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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To examine whether the lack of self-tolerance to beta cells is responsible for the development of type I diabetes in nonobese diabetic (NOD) mice, we attempted to induce T cell responses to cells from the islets of Langerhans. The data show that all NOD mice, irrespective of age, sex, and disease progression, possess islet cell-specific CD4+, MHC class II-restricted T cells. Both primary and secondary proliferative responses to islet cells were readily induced. The activation of T cells required presentation of islet cell Ag by APC in the responding lymph node cell population. Cells from other tissues, e.g., salivary gland, adrenal gland, and spleen, failed to activate autologous T lymphocytes. T cells specific for other Ag did not respond to islet cells, indicating that the proliferation is not the result of nonspecific stimulation by islet cell products. The presence of islet cell-reactive T cells is, however, not unique to NOD mice, because similar T cell reactivity was also demonstrated in non-diabetes-prone mouse strains. Hence, self-tolerance to islet cells appears to be absent. The results indicate a normal occurrence of islet cell-reactive T cells in both diabetes-prone as well as non-diabetes-prone mice. Thus, the lack of tolerance cannot be the initial cause of diabetes, but the activation of such autoreactive T cells may be important for the development of the disease.
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PMID:Absence of T cell tolerance to pancreatic islet cells. 135 4

Induction of expression of MHC class II antigens on the surface of cells that do not ordinarily express these proteins has been implicated in the pathogenesis of autoimmunity in diabetes mellitus and autoimmune thyroiditis. Platelets express class I but not class II HLA antigens. In this report, we describe a child with acute idiopathic thrombocytopenic purpura who at the time of the thrombocytopenic episode had class II (HLA-DR) antigens on his platelets. Following recovery, the HLA-DR antigens were no longer present on the platelets. We postulated that class II had been induced on his megakaryocytes by a cytokine such as interferon gamma, and that the induced expression of class II antigens contributed to the autoimmune disorder. To substantiate this possibility we next studied class I and II antigen expression on an erythroleukaemia cell line (HEL), which has many megakaryocytic features. Following treatment of HEL cells with interferon gamma, class I expression was increased and HLA-DR antigens were induced. These observations suggest that cytokine-mediated induced HLA-DR expression may contribute to the pathogenesis of a subset of thrombocytopenias.
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PMID:HLA-DR expression by platelets in acute idiopathic thrombocytopenic purpura. 139 Feb 43

Autoimmune diseases result from the activation of self-reactive T cells induced by autoantigens or by foreign antigens cross-reactive with an autoantigen. A striking characteristic of autoimmune diseases is the increased frequency of certain HLA alleles in affected individuals. Moreover, as demonstrated for example in rheumatoid arthritis and insulin-dependent diabetes mellitus, class II alleles positively associated with autoimmune diseases share amino acid residues in the hypervariable HLA regions involved in peptide binding. Therefore, it is likely that disease-associated HLA class II molecules have the capacity to bind the autoantigen and present it to T cells, thereby inducing and maintaining, under appropriate conditions, the autoimmune disease. The data reviewed here demonstrate MHC-selective inhibition of antigen-induced T cell responses in vivo by parenterally administered soluble, MHC-binding peptide competitors, under conditions in which the competitor is not immunogenic. This suggests the feasibility of a therapeutic approach based on blockade of MHC class II molecules in the treatment of HLA-linked autoimmune diseases.
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PMID:Inhibition of T cell activation by MHC blockade: a possible strategy for immunointervention in autoimmune diseases. 150 37

Antigen processing for presentation of peptide epitopes by major histocompatibility complex (MHC) class I molecules involves genes in the MHC class II region. Among these, PSF1 and PSF2 encode subunits of a transporter, which presumably delivers cytosolic peptides across the endoplasmic reticulum membrane to class I molecules. This close functional relationship of the transporter and class I heavy chain genes and their linkage within the MHC raise the question of whether PSF1 and PSF2, like most class I genes, are polymorphic. By single-strand conformation polymorphism analysis and DNA sequencing, a small number of amino acid sequence variants of both PSF1 and PSF2 was identified in a panel of cell lines. This limited polymorphism may contribute to a higher degree of variability at the level of the functional transporter, in which different alleles of the PSF1 and PSF2 subunits may be combined. A possible involvement of the PSF1 and PSF2 genes in susceptibility to MHC-associated diseases was examined in a preliminary assessment in patients with ankylosing spondylitis, insulin-dependent diabetes mellitus, or celiac disease.
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PMID:Allelic variants of the human putative peptide transporter involved in antigen processing. 157 Mar 16

