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)

Sequence variability in MHC class II molecules plays a major role in genetically determined susceptibility to insulin-dependent diabetes mellitus (IDDM). It is not yet clear whether MHC class II polymorphism allows selective binding of diabetogenic peptides or regulates some key intracellular events associated with class II-restricted Ag presentation. In this study, we have employed gene transfer techniques to analyze the intracellular events that control peptide acquisition by the unique class II molecule expressed by nonobese diabetic mice (I-Ag7). This structurally unique class II molecule fails to demonstrate stable binding to antigenic peptides and fails to undergo the conformational change associated with stable peptide binding to class II molecules. The experiments reported here demonstrate that I-Ag7 can productively associate with two protein cofactors important in class II-restricted Ag presentation, invariant chain (Ii) and DM. DM participates in the removal of the Ii-derived class II-associated Ii chain peptide and the p12 degradation product from the I-Ag7 molecule. In addition, I-Ag7 undergoes a conformational change when DM is expressed within the APC. Finally, DM can mediate accumulation of peptide/class II complexes on the surface of APCs. Collectively, our experiments indicate that the failure of the I-Ag7 molecule to stably bind peptide cannot be attributed to a failure to interact with the DM or Ii glycoproteins.
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PMID:The inability of the nonobese diabetic class II molecule to form stable peptide complexes does not reflect a failure to interact productively with DM. 974 59

Type 1 diabetes, insulin-dependent diabetes mellitus (IDDM) results from autoimmune T cell-dependent destruction of insulin producing beta-cells in the pancreatic islets of Langerhans. T cells from recent-onset IDDM patients specifically proliferate to beta cell membrane Ag enriched fractions, containing the mitochondrial 38 kD islet antigen (Imogen). Recently, we identified a peptide epitope (Imogen p55-70) that is recognized by a 38 kD-specific, Th1 clone from an IDDM patient. In animal models of autoimmune diseases, altered self peptide ligands (APL) have been used effectively in peptide-based immune prevention or therapy. No such APL, however, have been reported so far that can modulate autoreactive T-cell responses in IDDM. Here, we have designed APL of p55-70. These APL efficiently downregulate in vitro activation of the 38 kD-specific Th1 clone induced by either p55-70 or by native beta cell autoantigens. Self peptide reactive T-cell proliferation could be inhibited only when APL and the self peptide were present on the same APC. Unrelated peptides with equal HLA-DR binding affinity were not effective, excluding simple MHC competition as the mechanism for T-cell modulation. APL triggered upregulation of CD69 and CD25 expression, but not T-cell proliferation, TCR down-modulation or T-cell anergy. Thus, the p55-70 APL inhibit beta cell autoantigen-induced activation of an Imogen-reactive T-cell clone derived from an IDDM patient, by acting as partial TCR agonists that inhibit TCR down-modulation.
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PMID:Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes. 977 13

Nonobese diabetic (NOD) mice genetically deficient in B lymphocytes (NODJg mu(null)) are resistant to T cell-mediated autoimmune insulin-dependent diabetes mellitus (IDDM). Ig infusions from diabetic NOD donors did not abrogate IDDM resistance in NODJg mu(null) mice. However, T cell responses to the candidate pancreatic beta cell autoantigen glutamic acid decarboxylase (GAD), but not the control Ag keyhole limpet hemocyanin, were eliminated in NODJg mu(null) mice. To initially test whether they contribute to IDDM as APC, NOD B lymphocytes were transferred into NODJg mu(null) recipients. B lymphocytes transferred into unmanipulated NODJg mu(null) recipients were rejected by MHC class I-restricted T cells. Stable T and B lymphocyte repopulation was achieved in irradiated NODJg mu(null) mice reconstituted with syngeneic bone marrow admixed with NOD B lymphocytes. IDDM susceptibility was restored in NODJg mu(null) mice reconstituted with syngeneic marrow plus B lymphocytes, but not with syngeneic marrow only. T cell responses to GAD were restored only in NODJg mu(null) mice reconstituted with syngeneic marrow plus B lymphocytes. Hence, B lymphocytes appear to contribute to IDDM in NOD mice as APC with a preferential ability to present certain beta cell Ags such as GAD to autoreactive T cells.
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PMID:B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. 978 Jan 57

