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)

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

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

Complex protein antigens contain multiple potential T cell recognition epitopes, which are generated through a processing pathway involving partial antigen degradation via proteases, binding to MHC molecules, and display on the APC surface, followed by recognition via the T cell receptor. We have investigated recognition of the GAD65 protein, one of the well-characterized autoantigens in type I diabetes, among individuals carrying the HLA-DR4 haplotypes characteristic of susceptibility to IDDM. Using sets of 20-mer peptides spanning the GAD65 molecule, multiple immunostimulatory epitopes were identified, with diverse class II DR molecules functioning as the restriction element. The majority of T cell responses were restricted by DRB1 molecules; however, DRB4 restricted responses were also observed. Antigen-specific T cell clones and lines were derived from peripheral blood samples of pre-diabetic and IDDM patients and T cell recognition and response were measured. Highly variable proliferative and cytokine release profiles were observed, even among T cells specific for a single GAD65 epitope.
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PMID:Complexity of human immune response profiles for CD4+ T cell epitopes from the diabetes autoantigen GAD65. 1190 49

B lymphocytes partially contribute to autoimmune type 1 diabetes (T1D) as a subset of APC with a preferential ability to trigger pathogenic CD4 T cells. We hypothesized that this resulted from the unique ability of B lymphocytes to take up pancreatic beta cell proteins through Ig mediated capture. T1D was significantly delayed, but not prevented, in a NOD stock in which the B lymphocyte Ig repertoire was strongly restricted because of the allelic exclusion induced by transgenic Ig molecules specific for the disease irrelevant hen egg lysozyme (HEL) protein (NOD.IgHEL mice). However, introducing the Ig(mu)null mutation to eliminate the small residual numbers of non-transgenic B lymphocytes in the NOD.IgHEL stock strongly suppressed T1D to the same low levels that characterize B lymphocyte deficient NOD.Ig(mu)null mice. In contrast to standard NOD mice, both the NOD.IgHEL.Ig(mu)null and NOD.Ig(mu)null stocks were unable to generate T cell responses against the candidate diabetes autoantigen, glutamic acid decarboxylase. These results indicate that Ig-mediated capture of beta cell autoantigens accounts for why B lymphocytes have a greater capacity than other APC subtypes to trigger diabetogenic T cells. Hence, defects in B lymphocyte, as well as T lymphocyte, tolerance induction mechanisms may contribute to T1D in NOD mice.
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PMID:The preferential ability of B lymphocytes to act as diabetogenic APC in NOD mice depends on expression of self-antigen-specific immunoglobulin receptors. 1251 57

Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing beta cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-kappaB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-kappaB and its role in regulating the APC function of macrophages (Mphi) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mphi prepared from NOD mice exhibited increased NF-kappaB activation relative to NOR and BALB/c Mphi. This hyperactivation was detected for different NF-kappaB complexes and correlated with increased IkappaBalpha degradation. Furthermore, increased NF-kappaB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mphi to secrete IL-12(p70), TNF-alpha, and IL-1alpha, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IkappaBalpha. In contrast, elevated NF-kappaB activation had no significant effect on the capacity of NOD Mphi to stimulate CD4(+) or CD8(+) T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mphi exhibit hyperactivation of NF-kappaB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-kappaB influences Mphi APC function by regulating cytokine secretion but not T cell stimulation.
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PMID:NF-kappa B hyperactivation has differential effects on the APC function of nonobese diabetic mouse macrophages. 1257 41

