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

Type 1 diabetes results from the autoimmune destruction of pancreatic beta-cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. The recruitment of mononuclear cells within the islets of Langerhans is a critical step in the pathogenesis of the disease. Because chemokines are cytokines that promote migration of mononuclear cells, we hypothesized that polymorphisms in chemokine receptor or chemokine genes, CCR5 and SDF1, may be involved in susceptibility to or clinical expression of type 1 diabetes. The frequencies of the CCR5-delta32 and SDF1-3'A (801G-->A in the 3' untranslated region) variants were similar in 208 unrelated Caucasian patients with type 1 diabetes and in 120 Caucasian control subjects. They were not modified after stratification for the predisposing HLA-DR3 and -DR4 haplotypes. However, the SDF1-3'A variant was strongly associated with early onset (< 15 years) of the disease (odds ratio 2.6, P = 0.0019). On average, the presence of the SDF1-3'A allele was associated with a 5-year reduction in the age at onset of diabetes (P = 0.0067). Our results suggest that stromal cell-derived factor-1 may be implicated in the aggressiveness of the autoimmune process leading to type 1 diabetes. These preliminary data require replication in other populations.
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PMID:A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes. 1133 29

We investigated the expression of Th1- and Th2-associated chemokine receptors on peripheral blood lymphocytes at diagnosis and in the first phase of type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) of 25 patients with newly diagnosed type 1 diabetes, 10 patients with longstanding type 1 diabetes, and 35 healthy control subjects were examined for expression of the chemokine receptors CXCR4 (naive T-cells), CCR5 and CXCR3 (Th1 associated), and CCR3 and CCR4 (Th2 associated) on CD3+ lymphocytes. Furthermore, we analyzed chemokine serum levels (monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and RANTES [regulated on activation, normal T-cell expressed and secreted]) and phytohemagglutinin (PHA)-stimulated cytokine secretion of Th1- (gamma-interferon [IFN-gamma] and tumor necrosis factor-alpha [TNF-alpha]) and Th2 (interleukin [IL]-4 and -10)-associated cytokines by PBMC. The patients with newly diagnosed type 1 diabetes were followed for these parameters at 6-12 months after diagnosis. The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects). This reduction correlated with reduced IFN-gamma and TNF-alpha production of PBMCs after PHA stimulation and reversed 6-12 months after diagnosis to normal levels. CCR4 cells were reduced in both newly diagnosed and longstanding type 1 diabetic patients, which correlated to reduced PHA-stimulated IL-4 production. MIP-1alpha and MIP-1beta levels were considerably elevated in a subgroup of patients with newly diagnosed diabetes. We assume that Th1-associated peripheral T-cells are reduced in a narrow time window at the time of diagnosis of diabetes, possibly due to extravasation in the inflamed pancreas. Thus, chemokine receptor expression of peripheral blood lymphocytes may be a useful surrogate marker for the immune activity of type 1 diabetes (e.g., in intervention trials).
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PMID:Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. 1214 60

Infiltration of pancreatic tissue by autoreactive T-cells involves secretion of multiple cytokines and chemokine receptor expression. Genetically determined variation in cell surface expression of the chemokine receptor CCR5 may result in differences in inflammatory cell migration in response to relevant chemokines. Adolescents with type 1 diabetes (T1D) from Australia and New Zealand were genotyped for CCR5-delta32 (n = 626). The allele frequency was compared with that of 253 non-diabetic Australian adolescents and with that of 92 adults with systemic lupus erythematosus. A reduced allele frequency was seen in T1D compared with controls (0.092 vs. 0.123, p = 0.05). This difference was not seen for the cohort of patients with SLE (freq = 0.114). A reduction in the number of CCR5-delta32/delta32 homozygotes, who lack CCR5, in the T1D cohort was also seen and while not statistically significant (2 observed compared to 5.25 expected; p = 0.12) is interesting. These results suggest a partial protection from T1D for CCR5-delta32 homozygous individuals is possible and that CCR5 has a potential role in the pathogenesis of T1D.
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PMID:CCR5 genotyping in an Australian and New Zealand type 1 diabetes cohort. 1268 47

It is well known that type 1 diabetes mellitus (T1DM) is a complex genetic disease resulting from the autoimmune destruction of pancreatic beta cells. Several genes have been associated with susceptibility and/or protection for T1DM, but the disease risk is mostly influenced by genes located in the class II region of the major histocompatibility complex. The attraction of leukocytes to tissues is essential for inflammation and the beginning of autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytolines. Some studies have shown that CCR2-64I and CCR5-Delta 32 might be important for protection of susceptibility to some immunologically-mediated disorders. In the present study, we demonstrate the lack of association between CCR2-64I and CCR5-Delta 32 gene polymorphism and TIDM and we describe a new method for a simple and more precise genotyping of the CCR2 gene.
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PMID:Lack of association of CCR2-64I and CCR5-Delta 32 with type 1 diabetes and latent autoimmune diabetes in adults. 1277 Jul 95

