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)

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

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

Prostaglandins (PGs) are lipid molecules that profoundly affect cellular processes including inflammation and immune response. Pathways contributing to PG output are highly regulated in antigen-presenting cells such as macrophages and monocytes, which produce large quantities of these molecules upon activation. In this report, we demonstrate aberrant constitutive expression of the normally inducible cyclooxygenase PG synthase 2 (PGS(2)/ COX-2) in nonactivated monocytes of humans with insulin-dependent diabetes mellitus (IDDM) and those with islet autoantibodies at increased risk of developing this disease. Constitutive PGS(2) appears to characterize a high risk for diabetes as it correlates with and predicts a low first-phase insulin response in autoantibody-positive subjects. Abnormal PGS(2) expression in at-risk subjects affected immune response in vitro, as the presence of a specific PGS(2) inhibitor, NS398, significantly increased IL-2 receptor alpha-chain (CD25) expression on phytohemagglutinin-stimulated T cells. The effect of PGS(2) on CD25 expression was most profound in subjects expressing both DR04 and DQbeta0302 high-risk alleles, suggesting that this cyclooxygenase interacts with diabetes-associated MHC class II antigens to limit T-cell activation. These results indicate that constitutive PGS(2) expression in monocytes defines an antigen-presenting cell defect affecting immune response, and that this expression is a novel cell-associated risk marker for IDDM.
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PMID:Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus. 1044 43

Both genetic predisposition and environmental factors participate in the etiology of Type-1 diabetes. To test the role of the microbial product lipopolysaccharide (LPS) as an environmental trigger of autoimmune diabetes, we employed transgenic (tg) BDC2.5/NOD mice that bear an islet-specific CD4(+) T cell repertoire (>95%), but do not develop the spontaneous diabetes that typifies the NOD (nonobese diabetic) strain. LPS administration provoked diabetes in BDC2.5/NOD mice by their 16th week of age. However, LPS administration in NOD mice did not accelerate their diabetes. This finding indicates that the frequency of islet-specific T cells influences LPS-mediated diabetes. Furthermore, in vitro LPS-cultured splenocytes from BDC2. 5/NOD and BDC2.5-microMT (B-cell-deficient) mice effectively transferred diabetes into immunodeficient NOD-scid/scid mice but not immunosufficient NOD mice. Therefore, B lymphocytes are not required for LPS-provoked autoimmune diabetes. Flow cytometric analysis then revealed that LPS-stimulation in vitro induced the expression of an IL-2 receptor (CD25) on CD4 T cells; this indicates that the activation of islet-specific T cells is a prerequisite to eliciting diabetes in this situation. Overall, these results point to microbial LPS as an etiopathogenic agent of autoimmune diabetes.
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PMID:The microbial product lipopolysaccharide confers diabetogenic potential on the T cell repertoire of BDC2.5/NOD mice: implications for the etiology of autoimmune diabetes. 1077 2

Previously we have shown that autoimmune diabetes, induced in rats by a protocol of adult thymectomy and split-dose gamma irradiation, can be prevented by the transfer of a subset of CD4+ T cells with a memory phenotype (CD45RC-), as well as by CD4+CD8- thymocytes, from syngeneic donors. Further studies now reveal that in the thymus the regulatory cells are observed in the CD25+ subset of CD4+CD8- cells, whereas transfer of the corresponding CD25- thymocyte subset leads to acceleration of disease onset in prediabetic recipients. However, in the periphery, not all regulatory T cells were found to be CD25+. In thoracic duct lymph, cells that could prevent diabetes were found in both CD25- and CD25+ subsets of CD4+CD45RC- cells. Further, CD25- regulatory T cells were also present within the CD4+CD45RC- cell subset from spleen and lymph nodes, but were effective in preventing diabetes only after the removal of CD25- recent thymic emigrants. Phenotypic analysis of human thymocytes showed the presence of CD25+ cells in the same proportions as in rat thymus. The possible developmental relationship between CD25+ and CD25- regulatory T cells is discussed.
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PMID:CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25- subpopulations. 1097 23

Tolerance to beta cell autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4(+) CD25(+) CD62L(+) T cell-mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of beta cell antigens or CD3 antibodies is now being tested in clinical trials in prediabetics and/or recently diagnosed diabetes.
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PMID:Tolerance to islet autoantigens in type 1 diabetes. 1124 33

