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)

In Type I diabetes the observation of a decreased release of interleukin-2 (IL-2) and soluble IL-2 receptors by means of stimulated lymphocytes in vitro indicates that a primary immunoregulatory defect may be involved. To confirm this hypothesis we investigated the T-cell activation trend, evaluating the surface expression of IL-2 receptor (CD25), transferrin (CD71), HLA class II (DR), and CD69 phenotypes after in vitro stimulation with phytohemagglutinin (PHA; 1 and 10 micrograms/ml) and concanavalin A (12.5 micrograms/ml) in six newly diagnosed Type I diabetics and six islet cell- and insulin autoantibody-positive first-degree relatives. As controls were studied six long-standing Type I diabetics and six healthy subjects. T-cell cultures from the four groups were performed on the same day and examined at 0, 24, 48, 96, 120, and 144 hr. Cytometric analysis was performed, keeping PBMC gating constant on the basis of physical parameters (scatter and volume). Using both PHA concentrations, a lower level of CD25, CD71, CD69, and DR antigen expression was found in newly diagnosed patients at all observation times with respect to control cultures (P < 0.001). Unexpectedly, pre-Type I diabetic subjects, after 1 microgram/ml of PHA, showed a significantly reduced expression of CD69 (P < 0.001) and CD71 (P < 0.001). The levels remained low, also with high PHA, at the different observation periods, while CD25 expression was found to be reduced in prediabetics only after 1 micrograms/ml of PHA (P < 0.001). The long-standing patients showed a T cell activation trend very close to the latter. Our data show that in Type I diabetes and in the early phases of the disease, the initial activation signal(s) appears to be affected, particularly with one or more subsequent events necessary to initiate the appearance of "activation antigens." This study suggests that the natural history of immunoregulation in pre-Type I and Type I diabetes is characterized by a primary defect in this system, which also persists in patients with long-standing disease.
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PMID:Study of T-cell activation in type I diabetic patients and pre-type I diabetic subjects by cytometric analysis: antigen expression defect in vitro. 809 71

The nonobese diabetic mouse is a relevant model for insulin-dependent diabetes mellitus which results from the destruction of pancreatic beta cells by mononuclear cells infiltrating the islets of Langerhans. Other organs such as salivary glands display inflammatory infiltration. Using immunohistochemical and flow cytometry analyses, we have studied the expression of diverse homing and adhesion molecules in salivary glands and the pancreas in nonobese diabetic mice. In salivary glands, ICAM-1 was expressed by endothelial and dendritic cells within the lymphocytic infiltration. HEV-like structures expressing PNAd were observed in the areas of lymphocytic infiltration whereas MAdCAM-1 was absent. Lymphocytes infiltrating salivary glands expressed LFA-1 and Pgp-1 although Mel-14 Ag was absent. In infiltrated islets, ICAM-1 was expressed by endothelial cells, dendritic cells, and mononuclear cells. We confirm the presence of HEV-like structures expressing MAdCAM-1 and PNAd in inflamed islets. With regard to peripheral lymphocytes, the proportion of CD4 and CD8 cells expressing Mel-14 was decreased in the infiltrated islets, whereas the expression of LFA-1, Pgp-1, and LPAM-1/2 was increased. B lymphocytes exhibited up-regulation of LPAM-1/2. Moreover, the proportion of CD4, CD8, and B lymphocytes expressing CD69 was increased in the pancreas. These results indicate that first, infiltration of islets of Langerhans results at least partly from modifications of adhesion molecule expression in the pancreas, which allow extravasation of mononuclear cells into the islets via at least three different pathways; and second, that activated cells are concentrated in the infiltrates as compared with peripheral lymphoid organs.
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PMID:Expression of homing and adhesion molecules in infiltrated islets of Langerhans and salivary glands of nonobese diabetic mice. 820 21

Direct multi-colour flow cytometric analysis was employed in patients with Graves' disease (n = 10) to determine the immunophenotype in peripheral blood lymphocytes (PBL) at the time of diagnosis without treatment (PBLw) and prior to operation (PBLp) and in thyroid-derived lymphocytes (TL). Additionally, the secretion of anti-thyroperoxidase antibodies (anti-TPO) was measured during culture of isolated peripheral or thyroid-derived B cells. Among TL from patients with high serum levels of anti-TPO (6/10) a significantly (p < 0.01) higher percentage of B cells were detected compared to PBLp (TL: 21.7 +/- 7.2%; PBLp: 13.2 +/- 4.5%). Enriched thyroid-derived B cells only from these patients also showed high spontaneous anti-TPO secretion during culture. The difference between peripheral and thyroid-derived natural killer (NK) cells was highly significant (p < 0.001; TL: 5.6 +/- 6.3%; PBLp: 13.6 +/- 5.5%). Two patients were found with a higher number of NK cells within TL. These patients were among those who had a low number of B cells infiltrating the thyroid gland. Regarding the expression of several other differentiation antigens, i.e. CD4 and CD8, gamma/delta TCR bearing T cells and CD45R0 on CD4+ T cells as a marker for memory cells, on TL no differences could be detected between patients with or without anti-TPO. In TL 31.5 +/- 7.7% of CD3- cells expressed the HLA-DR antigen (vs. 6.1 +/- 2.4% in PBLp; p < 0.001). Half of these cells simultaneously expressed the activation antigen CD69. Surprisingly, the number of CD3+ TL bearing the IL-2 receptor (CD25) and transferrin receptor (CD71) was not increased. Taken together, the proportional distribution of B and NK cells within the thyroid correlates with the anti-TPO secretion in vivo and in vitro, suggesting different immune response regulation processes of TL.
Exp Clin Endocrinol Diabetes 1996
PMID:Different immunophenotype and autoantibody production by peripheral blood and thyroid-derived lymphocytes in patients with Graves' disease. 875 May 71