Macrophages play a critical role in the pathogenesis of Kilham rat virus (KRV)-induced autoimmune diabetes in diabetes-resistant BioBreeding (DR-BB) rats. This investigation was initiated to determine the role of macrophage-derived soluble mediators, particularly NO, in the pathogenesis of KRV-induced diabetes in DR-BB rats. We found that the expression of inducible NO synthase (iNOS), an enzyme responsible for NO production, was significantly increased during the early phase of KRV infection. Inhibition of iNOS by aminoguanidine (AG) treatment resulted in the prevention of diabetes in KRV-infected animals. The expression of IL-1beta, TNF-alpha, and IL-12 was significantly decreased in the spleen of AG-treated, KRV-infected DR-BB rats compared with PBS-treated, KRV-infected control rats. Subsequent experiments revealed that AG treatment exerted its preventive effect in KRV-infected rats by maintaining the finely tuned immune balance normally disrupted by KRV, evidenced by a significant decrease in the expression of IFN-gamma, but not IL-4, and a decrease in Th1-type chemokine receptors CCR5, CXCR3, and CXCR4. We also found that iNOS inhibition by AG decreased the KRV-induced expression of MHC class II molecules and IL-2R alpha-chain, resulting in the suppression of T cell activation, evidenced by the decreased cytolytic activity of CD8(+) T cells. We conclude that NO plays a critical immunoregulatory role by up-regulating macrophage-derived proinflammatory cytokines, up-regulating the Th1 immune response, and activating T cells, leading to type 1 diabetes after KRV infection, whereas suppression of NO production by AG treatment prevents KRV-induced autoimmune diabetes in DR-BB rats.
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PMID:Immunoregulatory role of nitric oxide in Kilham rat virus-induced autoimmune diabetes in DR-BB rats. 1524 Jul 27

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.
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PMID:Regulatory polymorphisms underlying complex disease traits. 1559 5

Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2-3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3-4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.
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PMID:Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect. 1624 62

The influx of autoreactive lymphocytes into the site of an autoimmune inflammation is mediated by certain chemokines. Autoimmune insulitis in type 1 diabetes is viewed as the result of destructive Th-1-cells and their corresponding antigen-presenting cells infiltrating the pancreatic islets. Blocking the chemokine receptors that mediate a Th-1-reaction has been shown to reduce autoimmunity in other experimental autoimmune disorders. We used the NOD mouse model to investigate the potency of anti-CCR2 and anti-CCR5 antibodies to inhibit the influx of Th-1-cells into the pancreatic islets, thus preventing diabetes onset. Eleven-week-old female NOD mice were treated with 500 microg of a monoclonal anti-CCR5 or anti-CCR2 or an isotype control antibody every third day over two weeks. We did not observe any preventive effect in either treatment group, but accelerated diabetes onset in the anti-CCR5 treated group. The number of autoantigen-specific Th-1-cells detected in the two treated groups was not reduced, but increased in the anti-CCR5 group. Redundancy within the chemokine system may account for this lack of prevention, or the intervention may have come too late in the disease process. Furthermore, blocking Th-1 chemokine receptors in the late autoimmune process may also inhibit regulatory T-cells, thus accelerating rather than preventing the disease.
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PMID:Transient chemokine receptor blockade does not prevent, but may accelerate type 1 diabetes in prediabetic NOD mice. 1667 7

The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.
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PMID:CCR5 in T cell-mediated liver diseases: what's going on? 1688 60

An important limitation in T cell studies of human autoimmune (type 1) diabetes is lack of direct access to cells infiltrating the pancreas. We hypothesized that cells recently released from the pancreas into the blood might express a characteristic combination of markers of activation. We therefore examined the recently activated circulating T cell population [CD3+, human leucocyte antigen D-related (HLA-DR+)] using cytokine production and 10 additional subset markers [CD69, CD25, CD122, CD30, CD44v6, CD57, CD71, CCR3 (CD193), CCR5 (CD195) or CXCR3 (CD183)], comparing newly diagnosed adult (ND) (age 18-40 years) patients (n=19) to patients with diabetes for >10 years [long-standing (LS), n=19] and HLA-matched controls (C, n=16). CD3+ DR+ cells were enriched by two-step immunomagnetic separation. No differences in basal or stimulated production of interleukin (IL)-4, IL-10, IL-13 or interferon (IFN)-gamma by CD3+ DR+ enriched cells were observed between the different groups of subjects. However, among the CD3+ DR+ population, significant expansions appeared to be present in the very small CD30+, CD69+ and CD122+ subpopulations. A confirmatory study was then performed using new subjects (ND=26, LS=15), three-colour flow cytometry, unseparated cells and three additional subset markers (CD38, CD134, CD4/CD25). This confirmed the expansion of the CD3+ DR+ CD30+ subpopulation in ND subjects. We conclude that a relative expansion in the T cell subpopulation with the activated phenotype CD3+ DR+ CD30+ is seen in the peripheral blood of subjects with newly diagnosed type 1 diabetes. This subpopulation represents less than 0 x 7% of circulating T cells and may provide a rich source of disease-specific T cells that can be isolated from blood.
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PMID:Activated T cell subsets in human type 1 diabetes: evidence for expansion of the DR+ CD30+ subpopulation in new-onset disease. 1730 96


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