HLA-DM stabilizes peptide-receptive class II alphabeta dimers and facilitates the capture of high affinity peptides, thus influencing the peptide repertoire presented by class II molecules. Variations in DM levels may therefore have a profound effect on the antigenic focus of T cell-mediated immune responses. Specifically, DM expression may influence susceptibility and resistance to autoimmune diseases. In this study the role of DM in HLA-DR4-restricted presentation of an insulin-dependent diabetes mellitus autoantigen, glutamate decarboxylase (GAD), was tested. Presentation of immunodominant GAD epitope 273-285 was regulated by endogenous DM levels in human B lymphoblasts. T cell responses to exogenous GAD as well as an endogenous cytoplasmic form of this Ag were significantly diminished with increasing cellular expression of DM. Epitope editing by DM was observed only using Ag and not small synthetic peptides, suggesting that this process occurred within endosomes. Results with cytoplasmic GAD also indicated that peptides from this compartment intersect class II proteins in endocytic vesicles where DM editing was facilitated. Changes in DM levels within APC may therefore influence the presentation of autoantigens and the development of autoimmune disorders such as type I diabetes.
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PMID:Editing of an immunodominant epitope of glutamate decarboxylase by HLA-DM. 1284 54

The resistance to activated protein C (APC-resistance) based on the presence of factor V Leiden (F V Leiden) is the most frequent thrombophilic condition in the white race population. It contributes to the origin of thrombosis especially in the venous part of blood vessels. Significant geographic differences have been detected within Europe. The aim of this retrospective study was to determine the frequency in the occurrence of F V Leiden: 1. in healthy (asymptomatic) Slovak population, 2. in their consanguineously unrelated members with thrombosis and 3. in patients with myocardial infarction (IM) without or with other known risk factors of this disease (nicotinism, obesity, hypertension, dyslipoproteinemia, diabetes mellitus), respectively. The detection of FV Leiden was made by molecular biology methods. The occurrence in a group of 152 healthy individuals was four % (6 persons) and this frequency corresponds to the geographic localization of the Slovak Republic in Europe. In a group of 349 patients with thrombosis in anamnesis, FV Leiden was detected in 103 persons (29.5%). The occurrence was higher than the usually reported incidence in these patients (20%). Likewise, in a group of 35 patients with IM without risk factors in anamnesis, the occurrence of FV Leiden (8.6%) was significantly higher in comparison with healthy population and the incidence further increased significantly in a group of 41 patients with IM and the presence of at least one risk factor (14.6%). The authors therefore suppose an active role of the Leiden mutation of FV gene in the pathogenesis of this disease.
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PMID:[Factor V Leiden and the Slovak population]. 1468 80

Although HLA-DQ8 has been implicated as a key determinant of genetic susceptibility to human type 1 diabetes, spontaneous diabetes has been observed in HLA-DQ8 transgenic mice that lack expression of murine MHC class II molecules (mII(-/-)) only when the potent costimulatory molecule, B7.1, is transgenically expressed on pancreatic beta cells. To study the contribution of HLA-DQ8 to the development of diabetes in this model, we crossed RIP-B7.1mII(-/-) mice with a set of transgenic mouse lines that differed in their HLA-DQ8 expression patterns on APC subpopulations, in particular dendritic cells and cortical thymic epithelial cells. Surprisingly, we found that even in the absence of HLA-DQ8 and CD4 T cells, a substantial fraction of the RIP-B7.1mII(-/-) mice developed diabetes. This disease process was remarkable for not only showing insulitis, but also inflammatory destruction of the exocrine pancreas with diffusely up-regulated expression of MHC class I and ICAM-1 molecules. Expression of HLA-DQ8 markedly increased the kinetics and frequency of diabetes, with the most severe disease in the lines with the highest levels of HLA-DQ8 on cortical thymic epithelial cells and the largest numbers of CD4 T cells. However, the adoptive transfer of diabetes was not HLA-DQ8-dependent and disease could be rapidly induced with purified CD8 T cells alone. Expression of B7.1 in the target tissue can thus dramatically alter the cellular and molecular requirements for the development of autoimmunity.
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PMID:Expression of the B7.1 costimulatory molecule on pancreatic beta cells abrogates the requirement for CD4 T cells in the development of type 1 diabetes. 1524 Jun 65


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