To better define prevailing activation of circulating T cell subsets in insulin-dependent diabetes mellitus (IDDM) of recent onset (DM; n = 31; median age +/- SD, 28 +/- 6.9 yr) and of long standing (DML; n = 27; age, 33 +/- 10.4 yr; median duration of disease, 105 months), CD4+ and CD8+ T cells were analyzed to determine their naive and memory subsets as well as their expression of human leukocyte antigen (HLA)-DR, interleukin-2 receptor alpha-chain (CD25), and CD69 by three-color flow cytometry. Twenty-six healthy subjects (HS; age, 32.0 +/- 8.2 yr) served as controls. No deviation was seen in either IDDM group compared to HS in CD25 expression on CD4+ or CD8+ cells or in their CD45RA+ or CD45RA- subsets. HLA-DR expression, however, was increased (P < 0.05) in total CD8+ cells and CD45RA+ cells, with CD45RA- CD8+ cells joining the prevailing pattern only in DML. Among CD4+ cells, increased expression of HLA-DR molecules was restricted to total and CD45RA- cells in DML. CD69 expression did not differ between IDDM and HS, but differed between DML (CD4+, CD8+, and CD45RA- CD4+) and DM only. In conclusion, our data demonstrate that HLA-DR expression in IDDM is restricted to memory cells (CD45RA-) among CD4+ cells in DML and is more markedly confined to naive (CD45RA+) than to memory CD8+ cells, whereas the early activation antigen CD69 is more readily expressed in DML than in DM. The observed activation of circulating T cells suggests an ongoing immune process in IDDM both at clinical manifestation and after long duration.
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PMID:Increased CD69 and human leukocyte antigen-DR expression on T lymphocytes in insulin-dependent diabetes mellitus of long standing. 962 61

Resident macrophages have been suggested to participate in the initiation of beta cell damage during the development of autoimmune diabetes. The purpose of this study was to determine if the endogenous production and release of interleukin 1 (IL-1) in human islets of Langerhans by resident macrophages results in the inhibition of beta cell function. Treatment of human islets with a combination of tumor necrosis factor (TNF) + lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) stimulates inducible nitric oxide synthase (iNOS) expression, nitric oxide production, and inhibits glucose-stimulated insulin secretion. The IL-1 receptor antagonist protein (IRAP) prevents TNF + LPS + IFN-gamma-induced iNOS expression and nitrite production, and attenuates the inhibitory effects on glucose-stimulated insulin secretion by human islets. Inhibition of iNOS activity by aminoguanidine also attenuates TNF + LPS + IFN-gamma-induced inhibition of insulin secretion by human islets. These results indicate that the inhibitory effects of TNF + LPS + IFN-gamma are mediated by nitric oxide, produced by the actions of IL-1 released endogenously within human islets. Reverse transcriptase polymerase chain reaction was used to confirm that TNF + LPS + IFN-gamma stimulates the expression of both IL-1alpha and IL-1beta in human islets. Two forms of evidence indicate that resident macrophages are the human islet cellular source of IL-1: culture conditions that deplete islet lymphoid cells prevent TNF + LPS + IFN-gamma-induced iNOS expression, nitric oxide production, and IL-1 mRNA expression by human islets; and IL-1 and the macrophage surface marker CD69 colocalize in human islets treated with TNF + LPS + IFN-gamma as determined by immunohistochemical analysis. Lastly, nitric oxide production is not required for TNF + LPS + IFN-gamma-induced IL-1 release in human islets. However, cellular damage stimulates IL-1 release by islet macrophages. These findings support the hypothesis that activated islet macrophages may mediate beta cell damage during the development of insulin-dependent diabetes by releasing IL-1 in human islets followed by cytokine-induced iNOS expression by beta cells.
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PMID:IL-1 produced and released endogenously within human islets inhibits beta cell function. 969 Oct 88

