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

In both human patients and murine models, the progression from insulitis to diabetes is neither immediate nor inevitable, as illustrated by the innocuous versus destructive infiltrates of BDC2.5 transgenic mice on the nonobese diabetic (NOD) versus C57BL/6.H-2g7 genetic backgrounds. Natural killer (NK)-cell-specific transcripts and the proportion of NK cells were increased in leukocytes from the aggressive BDC2.5/B6.H-2g7 lesions. NK cell participation was also enhanced in the aggressive lesions provoked by CTLA-4 blockade in BDC2.5/NOD mice. In this context, depletion of NK cells significantly inhibited diabetes development. NOD and B6.H-2g7 mice exhibit extensive variation in NK receptor expression, reminiscent of analogous human molecules. NK cells can be important players in type 1 diabetes, a role that was previously underappreciated.
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PMID:Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. 1514 Oct 80

Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag(-/-) background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag(-/-) T cells, which are all CD25(-), are transferred into islet antigen-expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4(-/-)/Rag(-/-) OVA-specific T cells (also CD25(-)) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen.
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PMID:Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen. 1521 Jul 48

Linkage analysis and congenic mapping in NOD mice have identified a susceptibility locus for type 1 diabetes, Idd5.1 on mouse chromosome 1, which includes the Ctla4 and Icos genes. Besides type 1 diabetes, numerous autoimmune diseases have been mapped to a syntenic region on human chromosome 2q33. In this study we determined how the costimulatory molecules encoded by these genes contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). When we compared levels of expression of costimulatory molecules on T cells, we found higher ICOS and lower full-length CTLA-4 expression on activated NOD T cells compared with C57BL/6 (B6) and C57BL/10 (B10) T cells. Using NOD.B10 Idd5 congenic strains, we determined that a 2.1-Mb region controls the observed expression differences of ICOS. Although Idd5.1 congenic mice are resistant to diabetes, we found them more susceptible to myelin oligodendrocyte glycoprotein 35-55-induced EAE compared with NOD mice. Our data demonstrate that higher ICOS expression correlates with more IL-10 production by NOD-derived T cells, and this may be responsible for the less severe EAE in NOD mice compared with Idd5.1 congenic mice. Paradoxically, alleles at the Idd5.1 locus have opposite effects on two autoimmune diseases, diabetes and EAE. This may reflect differential roles for costimulatory pathways in inducing autoimmune responses depending upon the origin (tissue) of the target Ag.
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PMID:The diabetes susceptibility locus Idd5.1 on mouse chromosome 1 regulates ICOS expression and modulates murine experimental autoimmune encephalomyelitis. 1521 Jul 70

At least two loci that determine susceptibility to type 1 diabetes in the NOD mouse have been mapped to chromosome 1, Idd5.1 (insulin-dependent diabetes 5.1) and Idd5.2. In this study, using a series of novel NOD.B10 congenic strains, Idd5.1 has been defined to a 2.1-Mb region containing only four genes, Ctla4, Icos, Als2cr19, and Nrp2 (neuropilin-2), thereby excluding a major candidate gene, Cd28. Genomic sequence comparison of the two functional candidate genes, Ctla4 and Icos, from the B6 (resistant at Idd5.1) and the NOD (susceptible at Idd5.1) strains revealed 62 single nucleotide polymorphisms (SNPs), only two of which were in coding regions. One of these coding SNPs, base 77 of Ctla4 exon 2, is a synonymous SNP and has been correlated previously with type 1 diabetes susceptibility and differential expression of a CTLA-4 isoform. Additional expression studies in this work support the hypothesis that this SNP in exon 2 is the genetic variation causing the biological effects of Idd5.1. Analysis of additional congenic strains has also localized Idd5.2 to a small region (1.52 Mb) of chromosome 1, but in contrast to the Idd5.1 interval, Idd5.2 contains at least 45 genes. Notably, the Idd5.2 region still includes the functionally polymorphic Nramp1 gene. Future experiments to test the identity of Idd5.1 and Idd5.2 as Ctla4 and Nramp1, respectively, can now be justified using approaches to specifically alter or mimic the candidate causative SNPs.
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PMID:Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. 1521 Jul 71

