Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of MHC class II determinants (HLA-DR, HLA-DP and Ia7) on peripheral blood monocytes (OKM1+ cells) was studied in 20 children with newly diagnosed IDDM. Monocytes of 10 children with IDDM and familial predisposition showed a statistically significant increase of HLA-DR expression when compared to control group (10 healthy children). There were no significant differences concerning Ia7 expression. HLA-DP expression was similar in all studied groups.
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PMID:MHC class II determinants on peripheral blood monocytes from newly diagnosed IDDM patients. 128 89

Current theories of the aetiology of RA point to a central role for the trimolecular complex comprising the MHC class II molecule on the surface of the APC, the antigenic peptide and the TCR on the disease-inducing T cell. Thus the arthritogenic T cell is an important target for new therapy. However, it cannot be directly identified because the causative antigen is unknown, so indirect techniques such as TCV and TCR peptide vaccination are required. In TCV, T cells thought to mediate the disease, in an activated and attenuated form, are injected into the patient, who then develops a specific immune response against these pathogenic T cells. TCV has been shown to be effective in protecting against and treating a variety of animal models of autoimmune disease, including AA, EAE and IDDM in NOD mice. The vaccines initially comprised clones and lines of T cells shown to be capable of transferring the disease, but later unseparated LN cells were also shown to be effective, paralleling more closely the human situation. Interestingly, it has become clear that TCV does not create its own regulatory network but amplifies a natural immunoregulatory network which forms as the disease develops. The major stimulating moiety on the vaccinating T cell is its receptor (anti-idiotypic response), although there is also an anti-ergotypic (anti-activated T cell) response. For this reason the technique of TCR peptide vaccination was developed, which utilizes only a short peptide from the TCR of the disease-causing cells to stimulate an immune response against them. This is effective in the prevention and treatment of EAE, where there is a preferential usage of TCR-V beta 8 by encephalitogenic T cells. The application of both these techniques to human autoimmune disease is in its infancy. Studies of TCV in MS and RA have not shown clear-cut clinical benefit, although immunological changes have been observed; comparison of methodology with the animal work and assessment of results are complex and further studies are in progress. Studies of TCR peptide vaccination in MS and RA are handicapped by the lack of a consensus on TCR usage in these conditions, but a limited study is underway in MS.
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PMID:Management of early inflammatory arthritis. Intervention with immunomodulatory agents: T cell vaccination. 152 47

Insulin-dependent diabetes mellitus can be transferred into young irradiated non-obese diabetic (NOD) mice by spleen cells from a diabetic NOD donor. T cells (both L3T4+ and Ly-2+) enter the pancreas 2 weeks following transfer. They are present initially at peri-islet locations but progressively infiltrate the islet with accompanying beta cell destruction. The infiltrate is heterogeneous with respect to V beta usage. Inflammatory macrophages (Mac-1+, F4/80+) can be detected at peri-islet locations at 1 week after transfer and continue to be recruited during the disease process. Their presence at the initiation of disease suggests that their primary function may be autoantigen presentation. Increased expression of major histocompatibility complex (MHC) class I molecules is observed on both endocrine and exocrine tissue in areas of intra-islet infiltration. MHC class II and ICAM-1 expression was restricted to the cells constituting the inflammatory infiltrate. Expression of these molecules was not observed on beta cells implying that presentation of autoantigen by the beta cell itself does not play a role in the beta cell destruction in NOD mice.
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PMID:Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression. 167 89

Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice.
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PMID:An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. 250 22

Experimental results and therapeutic strategies. Insulin-dependent diabetes mellitus (IDDM) results from an autoimmune aggression toward beta cells in genetically predisposed individuals. Examination of the frequency of the different antigens coded by the major histocompatibility complex reveals an increased proportion of DR3-DQ2 and DR4-DQ8 haplotypes in IDDM subjects. Sequencing DQ-beta chains in such patients indicates the absence of aspartate in position 57 when compared to control individuals. Islet cell cytoplasmic autoantibodies are early markers of ongoing autoimmunity in addition to insulin autoantibodies before administration of exogenous insulin. Experimental models of autoimmune diabetes like the NOD (NonObese Diabetes) mouse underline the predominant role of T lymphocytes in the constitution of both insulitis and beta cell destruction. In humans, an increased proportion of activated T lymphocytes can be observed but is not specific of the disease. This underlines the need for new cellular markers of the autoimmune process. Transgenic mice allow studies on the consequences of abnormal expression of new molecules on beta cell surface like cytokines or MHC class II molecules which represent a new field of investigation on the pathogenesis of IDDM. Prospective studies in first degree relatives of type I diabetic patients indicate the existence of an asymptomatic phase of beta cell destruction where specific autoimmune markers can be individualized. In some individuals abnormal insulin response to glucose--loss of first phase insulin release during intravenous glucose tolerance test--precedes insulin deficiency. The identification of an autoimmune process leading to beta cell destruction allows new therapeutic approaches with immunointervention at early stages of the disease.
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PMID:[Autoimmunity and insulin-dependent diabetes mellitus. Experimental data and therapeutic prospects]. 267 68