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

Defective exocytosis could underlie clinical and metabolic abnormalities in Type 2 diabetes. Because many SNARE proteins appear to be common mediators of exocytosis, we examined phorbol myristate acetate-stimulated expression of CD11b and CD69 on polymorphonuclear leukocytes (PMN) from Type 2 diabetic subjects with hypertension and microalbuminuria (D-htma), hypertension only (D-ht) or uncomplicated (D-uc), and normal controls (NC) by flow cytometry. CD11b expression was rapid (half maximal by 7 min), initially on all PMN. CD69 expression took place subsequently but on PMN that did not express CD11b. The proportion of CD11b-positive PMN at 30 min was higher in all diabetic groups than in NC. Expression of CD11b was higher and CD69 lower in D-uc and D-htma but were similar in NC and D-ht. In Type 2 diabetes the transition from the CD11b-positive to CD69-positive state is impaired. The defect in the process of CD69 expression appeared most marked in diabetic subjects with hypertension and microalbuminuria.
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PMID:Dysregulation of PMN antigen expression in Type 2 diabetes may reflect a generalized defect of exocytosis: influence of hypertension and microalbuminuria. 1038 Sep 2

Microalbuminuria in Type I diabetes involves a cell membrane abnormality and is associated with a large increase in cardiovascular risk. The hypothesis that the membrane abnormality alters granule exocytosis in neutrophils, which could contribute to the increased incidence of cardiovascular disease, was investigated. PMA-stimulated expression of CD11b and CD69 on neutrophils from normal controls (NC), long-term uncomplicated Type I diabetic control patients (DC) and diabetic nephropathy patients (DN) was determined by fluorescence activated cell scanning. Neutrophils from DN were faster than neutrophils from either NC or DC to exocytose primary granules with CD69 following initial expression of the adhesion molecule CD11b. However, a larger proportion of neutrophils from DN failed to withdraw CD11b from the cell membrane after 90 min incubation. The protein kinase C (PKC) inhibitor, bisindolylmaleimide (BIM), showed that a larger proportion of neutrophils from DN, compared with DC or NC, exocytosed primary granules independent of PKC. The calpain inhibitor, E64d, showed that a larger proportion of neutrophils from both groups of diabetic patients, compared with NC, exocytosed primary granules independent of calpain. Cytoskeletal disruption with cytochalasin D had an effect on CD11b and CD69 exocytosis similar to that of BIM and E64d. The pathways controlling granule exocytosis in neutrophils from diabetic patients are abnormal. A change characteristic of DN causes rapid exocytosis of primary granules, and also causes the adhesion molecule CD11b to persist on an increased proportion of neutrophils. This will make an important contribution to increased vascular damage in these patients.
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PMID:Abnormalities in primary granule exocytosis in neutrophils from Type I diabetic patients with nephropathy. 1174 62

Type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse begins with activation of islet-reactive T helper-1 (Th1) cells by dendritic cells (DCs). Since multiple genetic loci contribute to T1D, we evaluated the hypothesis that NOD DCs possess inherent characteristics that contribute to the autoimmune phenotype. When compared to a representative Th1 (C57BL/6) and Th2 (BALB/C) control strain, in vitro generated NOD myeloid DCs matured normally. Functionally, NOD DCs exhibited higher expression of CD80/86 and IL-12 production during stimulation of nai;ve T cells, even in comparison to C57BL/6 DCs, the prototype strain for vigorous, Th1-biased immunity. These features of NOD DCs translated into aberrantly elevated IFN-gamma synthesis, enhanced T-cell proliferation, and heightened CD69 expression. Further, NOR DCs, from an NOD-related, autoimmune-resistant strain, did not display this hyper-responsiveness, suggesting that these abnormalities are genetic features of NOD DCs that are related to disease pathogenesis. Cumulatively, these results indicate that NOD DCs are inherently biased towards abnormally high costimulation and Th1-induction, two features that would be expected to confer activation and persistence of autoreactive T cells.
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PMID:Myeloid dendritic cells in non-obese diabetic mice have elevated costimulatory and T helper-1-inducing abilities. 1236 56

The activation requirements of autoreactive CD4(+) T-cells were investigated in GAD65-specific HLA-DR0401-restricted clones derived from a diabetic patient using major histocompatibility complex (MHC) class II tetramers (TMrs) as stimulating agents. Despite the fact that TMrs loaded with an immunodominant-altered GAD peptide (TMr-GAD) bound a limited number of T-cell receptors, they were capable of efficiently delivering activation signals. These signals ranged from the early steps of phospholipase C (PLC)-gamma(1) phosphorylation and Ca(2+) mobilization to more complex events, such as CD69 upregulation, cytokine mRNA transcription and secretion, and proliferation. All the effects triggered by TMr-GAD were dose dependent. On the contrary, [(3)H]-thymidine incorporation decreased at high TMr-GAD concentrations because of activation-induced cell death (AICD) after initial proliferation. Lower-avidity clones (as defined by TMr-GAD binding) were less sensitive to activation as well as less susceptible to AICD compared with higher-avidity clones. Induction of apoptosis is a potential immunomodulatory target for therapeutic applications of MHC class II multimers, but the relative resistance of low-avidity T-cells may limit its benefits.
Diabetes 2004 Apr
PMID:Differential recognition and activation thresholds in human autoreactive GAD-specific T-cells. 1504 12


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