Alterations in lymphocytes are a common finding in both type I and type II diabetes. Autoimmune phenomena in type I diabetes, the stage of the diabetic disorder and metabolic effects of therapeutic interventions may also affect actual distribution of lymphocyte phenotypes. This study investigated immunological effects specific to standardized hyperglycemia in non-diabetic individuals to exclude immunological changes potentially related to diabetes stage and treatment. 37 subjects (mean age +/- SD 39 +/- 5 years) underwent a sequence-controlled crossover with oral administration of a solution containing either 75 g glucose or artificial sweetener (i.e. placebo). At rest and at two hours, counts of white blood cells (WBC), mixed lymphocytes, mature T-cells (CD3), T-helper cells (CD4), T-suppressor/ cytotoxic cells (CD8), B-cells (CD19), natural killer cells (CD16/CD56), and interleukin-2 receptor bearing peripheral blood mononuclear cells (CD25) were measured by flow cytometry. Subjects showed a significant decrease in WBC, lymphocytes, and all lymphocyte subsets with the OGTT compared with the placebo solution (p < .05 to p < .001). In non-diabetic individuals, short-term hyperglycemia induces immunological changes that may be relevant to explain similar findings in patients with diabetes mellitus. Future studies need to validate these findings and their potential clinical implications in a diabetic population.
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PMID:Short-term hyperglycemia induces lymphopenia and lymphocyte subset redistribution. 1144 16

Regulation of the immune response to self-antigens is a complex process that depends on maintaining self-tolerance while retaining the capacity to mount a robust immune response to foreign antigens. Autoreactive T cells specific for these autoantigens are present in most normal individuals but are kept under control by multiple diverse peripheral tolerance mechanisms. In the last few years, there has been a re-emergence of suppressor cells as among the most central of these regulatory mechanisms. These cells, which express CD4, CD25, and CD62L, develop in the thymus and survive in a CD28-dependent manner in the periphery to maintain the homeostatic equilibrium of immunity and tolerance. In this review, we will summarize studies of these regulatory cells as they relate to autoimmune diseases and more specifically to type 1 diabetes and attempt to address some of the many outstanding questions. Finally, evidence is provided to support the ability of anti-CD3 mAbs to stimulate the regulatory T cells and reset the rheostat of immune tolerance in an animal model of autoimmune diabetes, the NOD mouse.
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PMID:Suppressor T cells--they're back and critical for regulation of autoimmunity! 1172 31

Interleukin 2 (IL-2)--a Th1 lymphocyte-derived cytokine is at present considered to play an important role in the etiopathogenesis of insulin-dependent diabetes mellitus. In the previous studies increased, decreased and unchanged IL-2 levels in patients with recent onset of insulin-dependent diabetes mellitus (IDDM) were found. These differences could be a result of different metabolic status or/and a different stage of the autoimmune process. The aim of our study was to estimate in vitro secretion of IL-2 and CD25 antigen expression by the peripheral blood T lymphocytes in subjects at the preclinical stage of IDDM (prediabetes), but still without metabolic disturbances. In 27 first degree relatives of IDDM patients with antibodies against different pancreatic islet cell antigens (ICA, GADA, IAA, IA-2) CD25 antigen expression on peripheral blood lymphocytes T was measured by flow cytometry and IL-2 concentration in supernatants of 48 and 72 h cultures of peripheral whole blood with 10 microg/ml PHA was estimated by ELISA. The control group was comprised of 34 age and sex-matched healthy volunteers. In the studied high risk IDDM subjects the decreased CD25 expression in peripheral CD4+ lymphocytes T and a negative correlation between the percentage of CD25+ cells and islet cell antibodies (ICA) titres was observed. No differences in IL-2 levels in supernatants of 48 h and 72 h blood cultures was found in subjects with single antibody (ICA+) in comparison to healthy controls. A significant increase of IL-2 secretion at 72 h of PHA stimulation was shown in first degree relatives of IDDM patients with a combination of 3 or more antipancreatic-B cell antibodies. There were also a significant negative correlation between glutamic acid decarboxylase antibodies (GADA) titres and IL-2 levels in 72 h of culture. The present study suggests the involvement of IL-2 in the pathogenesis of IDDM. The estimation of CD25 antigen expression in the peripheral blood lymphocytes could be an additional immunological marker of identification of subjects in prediabetes.
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PMID:In vitro secretion of interleukin 2 and expression of IL-2 receptor in peripheral blood lymphocytes in high risk of insulin-dependent diabetes mellitus subjects. 1172 28

Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in V(alpha)24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.
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PMID:Multiple immuno-regulatory defects in type-1 diabetes. 1178 58


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