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease whose notorious pathologic feature is insulitis accompanied by destruction of beta-cells. In this morphological study, we examined the pancreatic events during the onset of diabetes in spontaneously diabetic BB/Organon rats. Dendritic cells were the first cells to accumulate around the islets, followed by lymphocytes. Scavenger macrophages and MHC class II-positive beta-cells were only seen late in the disease. These observations suggest a role for antigen-presenting dendritic cells in the onset of the beta-cell-specific autoimmune reaction and emphasize the necessity to distinguish between the several monocyte-macrophage subtypes in studies on the pathogenesis of IDDM.
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PMID:Dendritic cells and scavenger macrophages in pancreatic islets of prediabetic BB rats. 268 15

The heterozygous effect observed for the HLA and disease association in insulin dependent diabetes, juvenile rheumatoid arthritis and coeliac disease is interpreted in the view of recent cellular and molecular data of MHC class II molecules demonstrating the existence of hybrid HLA DQ molecules and conformational determinants created by Trans (or Cis) complementation. It is postulated that unique determinants created de novo by such mechanisms represent the structural basis for the altered immune response leading to the pathogenesis of these auto-immune diseases.
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PMID:[A model and 3 examples for understanding HLA and diseases: cis and trans complementation of MHC class II in juvenile insulin-dependent diabetes, juvenile rheumatoid arthritis and celiac disease]. 309 58

The revolution in molecular techniques has allowed dissection of the autoimmune response in a way impossible to imagine 10 yr ago. There have been spectacular advances in our understanding of self-tolerance mechanisms and how these may fail, combined with a detailed comprehension of antigen presentation, functional T cell subsets, and TCR utilization in autoimmunity, albeit usually in animal models that resemble, but do not exactly duplicate, human diseases. More gradually, these findings are being translated to thyroid autoimmunity, where the major achievement of the last decade has been the molecular characterization of the three main thyroid autoantigens. This in turn has allowed epitope identification, although again the only clear data so far have come from animal models of EAT. Another advance has been the recognition that the thyrocyte is not a helpless target of autoaggression, being capable of expressing a wide array of immunologically active molecules, which may exacerbate or diminish the autoimmune response. In 1983, there was considerable excitement at the discovery of the first of these phenomena, namely MHC class II expression, but its possible role in autoantigen presentation remains to be defined. By analogy with pancreatic beta-cells, and based on our own data, we believe that class II-expressing thyrocytes have little, if any, such role and suspect that instead this may be a mechanism for inducing peripheral tolerance. Defining the contribution of thyrocytes to the intrathyroidal autoimmune response, whether from released cytokines or surface-bound molecules, will be crucial to our future understanding, as well as holding the promise that these thyroid-derived products might be therapeutic targets. Despite molecular developments in HLA analysis, there have been no really major improvements in our understanding of the immunogenetics of thyroid autoimmunity, equivalent to those made in type 1 diabetes mellitus. The available data suggest strongly that non-MHC genes play an important role in susceptibility, and novel approaches will be required to identify these. On the other hand, we know more about the importance of environmental and endogenous (most probably hormonal) factors in thyroid autoimmunity. Understanding the basic immunological changes in the postpartum period is still poor, however, as most studies to date have concentrated on epidemiology and clinical delineation. As PPTD undergoes spontaneous remission, elucidation of these mechanisms has clear implications for treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Autoimmune thyroid disease: further developments in our understanding. 770 81

The pancreatic-duct system was observed during the initial stage of type 1 diabetes in C57BL/6J mice rendered diabetic with low doses of streptozocin. Light microscopy revealed that the ducts located in close proximity to islets (islet ducts) were involved in the infiltrating process: inflammatory cells extended from the islets to these ducts. However, ducts that were located far from islets (non-islet ducts) were generally free from infiltration. Immunocytochemistry revealed that both islet ducts and non-islet ducts express MHC class II and ICAM-1 molecules: this positivity seems to be mainly expressed by elements infiltrating the connective layer or by endothelial of vessels surrounding ducts. Strong ICAM-1 positivity demonstrates that adhesiveness is widely represented in early diabetes in this animal model. At the ultrastructural level only a few endocrine elements were observed scattered within the epithelial layer and single infiltrating elements were rarely encountered within the connective layer of ducts. The existence of other sites of "activation" other than the islets of Langerhans, in this as well as in other animal models of types 1 diabetes, is consistent with the hypothesis of an initially more widespread and less specific process that later undergoes restriction.
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PMID:Pancreatic duct infiltration in the low-dose streptozocin-treated mouse. 798

Until recently, localization of genes involved in multifactorial diseases, such as diabetes, was thought to be impracticable. The recent development of microsatellite genetic markers detected by PCR has facilitated detailed genetic analysis of complex traits. Microsatellite markers have been utilized for genetic analysis of NOD mice which spontaneously develop autoimmune IDDM similar to the human disease. There is evidence for ten distinct loci that affect the development of insulitis and diabetes in NOD mice. One of these loci, designated Idd-1, has been linked to the MHC on chromosome 17. Transgenic mouse experiments have shown that Idd-1 is composed of MHC class II genes I-A beta and I-E alpha.
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PMID:[Current studies on the identification of susceptibility genes for IDDM in NOD mice]. 798 13


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