Endothelial cells form a multifunctional cell lining that covers all of the inner surface of blood vessels and regulates several important physiological and pathological reactions. These include inflammation/immune reaction, blood vessel tonus, hemostasis/thrombosis, angiogenesis and so on. Thus, abnormalities of endothelial function may play crucial roles in the development of angitis syndrome, thrombosis/embolism, bleeding disseminated intravascular coagulation (DIC), and neovascularization in some pathological states including tumor growth and diabetic retinopathy. Research on endothelial cells now forms a new frontier termed 'Endotheliology'. Recent advances of the functional and structural aspects of endothelial cells are reviewed here mainly from the viewpoint of endothelial regulation of coagulation and the fibrinolytic system. First we show that the natural endothelial membrane protein thrombomodulin is localized not only on apical endothelial surface but also in caveolae. Since it has been reported that such factors involved in coagulation/fibrinolysis as tissue factor, tissue factor pathway inhibitor (TFPI), thrombin receptor and urokinase receptor are also localized in the caveolae, this membrane structure may act as a special component to regulate coagulation/fibrinolysis on the endothelial membrane surface. Next we demonstrate the signaling pathway of the thrombin receptor. Thrombin cleaves the N-terminus of the receptor as a substrate, exposing a new N-terminus. This newly exposed N-terminus acts as a ligand and activates platelets, endothelial cells and vascular smooth-muscle cells. We have identified that the signal from the thrombin receptor activates NF-kappaB through the activation of protein C kinase, tyrosine kinase and MAP kinase, and results in proliferation of the cells. We have also shown that the receptor is over-expressed on platelets from diabetes patients.
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PMID:Biology of endothelium. 981 71

A 35 year old woman presented with acute myocardial infarction without any of the usual risk factors: she had never smoked; she had normal blood pressure; she did not have diabetes; plasma concentrations of total cholesterol and high and low density lipoprotein cholesterol, fibrinogen, homocysteine, and Lp(a) lipoprotein were normal. She was not taking oral contraceptives or any other medication. Coronary angiography showed occlusion of the left anterior descending coronary artery but no evidence of arteriosclerosis. Medical history disclosed a previous leg vein thrombosis with pulmonary embolism. Coagulation analysis revealed protein C deficiency. The recognition of protein C deficiency as a risk factor for myocardial infarction is important as anticoagulation prevents further thrombotic events, whereas inhibitors of platelet aggregation are ineffective.
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PMID:Recurring myocardial infarction in a 35 year old woman. 1002 61

Women with diabetes mellitus have an increased risk of developing coronary heart disease which may be related at least partially to unfavourable changes in haemostasis. The effect of oestrogen replacement therapy on haemostasis has not been studied systematically in women with non-insulin-dependent diabetes mellitus (NIDDM) and therefore this study was performed for that purpose. Twenty-five postmenopausal women with NIDDM were treated with 2 mg of 17-beta-oestradiol orally for 3 months in a double-blind, crossover, placebo-controlled trial. During the last 16 days of active treatment, 1 mg of norethisterone acetate was added for 10 days for endometrial protection. Blood samples were taken at baseline and after 68 days of active or placebo treatment. Treatment with oestradiol was followed by a marked decrease in the activity of plasminogen activator inhibitor, compared with placebo. The activity of tissue plasminogen activator increased significantly. Levels of antithrombin decreased during treatment with oestradiol, whereas no changes were seen in levels of fibrinogen, von Willebrand factor, prothrombin fragment 1+2, protein S, protein C or resistance to activated protein C. In conclusion, oestrogen replacement therapy in postmenopausal women with NIDDM improved the fibrinolytic activity, while only clinically insignificant alterations in the clotting system were seen. These changes in haemostasis may have a favourable impact on the risk for coronary heart disease in diabetic women.
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PMID:The effects of oestrogen replacement therapy on haemostatic variables in postmenopausal women with non-insulin-dependent diabetes mellitus. 1019 56

Insulin Dependent Diabetes Mellitus (IDDM type I) is the result of autoimmune destruction of insulin producing pancreatic beta-cells by the cellular immune system, specifically, autoreactive T cells. Disease progression is evident by multiple autoantibodies responding to self-antigens in a cascade mechanism, wherein the first self-antigen induces the activation of the immune system, leading to the destruction of beta-cells and consequently, exposure of other antigens. Glutamic Acid Decarboxylase (GAD) is recognized in the literature as a primary autoantigen involved in the cascade. We questioned the immunological involvement of this autoantigen in the overall progression of the disease, specifically if antigen recognition by the cellular immune system (T cells) is necessary for organ specific autoimmunity and cellular toxicity. We tested this hypothesis by isolating, purifying and injecting monoclonal antibodies against GAD (anti-GAD Ab; 0.1 mg or 0.3 mg) into non-obese diabetic (NOD) mice on a weekly basis. We suggest that the anti-GAD Ab will bind to the GAD antigen, or perhaps bind to the epitope presented in association with APC-MHC and prevent T cell recognition, thereby delaying disease onset. Our results demonstrate a delay in the onset of diabetes and a decrease in the severity of insulitis in our test animals, when compared to controls. The mechanism of action of the anti-GAD Ab may be associated with a passive protection mechanism, as evidenced by the fact that splenocytes transferred from anti-GAD Ab treated mice did not prevent or delay diabetes in syngeneic irradiated NOD mice. The mechanism of diabetes prevention by administration of anti-GAD antibody could be associated with an interference in recognition of GAD by T cells, and continuing research will be perform to investigate this hypothesis.
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PMID:Anti-GAD monoclonal antibody delays the onset of diabetes mellitus in NOD mice. 1045 Sep 31