Bone marrow transplantation blocks diabetes pathogenesis and reverses autoimmunity in nonobese diabetic (NOD) mice. However, there is a greater barrier to engraftment in the context of autoimmunity. In the present study, we characterized which recipient cells influence engraftment in prediabetic NOD mice, with the goal to replace myelotoxic conditioning with antigen-specific deletion of reactive host cells. Preconditioning of NOD mice with anti-CD8 and anti-CD154 monoclonal antibodies (mAbs) synergistically enhanced engraftment and significantly reduced the minimum total body irradiation (TBI) dose for engraftment. Strikingly, preconditioning with anti-CD4 mAb significantly impaired engraftment, negating the beneficial effect of anti-CD8, and resulted in a requirement for more TBI-based conditioning compared with controls conditioned with TBI alone. Similarly, more TBI was required when anti-T-cell receptor beta (TCRbeta) mAb was administered as preconditioning. The addition of anti-CD152 to CD154 preconditioning abrogated the engraftment-enhancing effect of anti-CD154. Taken together, these data indicate a role for CD4+ regulatory T cells in vivo which require signaling via CD152 in the induction of chimerism and tolerance in NOD recipients. Notably, disease prevention and reversal of autoimmunity was absolutely correlated with the establishment of chimerism. These studies have important implications for the design of novel clinical approaches to treat type 1 diabetes.
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PMID:Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of alpha beta-TCR+ and CD4+ cells negates the effect. 1549 51

Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to self-antigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4(+)CD25(+) T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4(+)CD25(+) Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4(+)CD25(+) T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P = 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-gamma (P = 0.005) and decreased interleukin-10 production (P = 0.03). These deficiencies may reflect a disturbance in the balance of the CD4(+)CD25(+) population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P = 0.007) and intracellular CTLA-4 (P = 0.01). These data demonstrate deficiency in function of the CD4(+)CD25(+) Treg population that may influence the pathogenesis of type 1 diabetes.
Diabetes 2005 Jan
PMID:Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. 1561 15

IL-10, a powerful anti-Th1 cytokine, has shown paradoxical effects against diabetes. The mechanism underlying such variable function remains largely undefined. An approach for controlled mobilization of endogenous IL-10 was applied to the NOD mouse and indicated that IL-10 encounter with diabetogenic T cells within the islets sustains activation, while encounter occurring peripheral to the islets induces tolerance. Insulin beta-chain (INSbeta) 9-23 peptide was expressed on an Ig, and the aggregated (agg) form of the resulting Ig-INSbeta triggered IL-10 production by APCs, and expanded IL-10-producing T regulatory cells. Consequently, agg Ig-INSbeta delayed diabetes effectively in young NOD mice whose pathogenic T cells remain peripheral to the islets. However, agg Ig-INSbeta was unable to suppress the disease in 10-wk-old insulitis-positive animals whose diabetogenic T cells have populated the islets. This is not due to irreversibility of the disease because soluble Ig-INSbeta did delay diabetes in these older mice. Evidence is provided indicating that upon migration to the islet, T cells were activated and up-regulated CTLA-4 expression. IL-10, however, reverses such up-regulation, abolishing CTLA-4-inhibitory functions and sustaining activation of the islet T lymphocytes. Therefore, IL-10 supports T cell tolerance in the periphery, but its interplay with CTLA-4 sustains activation within the islets. As a result, IL-10 displays opposite functions against diabetes in young vs older insulitis-positive mice.
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PMID:IL-10 diminishes CTLA-4 expression on islet-resident T cells and sustains their activation rather than tolerance. 1563 84

