young NOD mice immunized with mbPPI along with mB7.1/CD40L DNA vectors significantly reduced diabetes incidence while treatment with CTLA4/IgG1 exacerbated diabetes. In conclusion, the combination of mbPPI and mB7.1/CD40L was able to protect against autoimmunity and diabetes in NOD mice possibly by promoting a more efficient presentation of autoantigen PPI and inducing specific tolerance to PPI by negatively regulating autoreactive T cells.
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PMID:DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice. 1610 64

We aimed to assess the possible contribution of the PAX4 transcription factor gene to the genetic background of type 1 diabetes. We analyzed four coding polymorphisms of the PAX4 gene in 498 cases with type 1 diabetes and 825 control subjects from Finland and Hungary. All patients were diagnosed under the age of 15 years according to the World Health Organization criteria. All four PAX4 variants (three in exon 9 and one in exon 3) were genotyped using DNA sequencing. In addition, all Finnish subjects were typed for HLA DR-DQ, insulin gene (-23) HphI, and CTLA4 CT60 polymorphisms. The +1,168 C/A coding variant of PAX4 was found to be polymorphic in both populations (P321H, rs712701). No difference was observed in the genotype frequencies between cases and control subjects, nor was any disease association detected when patients were stratified according to age at diagnosis, sex, HLA, insulin gene, or CTLA4 genotypes. Our data indicate that the +1,168 C/A variant of PAX4 gene does not play any essential role in genetic type 1 diabetes susceptibility. The strong coherence between the datasets of the two ethnic groups studied with highly contrasting disease incidence, socioeconomic characteristics, and profoundly diverse environment emphasizes the impact of this finding.
Diabetes 2005 Sep
PMID:Lack of association of PAX4 gene with type 1 diabetes in the Finnish and Hungarian populations. 1612 75

Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [lambda(S)] approximately 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific lambda(S) approximately 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] approximately 1.9), CTLA4 (chromosome 2q33, allelic OR approximately 1.2), and PTPN22 (chromosome 1p13, allelic OR approximately 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10(-52)), nine non-HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10(-4)). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect (lambda(S) > or = 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.
Diabetes 2005 Oct
PMID:Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. 1618 4

There are two peaks in the distribution of the age of onset of type 1 diabetes mellitus (T1DM)--the first in early childhood and the second at the time of puberty. Although T1DM results from the interaction of genetic and non-genetic factors, it has not been established which factors contribute to the bimodal distribution. The genetic component of T1DM is in large part related to genes from the human leukocyte antigen (HLA) complex (IDDM1); however, loci from the variable nucleotide tandem repeat (VNTR) region of the insulin (INS) gene (IDDM2) and more recently, the cytotoxic T-lymphocyte-associated protein-4 region (CTLA4, IDDM12) have also been implicated. Therefore, we examined the potential interaction between these loci through the influence of the age of onset of T1DM in diabetic and control Caucasian individuals. We discovered that younger individuals with HLA-DRB1*0301/DRB1*04 and INS I/I genotypes exhibited increased susceptibility to T1DM, whereas the interaction of INS I/I and CTLA4 G/G genotypes was more common in older children with T1DM. Combining the age of onset of T1DM with specific genotypes may operate to produce a single disease through different underlying causes.
Pediatr Diabetes 2005 Dec
PMID:Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus. 1639 Mar 90

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.
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PMID:Costimulation and autoimmune diabetes in BB rats. 1661 20

Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
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PMID:FOXP3 controls regulatory T cell function through cooperation with NFAT. 1687 58

The CTLA4 gene is important for T lymphocyte-mediated immunoregulation and has been associated with several autoimmune diseases, in particular, type 1 diabetes. To model the impact of natural genetic variants of CTLA4, we constructed RNA interference (RNAi) "knockdown" mice through lentiviral transgenesis. Variegation of expression was observed in founders but proved surmountable because it reflected parental imprinting, with derepression by transmission from male lentigenics. Unlike the indiscriminate multiorgan autoimmune phenotype of the corresponding knockout mice, Ctla4 knockdown animals had a disease primarily focused on the pancreas, with rapid progression to diabetes. As with the human disease, the knockdown phenotype was tempered by genetic-modifier loci. RNAi should be more pertinent than gene ablation in modeling disease pathogenesis linked to a gene-dosage variation.
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PMID:Modeling CTLA4-linked autoimmunity with RNA interference in mice. 1706 Jun 11

In 1982 we proposed the presence of a subtype of type 1 diabetes [slowly progressive insulin-dependent diabetes mellitus (SPIDDM)], which was characterized by persistently positive islet cell antibody, late age of onset, noninsulin-dependent diabetes, and slowly progressive beta cell failure. Since then many studies demonstrated that this subtype of type 1 diabetes is prevalent in many ethnic groups and was later called the latent autoimmune diabetes in adults (LADA). Recent epidemiological studies reported that about 10% of patients with apparent type 2 diabetes have at least one autoantibodies against islet-specific antigen with high potential to progress to insulin-dependent state. Between SPIDDM and LADA some differences are reported in terms of some genetic predispositions including HLA class II and class I genes, vitamin D receptor gene, and CTLA4 genes. Common features in SPIDDM and LADA including preserved beta cells at the onset of diabetes and weak T cell response to residual beta cells suggest that these subtypes of type 1 diabetes are suitable candidates for prevention treatment for further progression of beta cell failure.
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PMID:Immunopathological and genetic features in slowly progressive insulin-dependent diabetes mellitus and latent autoimmune diabetes in adults. 1713 May 33


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