Diabetes mellitus is associated with vascular and neurological complications. We have investigated the presence of antibodies to phospholipids and to phospholipid binding plasma proteins in blood samples collected from 68 clinically and biochemically characterized type I and type II diabetic patients and from 252 healthy blood donor controls. Each sample was analysed for antibodies to three phospholipids (cardiolipin, phosphatidylserine and phosphatidylethanolamine), the antibody isotypes (IgA, IgG and IgM), and whether antibody activity was plasma protein-dependent. Patients were considered to have anti-phospholipid antibodies when one or more of these 18 tests was found above predetermined control values. The results of these experiments revealed an increased incidence of anti-phospholipid antibodies in diabetic patients compared with control subjects. The incidence of IgA isotype to phosphatidylethanolamine was higher than the incidence of other isotypes to other phospholipids, and their reactivities were independent of phospholipid-associated proteins. In addition, these antibody findings were studied for associations with prothrombin degradation products, activated factor VII and activated protein C, and with the incidence of diabetic complications. The anti-phosphatidylethanolamine antibody association with proliferative retinopathy was significant.
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PMID:Qualitative and quantitative studies of autoantibodies to phospholipids in diabetes mellitus. 1054 Jan 56

Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. To understand the mechanism, knowledge of the molecular nature of the specific TCR/peptide/class II interactions involved in the disease process is required. To this end, we have introduced the diabetes-associated human class II HLA-DQ8 allele (DQA1*0301/DQB1*0302) as a transgene into mice and analyzed T cell responses restricted by this molecule to an important Ag in human diabetes, human glutamic acid decarboxylase 65. Hybridomas were used to determine the particular peptides from this Ag presented by HLA-DQ8 to T cells and to map the core minimal epitopes required for T cell stimulation. Analysis of these core epitopes reveals a motif and relevant features for peptides that are immunogenic to T cells when presented by HLA-DQ8. The major immunogenic epitopes of glutamic acid decarboxylase 65 do not contain a negatively charged residue that binds in the P9 pocket of the HLA-DQ8 molecule. PBMC from HLA-DQ8+ diabetic and nondiabetic individuals respond to these peptides, confirming that the mouse model is a useful tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.
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PMID:Determination of glutamic acid decarboxylase 65 peptides presented by the type I diabetes-associated HLA-DQ8 class II molecule identifies an immunogenic peptide motif. 1057 Mar 21

Systemic gene therapy involves the transfer into the body of a gene whose protein product reaches the blood and has a beneficial effect on a patient. Both retroviral and adenovirus-associated viral vectors have resulted in stable but only moderate systemic levels of blood proteins. Adenoviral vectors have resulted in very high levels of expression that diminishes over days or weeks. Hepatic gene therapy has achieved levels of the anticoagulant protein C in blood that would protect against spontaneous thromboses in homozygous protein-C deficiency, and levels of tissue plasminogen activator that can lyse pulmonary emboli. Hypercholesterolemia has been ameliorated transiently by transfer of the low-density lipoprotein receptor gene into the livers of animals with familial hypercholesterolemia or by promoting lipid transfer via a variety of alternative mechanisms. Hypertension has been reduced by the transfer of genes for kallikrein or atrial natriuretic peptide into the liver, or by expressing antisense for the angiotensin II type I receptor after intravenous injection in neonates. Finally, fasting but not fed hyperglycemia has been ameliorated in animal models of diabetes by transfer of an insulin gene into the liver or by expression of insulin from implanted fibroblasts. Gene therapy has the potential to treat these cardiovascular diseases. However, improvements in levels of long-term expression and the ability to regulate expression in response to physiologic changes will be required before this approach will be implemented for most of these disorders in humans.
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PMID:Systemic gene therapy for cardiovascular disease. 1063 21


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