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)

Thrombomodulin, an endothelial membrane glycoprotein, is an essential part of the protein C anti-coagulant pathway. It may also have a role in the regulation of fibrinolysis. We carried out a cross-sectional study to assess the association of soluble thrombomodulin (sTM) with peripheral artery disease (PAD) in a stratified random sample (n=863) of otherwise healthy black and white participants of the Atherosclerosis Risk in Communities (ARIC) Study. PAD was more common in black than in white participants and associated with classical risk factors in an expected manner; positively with age, smoking, hypertension, diabetes (P=0.05), and LDL-cholesterol, and inversely with HDL-cholesterol. Significant positive associations were observed also with fibrinogen and white blood cell count. Overall, the sTM concentration was not a significant predictor of PAD. The association was, however, modified by the level of factor VIII:C in whites (P=0.002 for the interaction), but not in blacks. Protein C was inversely associated with PAD prevalence (odds ratio 0.33, 95% CI 0.18--0.61, P=0.0004). sTM was inversely associated with plasminogen, but no associations with t-PA, PAI-1, or D-dimer were seen. In conclusion, the present results provide some additional evidence on the role of thrombomodulin-protein C pathway in atherosclerotic disease and support our earlier observation on interaction between sTM and factor VIII:C.
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PMID:Cross-sectional association of soluble thrombomodulin with mild peripheral artery disease; the ARIC study. Atherosclerosis Risk in Communities. 1147 30

Transgenic restoration of normally absent H2-E MHC class II molecules on APC dominantly inhibits T cell-mediated autoimmune diabetes (IDDM) in nonobese diabetic (NOD) mice. We analyzed the minimal requirements for transgenic H2-E expression on APC subtypes (B lymphocytes vs macrophages/dendritic cells (DC)) to inhibit IDDM. This issue was addressed through the use of NOD stocks transgenically expressing high levels of H2-E and/or made genetically deficient in B lymphocytes in a series of genetic intercross and bone marrow/lymphocyte chimera experiments. Standard (H2-E(null)) NOD B lymphocytes exert a pathogenic function(s) necessary for IDDM. However, IDDM was inhibited in mixed chimeras where H2-E was solely expressed on all B lymphocytes. Interestingly, this resistance was abrogated when even a minority of standard NOD H2-E(null) B lymphocytes were also present. In contrast, in NOD chimeras where H2-E expression was solely limited to approximately half the macrophages/DC, an active immunoregulatory process was induced that inhibited IDDM. Introduction of a disrupted IL-4 gene into the NOD-H2-E transgenic stock demonstrated that induction of this Th2 cytokine does not represent the IDDM protective immunoregulatory process mediated by H2-E expression. In conclusion, high numbers of multiple subtypes of APC must express H2-E MHC class II molecules to additively inhibit IDDM in NOD mice. This raises a high threshold for success in future intervention protocols designed to inhibit IDDM by introduction of putatively protective MHC molecules into hemopoietic precursors of APC.
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PMID:Inhibition of autoimmune diabetes in nonobese diabetic mice by transgenic restoration of H2-E MHC class II expression: additive, but unequal, involvement of multiple APC subtypes. 1149 31

Thrombomodulin is a glycoprotein that can bind to thrombin and activate protein C, thus mitigating the effects of cytokines produced by inflammatory and immunological processes. The molecule exerts a protective function on endothelial cells. Thrombomodulin is cleaved to its soluble form by neutrophil elastase and by other substances produced during acute and chronic inflammatory responses, immunologic reactions and complement activation. ELISA technique yields normal serum levels of 3.1 +/- 1.3 ng/ml; in males these levels are higher; TM levels also rise during menopause. Other circumstances associated with an increase of serum TM levels are smoking, disseminated intravascular coagulation (DIC), cardiac surgery, atherosclerosis, ARDS, liver cirrhosis, diabetes mellitus, cerebral and myocardial infarction, and multiple sclerosis. Serum levels of TM represent an useful prognostic index, because they are associated with an increase in mortality rate, or however a progression of the underlying pathological condition.
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PMID:Clinical importance of thrombomodulin serum levels. 1155 26

Despite the impressive protection of B cell-deficient (muMT(-/-)) nonobese diabetic (NOD) mice from spontaneous diabetes, existence of mild pancreatic islet inflammation in these mice indicates that initial autoimmune targeting of beta cells has occurred. Furthermore, muMT(-/-) NOD mice are shown to harbor a latent repertoire of diabetogenic T cells, as evidenced by their susceptibility to cyclophosphamide-induced diabetes. The quiescence of this pool of islet-reactive T cells may be a consequence of impaired activation of T lymphocytes in B cell-deficient NOD mice. In this regard, in vitro anti-CD3-mediated stimulation demonstrates impaired activation of lymph node CD4 T cells in muMT(-/-) NOD mice as compared with that of wild-type counterparts, a deficiency that is correlated with an exaggerated CD4 T cell:APC ratio in lymph nodes of muMT(-/-) NOD mice. This feature points to an insufficient availability of APC costimulation on a per T cell basis, resulting in impaired CD4 T cell activation in lymph nodes of muMT(-/-) NOD mice. In accordance with these findings, an islet-reactive CD4 T cell clonotype undergoes suboptimal activation in pancreatic lymph nodes of muMT(-/-) NOD recipients. Overall, the present study indicates that B cells in the pancreatic lymph node microenvironment are critical in overcoming a checkpoint involving the provision of optimal costimulation to islet-reactive NOD CD4 T cells.
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PMID:Impaired activation of islet-reactive CD4 T cells in pancreatic lymph nodes of B cell-deficient nonobese diabetic mice. 1159 59

Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR Vbeta3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most Vbeta3(+) immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed that a high frequency of NOD Vbeta3(+) T cells that escape deletion are activated in vivo and that this phenotype is linked to the Mtv-3 locus. One potential mechanism of SAg presentation to peripheral T cells is by activated B cells. Consistent with this idea, we found that NOD mice harbor a significantly higher frequency of activated B cells than nondiabetes-prone strains. These activated NOD B cells expressed cell surface molecules consistent with APC function. At the molecular level, the IgH repertoire of activated B cells in NOD mice was equivalent to resting B cells, suggesting a polyclonal response in vivo. Genetic analysis of the activated B cell phenotype showed linkage to Idd1, the NOD MHC haplotype (H-2(g7)). Finally, Vbeta3(+) thymocyte deletion and peripheral T cell activation did not require B cells, suggesting that other APC populations are sufficient to generate both Mtv-3-linked phenotypes. These data provide insight into the genetic regulation of NOD autoreactive lymphocyte activation that may contribute to failure of peripheral tolerance and the pathogenesis of type I diabetes.
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PMID:Genetic control of T and B lymphocyte activation in nonobese diabetic mice. 1173 40

We report a mouse model for the spontaneous development of autoimmune diabetes: the 3A9 T cell receptor (TCR) transgenic mouse, which contains T cells that recognize the 52 - 61 family of hen egg-white lysozyme (HEL) peptides in the context of MHC class II I-A(k) molecules, was bred to the ILK3 mouse, that expresses HEL protein via the rat insulin promoter (RIP). Despite partial tolerance of 3A9 T cells in ILK3 mice, spontaneous diabetes developed in 64 % of 3A9xILK3 mice by 20 weeks of age. We provide evidence that APC from peri-pancreatic nodes have a large content of peptide-MHC complex and stimulate 3A9 T cells. We also report that cross presentation of HEL from beta cells to APC is 26-fold more efficient than presentation of soluble HEL. We previously reported on a biochemical margin of safety, based on the observation that activation of naive 3A9 T cells required 100-fold more peptide-MHC complexes than required for deletion of 3A9 thymocytes. We speculate that the high local density of autologous peptide-MHC complexes can be a determining factor that leads to the activation of autoreactive CD4 T cells and, consequently, to the development of autoimmunity.
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PMID:The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: studies in HEL transgenic mice. 1174 64

We have recently demonstrated that dendritic cells (DC) prepared from nonobese diabetic (NOD) mice, a spontaneous model for insulin-dependent diabetes mellitus, exhibit elevated levels of NF-kappaB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-kappaB activation on the APC function of bone marrow-derived DC prepared from NOD vs BALB/c and nonobese diabetes-resistant mice. NOD DC pulsed with either peptide or virus were found to be more efficient than BALB/c DC at stimulating in vitro naive Ag-specific CD8+ T cells. The T cell stimulatory capacity of NOD DC was suppressed by gene transfer of a modified form of IkappaBalpha, indicating a direct role for NF-kappaB in this process. Furthermore, neutralization of IL-12(p70) to block autocrine-mediated activation of DC also significantly reduced the capacity of NOD DC to stimulate T cells. Despite a reduction in low molecular mass polypeptide-2 expression relative to BALB/c DC, no effect on proteasome-dependent events associated with the NF-kappaB signaling pathway or Ag processing was detected in NOD DC. Finally, DC from nonobese diabetes-resistant mice, a strain genotypically similar to NOD yet disease resistant, resembled BALB/c and not NOD DC in terms of the level of NF-kappaB activation, secretion of IL-12(p70) and TNF-alpha, and the capacity to stimulate T cells. Therefore, elevated NF-kappaB activation and enhanced APC function are specific for the NOD genotype and correlate with the progression of insulin-dependent diabetes mellitus. These results also provide further evidence indicating a key role for NF-kappaB in regulating the APC function of DC.
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PMID:Elevated NF-kappaB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function. 1175 62