+49 A/G polymorphism of CTLA-4 gene has been suggested to be associated with type 1 diabetes in some populations. However, a functional significance of the +49 A/G polymorphism is unknown, because it is believed the polymorphism does not affect the function of the CTLA-4 molecule. In this study, we examined the +49 A/G polymorphism of the CTLA-4 gene in 30 Japanese type 1 diabetic patients (14 type 1B and 16 type 1A) and 40 non-diabetic subjects in a case-control study, and stratified patients according to genotype of the polymorphism. The distribution of genotype frequencies differed between type 1 diabetic patients and controls (p<0.01). When the subjects were subdivided into type 1A and type 1B subgroups, a significant difference in G allele frequency was found only between type 1B patients and controls, whereas G allele frequency tended to be higher in type 1A diabetic patients than controls. Type 1B patients displayed more severe metabolic decompensation (higher plasma glucose concentration, lower urinary C-peptide levels, higher insulin requirement, and higher serum amylase levels), and were found to be more prone to diabetic ketoacidosis than type 1A patients. After stratification by genotype, differences in urinary C-peptide and serum amylase levels between type 1A and type 1B patients were found to be due to differences in the GG genotype subgroup, whereas in the AG subgroup those differences disappeared. In conclusion, the +49 A/G polymorphism of CTLA-4 gene was associated with the occurrence of type 1B diabetes in a Japanese population, and type 1B diabetics with a GG genotype were associated with more severe cell dysfunction than their type 1A counterparts.
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PMID:Association between CTLA-4 +49 A/G polymorphism and type 1B diabetes in Japanese population. 1571 Oct 22

CTLA-4 is a homeostatic regulator of T cell activation and is believed to play a critical role in peripheral tolerance. The contribution of CTLA-4 gene variants to type 1 diabetes has been analyzed in several ethnic groups. In this study, the association of CTLA-4 +49 A/G polymorphism with type 1 diabetes was investigated in Iranian patients. One hundred and nine patients and 331 healthy subjects formed the studied populations. CTLA-4 A/G polymorphism at position 49 in exon 1 was identified using PCR-SSCP and PCR-RFLP methods. Patient numbers with A/G, A/A and G/G genotypes were 78 (71.5%), 21 (19.3%) and 10 (9.2%) while in healthy controls, these were 149 (45%), 146 (44.2%) and 36 (10.8%), respectively. A significant decrease in the frequency of the A/A genotype was observed in the diabetes group (p = 0.000004). In diabetic subjects, the allele frequency of G was also higher than in controls (45% versus 33.4%, p = 0.00269). The differences in the genotypes and the alleles were greater in patients with younger age of diabetes onset (age < or = 15 years) compared with controls (p = 0.000001 and p = 0.000579, respectively). The distribution of the CTLA-4 polymorphism between patients did not show any significant difference according to diabetic ketoacidosis at onset. In conclusion, the result of this study in combination with the previous reports of other ethnic populations showed that CTLA-4 +49 A/G polymorphism confers genetic susceptibility to type 1 diabetes, particularly in younger individuals.
Diabetes Res Clin Pract 2005 May
PMID:CTLA-4 +49 A/G polymorphism is associated with predisposition to type 1 diabetes in Iranians. 1586 Feb 38

Autoimmune diabetes is a complex, multifactorial disease caused by the interaction of genetic and environmental factors. This autoimmune diabetes is commonly manifested in childhood and adolescence with a fast onset (type 1 diabetes, IDDM) and it can occur in adult patients with a slow onset with delayed insulin requirement, (latent autoimmune diabetes in adults, LADA ). Autoimmune diabetes has strong class II HLA association mainly with DQB gene which constitutes the first susceptibility locus. However, association with the 5'INS- VNTR and CTLA-4 genes has been established. In this study, we analysed the polimorphic allele frequencies of DQB HLA gene in 63 LADA patients, 70 IDDM and 79 control subjects. The HLA DQB1 alleles typing was detected through Olerup SSP DQ kit using sequence specific primers. We observed a positive association of *0201-*0302 and *0201-*0201 genotypes in both types of diabetic patients compared to the control group (p < 0.05). Moreover, *0201-*0302 genotype was higher in IDDM than in LADA (p < 0.05). On the other hand, the *0602 protective allele analysis showed a high prevalence in the normal group compared to the diabetic population. In Argentina, the most frequent allele of susceptibility in LADA and IDDM patients was the *0201. Summing up, the finding of an increase in the *0201 allele, both in allelic and genotypic frequencies, allows the characterisation of our population of patients, LADA and IDDM, unlike other populations, in which the most frequent allele is *0302.
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PMID:[HLA DQB1 genotyping in latent autoimmune diabetes of adults (LADA)]. 1604 35


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