Expression of major histocompatibility complex (MHC) class II protein in islet beta-cells of transgenic mice causes severe diabetes without an attendant autoimmune component. Little is known of the aberrant beta-cell function and site of biological lesions responsible for the diabetic state. Therefore, changes in (pro)insulin production, processing, sorting, storage, and secretion were evaluated using the in vitro perfused pancreas from male hyperglycemic BALB/cBYJ Tg (O pinsproA alpha d pinsproA beta d) mice and a RIA capable of detecting mouse insulin or proinsulin with quantitative equivalency. Results were compared to control pancreases from normal BALB/cBYJ mice. Extractable pancreatic insulin plus proinsulin content in the transgenics was 4% of normal. Normal pancreases responded characteristically with a diphasic insulin release during 30-min stimulation by glucose, a response that was enhanced by subsequent forskolin. In contrast, hormone release from transgenic pancreases was undetectable; based on the sensitivity of the immunoassay, fractional secretion of the residual pancreatic hormone content from the transgenic pancreases was less than 25% of normal. Proinsulin or insulin constitutive release was also not detected in the absence or presence of glucose-containing stimuli even when experiments were extended to 3 h. In contrast, fractional secretion in response to nonglucose stimuli (carbachol-leucine and arginine-leucine) was greater than normal from the transgenic diabetic pancreases. Responses to glucose stimuli did not normalize even after 90 min in the absence of glucose. In other experiments, pancreases were stimulated with carbachol/leucine/forskolin for 90 min, and the proportion of proinsulin to insulin released by the regulated pathway was determined after Sep-Pak and HPLC separation of combined eluates. Proinsulin was undetectable (and, therefore, accounted for less than 10% of the total hormone secretion). It is concluded from the observations of hyperglycemia, low pancreatic insulin content, and impaired release that insulin production in the pancreas of the MHC diabetic transgenic is severely depressed. The limited insulin production and chronic hyperglycemia do not (as speculated) cause missorting to a constitutive pathway or impaired conversion of proinsulin to insulin, since a proportionately increased proinsulin release does not occur. Although the response of the secretory process to glucose-containing stimuli is almost completely destroyed, fractional secretion in response to nonglucose stimuli is enhanced. The possible contribution of hyperglycemia-induced beta-cell desensitization or specific lesions in the glucose recognition signals induced by MHC expression are discussed. Results suggest that expression of MHC class II protein causes highly specific beta-cell lesions which, in themselves, could be a contributing factor in human insulin-dependent diabetes.
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PMID:Effect on insulin production sorting and secretion by major histocompatibility complex class II gene expression in the pancreatic beta-cell of transgenic mice. 163 31

The etiology of insulin-dependent diabetes mellitus (IDDM) is multifactorial. The final cause of the disease, the specific destruction of the islet beta-cells, is the result of a cellular/humoral autoimmune process that operates in individuals with a particular genetic background in response to an external triggering factor(s). The most likely environmental triggers are virus infections and dietary factors. Among the latter group dietary proteins, mainly cow milk proteins, have been found to be important. Elimination of intact cow milk proteins from the diet significantly reduced the incidence of IDDM in the spontaneously diabetic BB rat, the elimination being most effective when it occurs during the pre-weaning period. Conversely, in newly discovered diabetics (both rats and children) increased levels of antibodies to cow milk proteins as compared with non-diabetic controls were found. These higher titres of antibodies were against beta-lactoglobulin and anti-bovine serum albumin. In further studies we found that antibodies to bovine serum albumin cross-react with a beta-cell membrane protein of Mr 69,000 and that this protein is likely induced by interferon. At the molecular level, a region of the bovine serum albumin has distinct homology to the beta-subunits of the MHC class II proteins Ia, DQ and DR, and antibodies raised against this bovine serum albumin region identified the same 69K beta cell membrane protein, in the same manner as antibodies to the third hypervariable region of DR-beta did. Our hypothesis is that bovine milk proteins (mainly bovine serum albumin) might be an important environmental factor providing specific peptides that share antigenic epitopes with host cell proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM). 171 25

Pancreatic islet cells are the targets of an autoimmune response in type I diabetes. In the nonobese diabetic (NOD) mouse model of autoimmune diabetes, expression of major histocompatibility complex (MHC) class I proteins was inversely correlated with diabetes; in this mouse a mutation in the MHC class II-linked gene for the putative MHC class I peptide transporter was also present. Mice deficient in MHC class I expression because they do not produce beta 2-microglobulin also developed late onset autoimmune diabetes. In cells from humans with type I diabetes expression of MHC class I was decreased; subsets of prediabetics categorized as most likely to become hyperglycemic also had low MHC class I. T cell responses to self antigens are faulty in diabetics. In sets of genetically identical twins that are discordant for diabetes, the defect appeared to reside with the antigen presenting cell. Thus, a lack of surface MHC class I protein is associated with autoimmune diabetes; the concomitant defect in antigen presentation may impair the development of self tolerance, which could result in autoimmune disease.
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PMID:Linkage of faulty major histocompatibility complex class I to autoimmune diabetes. 135 67