To evaluate the association between haemostatic parameters and increased risk of myocardial infarction (MI) at a young age, we measured fibrinogen, factor VII, antithrombin III, protein C, protein S, tissue factor (TF), free form tissue factor pathway inhibitor (TFPI), plasminogen, alpha2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor-I (PAI-I), and lipoprotein (a) in 140 young men with MI before age 45 and 150 age-matched healthy men. TF, TF/TFPI ratio, PAI-I, PAI-I/tPA ratio, plasminogen, and lipoprotein (a) in young MI patients were all significantly higher than controls, while TFPI, antithrombin II, and tPA were significantly lower (P <0.001 of each). Significant determinants of MI risk were PAI-I/tPA ratio (R2 = 0.300, P <0.001), TF/TFPI ratio (R2 = 0.049, P <0.001), antithrombin III (R2 = 0.034, P <0.001), hyperlipidaemia (R2 = 0.019, P = 0.004), diabetes (R2 = 0.014, P = 0.015), lipoprotein (a) (R2 = 0.012, P = 0.023), alpha2-antiplasmin (R2= 0.014, P = 0.012), and protein C (R2= 0.012, P = 0.018). We conclude that the imbalances of PAI-I/tPA and TF/TFPI are significantly associated with MI at a young age, perhaps mediated via impaired fibrinolytic activity.
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PMID:Imbalance of plasminogen activator inhibitor-I/ tissue plasminogen activator and tissue factor/tissue factor pathway inhibitor in young Japanese men with myocardial infarction. 1181 7

Recently, a newly identified human HERV-K18 like endogenous retrovirus (IDDMK(1,2)22) has been associated to the etiology of type I diabetes (IDDM). Although the exact mechanism remains unclear, it was postulated that the 3' end ORF product of the env gene of IDDMK(1,2)22 would trigger a V beta 7-specific human T cell expansion leading to their infiltration in the pancreas of afflicted patients and to the autoimmune destruction of the insulin-producing beta cells. Since then, such superantigen (SAg)-like activity as well as the association between the IDDMK(1,2)22 virus and IDDM pathogenesis have been challenged. To further characterize functionally the putative IDDMK(1,2)22-encoded SAg, we have cloned from human DNA the identical 462bp ORF sequence originally described. The IDDMK(1,2)22 ORF fragment was transfected in the same human B cell line (Raji) originally used as APC to demonstrate the V beta 7 specificity. The immunostimulatory potential of IDDM ORF was tested on murine T cell hybridomas and compared to the well-characterized mouse mammary tumor virus Mtv7 SAg transfected in the same conditions. A panel of 16 T cell hybridomas encompassing 14 different V betas was analyzed. We have failed to detect IDDMK(1,2)22-induced IL-2 production from any of these hybridomas, even those bearing the murine V beta 1 mV beta 1, V beta 4 or V beta 10 TcR beta chains which are most closely related to the human V beta 7 (hV beta 7). Our results suggest that IDDMK(1,2)22 ORF is devoid of superantigenic activity as defined by classical criteria.
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PMID:Human endogenous retrovirus IDDMK(1,2)22 and mouse mammary tumor virus superantigens differ in their ability to stimulate murine T cell hybridomas. 1184 50

Thrombomodulin is an endothelial cell surface receptor for thrombin. It plays an important role in the regulation of blood coagulation by decreasing thrombin activity and activating protein C. This study examined the possible association between the thrombomodulin -33G/A polymorphism and acute myocardial infarction. We recruited 278 patients (mean age 57.5 years, 241 men) with documented myocardial infarction and 450 age- and sex-matched control subjects. Polymerase chain reaction and single-strand conformation polymorphism was used to define the thrombomodulin -33G/A polymorphism. The frequency of the thrombomodulin GA+AA genotype among patients with myocardial infarction was higher than that in control subjects (22.7% vs. 16.2%, odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0 to 2.2). The -33G/A polymorphism (GA+AA genotype) was significantly associated with myocardial infarction (OR 1.6, 95% CI 1.1 to 2.5) as was hypertension, diabetes mellitus and smoking. Among young myocardial infarction patients (age < or =45 years, n = 72), the frequency of -33G/A polymorphism was more significantly higher than that in control subjects (29.2% vs. 16.2%, OR 2.1, 95% CI 1.2 to 3.8). The -33G/A polymorphism (OR 2.3, 95% CI 1.3 to 4.1) and smoking (OR 4.5, 95% CI 2.5 to 7.9) were the only independent risk factors for young myocardial infarction. Furthermore, among patients who did not smoke, the polymorphism was associated with a nonsignificant increase in the risk of young myocardial infarction (OR 1.9, 95% CI 0.6 to 5.6); whereas, in the presence of smoking, the increase was statistically significant (OR 2.3, 95% CI 1.2 to 4.7). Smoking carriers of the thrombomodulin -33G/A polymorphism had a nearly 10-fold increased risk of young myocardial infarction (OR 9.8, 95% CI 4.3 to 22.4) when compared with nonsmoking non-carriers. We concluded that there was a significant association between the thrombomodulin -33G/A polymorphism and myocardial infarction in our population, especially in young patients. The clinical effect of this genetic factor was enhanced by smoking.
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PMID:Synergistic effect of thrombomodulin promoter -33G/A polymorphism and smoking on the onset of acute myocardial infarction. 1184 62


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