The expression of MHC class II molecules on beta-cells of the pancreatic islet has been proposed to play a role in the genesis of insulin-dependent diabetes mellitus in the NOD mouse. We investigated this by immunofluorescent double labeling of islet cells with anti-MHC and anti-CD45 to identify cells of hematopoietic origin. MHC class I expression increased with age on CD45- islet cells. MHC class II expression was not observed on CD45- islet cells at any age; the only cells in the islet that were MHC class II positive were also CD45+. This indicates that all MHC class II-positive cells in the islet are lymphoid cells that infiltrate the islet, whereas the islet endocrine cells express no MHC class II molecules. However, an increase in MHC class I expression occurred on beta-cells, and this may play a role in immunopathogenesis.
Diabetes 1991 May
PMID:Exclusive expression of MHC class II proteins on CD45+ cells in pancreatic islets of NOD mice. 182 81

An early molecular event in the evolution of insulin-dependent diabetes in humans and NOD mice appears to involve the interaction of MHC class II molecules, beta-cell autoantigen-derived peptides, and receptor molecules of helper T lymphocytes. To examine the influence of T-lymphocyte-receptor beta-genes on the development of beta-cell autoimmunity, (NOD x NZW)F1 x NOD backcrossed (BC) mice were studied for the development of insulitis, because insulitis is the pathognomonic histological lesion of autoimmune diabetes. Heterozygosity for H-2nod was permissive for the development of pancreatic interstitial inflammation and peri-islet insulitis, whereas homozygosity for H-2nod was highly associated with insulitis. However, (NOD x NZW)F1 x NOD BC mice developed insulitis regardless of homozygosity or heterozygosity for T-lymphocyte receptor beta nod. Therefore, in our study, T-lymphocyte receptor beta nod did not function as an autosomal-recessive beta-cell autoimmunity gene.
Diabetes 1990 Aug
PMID:Immunogenetic analysis of beta-cell autoimmunity in NOD mice. Relationship of insulitis to T-lymphocyte-receptor beta nod and A beta nod genes. 197 74

This study examines whether the survival of allografted rat islet beta-cells is influenced by the presence of other pancreatic donor cells. Grafts (RT1u/l) of different cellular composition were intraportally transplanted in streptozocin-induced diabetic rats (RT1n/n). All grafts corrected the diabetic state within 3 days. Implants of freshly isolated islets contained various endocrine and nonendocrine cell types; they became diffusely infiltrated within 1 wk and were completely destroyed within 2 wk. A 4-day culture period did not lead to major changes in the cellular composition of the islets or in their survival as allograft. Islet cell aggregates prepared after islet dissociation and cell purification were less acutely infiltrated and less rapidly rejected. Aggregates composed of sorted MHC class II-negative cells maintained basal normoglycemia in 3 of 5 recipients for 5 wk but only in 1 of 5 for 20 wk. Aggregates of purified islet beta-cells remained relatively free of diffuse infiltrations during the 1st wk and preserved the normalized state in 7 of 13 recipients for 5 wk; after 20 wk, 6 of 13 were still aglucosuric, but 40% of the implants were diffusely infiltrated and depleted of insulin. Reaggregation of purified islet beta-cells with purified islet endocrine non-beta-cells promoted their long-term survival as allograft: 11 of 13 recipients of mixed islet endocrine cells maintained normal basal glycemia over 20 wk; their implants contained relatively constant insulin reserves and remained virtually devoid of diffuse infiltrations. These results demonstrate that techniques aiming at the elimination of surface MHC class II-positive cells are less successful in preparing rat islet allografts of low immunogenicity than methods of positive cell selection. Pure islet beta-cells are immunogenic as an allograft but illicit a milder and less-acute immune attack than undissociated islet tissue. Nonendocrine and damaged islet cells are suspected of enhancing the rapidity and intensity of the cytotoxic reaction. Survival of allografted beta-cells is markedly prolonged by the presence of islet endocrine non-beta-cells within the graft. The mechanisms underlying this effect have not yet been elucidated; they may involve immune and metabolic interactions of the endocrine non-beta-cells. We conclude that purification of islet endocrine cells represents a new and powerful method for preparing insulin-producing allografts that can survive in hosts without pharmacological immunosuppression.
Diabetes 1991 Jul
PMID:Transplantation of purified islet cells in diabetic rats. II. Immunogenicity of allografted islet beta-cells. 206 Jul 28


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