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

Tetrahydrobiopterin (BH4) is a pteridine product which is released by rodent macrophages on activation by cytokines. We have used serial pancreatic biopsy, and measurement of serum biopterin at 30, 60, 90 and 120 days in the BB/S rat to relate histological change to macrophage activation during the course of pre-diabetes. Using immunohistochemistry, and an arbitrary scoring system read blind and standardised against day 30, we found that pancreatic MHC class I, MHC class II and infiltrating macrophage staining were up-regulated in the BB/S diabetes-prone rats (n = 17) at day 60, markedly so at day 90, and less so at day 120. Staining for resident pancreatic macrophages remained unchanged throughout in diabetes prone, diabetes resistant and Wistar (n = 28) control animals. Serum biopterin fell progressively and identically with age in BB diabetes resistant rats (n = 11) and Wistar controls. No change in weight gain or biopterin levels was observed in the biopsied animals. Mean serum biopterin levels in diabetes prone rats (of which 13 of 17 became diabetic at median 85 days) were the same as in diabetes resistant and Wistar rats at days 30, 60 and 120, but showed a striking and highly significant elevation (p < 0.001) at day 90. Although macrophages infiltrate the islet early in pre-diabetes, the timing of their activation is unknown. The rise in biopterin we observed is a potentially important immunological event which occurred late in the progression of pre-diabetes. This acute terminal event has not been reported previously, and may modify current concepts concerning the tempo of cell destruction during pre-diabetes.
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PMID:Serum biopterin--a novel marker for immune activation during pre-diabetes in the BB rat. 805 83

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.
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PMID:Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice. 810 62

The non-obese diabetic (NOD) mouse strain which spontaneously develops diabetes is a model for human Type 1 (insulin-dependent) diabetes mellitus. At least one of several genes controlling diabetes in the NOD mouse has been mapped to the MHC. Although previous experiments have implicated the MHC class II genes in the development of the disease, the existence of other MHC linked susceptibility genes has not been ruled out. In order to identify these susceptibility genes we have further characterized the MHC haplotype of the NOD mouse and two non-diabetic sister strains, the non-obese non-diabetic (NON) and cataract Shionogi (CTS). We have examined the mouse MHC class III region for the presence of homologous genes to 17 newly isolated human MHC class III region genes (G1, G2, G4, G6, G7a/valyl-tRNA synthetase, HSP70, G8, G9, G10, G12, G13, G14, G15, G16, G17 and G18). We detect unique hybridizing DNA fragments for 16 of the 17 genes in six inbred mouse strains (NOD, NON, CTS, B10, BALB/c and CBA/J) indicating that this part of the H-2 region is similar to the human MHC class III region. Using a panel of restriction enzymes we have defined RFLPs for 6 (G2, G6, HSP70, G12, G16, G18) of the 16 cross-hybridizing probes. The RFLPs demonstrate that NOD, NON and CTS mouse strains each have a distinct MHC haplotype in the MHC class III region.
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PMID:RFLP analysis of the MHC class III region defines unique haplotypes for the non-obese diabetic, cataract Shionogi and the non-obese non-diabetic mouse strains. 810 33

The non-obese diabetic (NOD) mouse spontaneously develops an insulin-dependent diabetes mellitus that resembles human type I diabetes. This disease can be transferred by purified T cells or cloned T cell lines, implicating an autoimmune T cell attack on the pancreatic beta cells of the islets of Langerhans. As all T cell responses involve recognition of peptides bound to MHC molecules displayed at the cell surface, we have examined self peptides binding to the MHC molecules on spleen cells of the NOD mouse. Peptides eluted from the MHC class I molecule Kd have sequences that conform to known motifs for peptides binding this molecule in other strains of mice. The NOD mouse expresses the unique MHC class II molecule I-Ag7. Peptides eluted from I-Ag7 have sequences that implicate an acidic residue in the C terminus of the peptide as important for binding. The role of this residue in binding has been confirmed by direct peptide-binding analysis. This C-terminal acidic amino acid may interact with an arginine residue in the MHC class II alpha-chain that is exposed when beta-chain residue 57 is mutated to serine, or to the unique beta-chain residue histidine 56. These data may provide valuable insights into the nature of autoantigenic peptides presented by NOD mouse MHC molecules by defining the nature of I-Ag7-peptide binding.
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PMID:Self peptides isolated from MHC glycoproteins of non-obese diabetic mice. 813 41

We examined pancreas biopsy specimens from 18 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients to elucidate the mechanism underlying beta cell destruction. Pancreas islets were seen in all patients and insulitis in eight patients. Infiltrating mononuclear cells consisted of CD4+T, CD8+T, B lymphocytes, and macrophages. Among them, CD8+T lymphocytes were predominant and macrophages followed. The expression of MHC class I antigens was increased in islet and endothelial cells in nine patients. MHC class II expression was increased in endothelial cells of the same patients. The expression of intercellular adhesion molecule-1 was increased in endothelial cells in two of the nine patients with MHC hyperexpression; in one of them, lymphocyte function-associated antigen-3 expression was also increased. Out of the eight patients with insulitis, seven showed MHC class I hyper-expression, whereas 2 of the 10 patients without insulitis showed the phenomenon (P < 0.05). The relation between insulitis and the hyperexpression of adhesion molecules was not evident. In conclusion, we revealed the close relation between CD8+T lymphocyte-predominant insulitis and MHC class I hyperexpression in islet cells. This suggests that infiltrating CD8+T lymphocytes recognize islet autoantigens in association with increased MHC class I molecules and act as major effector cells in autoimmune response against islet cells in IDDM pancreases. The role of adhesion molecules in the pathogenesis of IDDM still remains to be elucidated.
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PMID:Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. 822 46

The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.
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PMID:I-E+ nonobese diabetic mice develop insulitis and diabetes. 835 54

In a model of congenic and intra-MHC recombinant rat strains, the differential role of various histocompatibility antigens in renal subcapsular transplantation of purified islets of Langerhans is evaluated. Class I MHC antigens of the RT1.A region, expressed on the endocrine cells of the islets themselves, do not induce graft rejection on their own. MHC class I antigens as encoded by the RT1.C region do not induce rejection either. MHC class II antigens as encoded by the RT1.B/D region are not expressed on the endocrine pancreas, not even during rejection. Although interstitial dendritic cells situated within the islets express these antigens, an isolated RT1.B/D incompatibility of islets is associated with prolonged survival in contrast to rapid rejection of fully MHC-mismatched grafts. Unlike other organs, islets matched for all MHC antigens, but incompatible at minor histocompatibility antigens, undergo rejection early after transplantation.
Diabetes 1993 Jan
PMID:The role of histocompatibility antigens in transplantation of isolated islets of Langerhans in the rat. 842 Aug 22

The work presented in this review suggests that in human and murine type I diabetes, defective MHC class I expression on APC is linked to autoimmunity. The defect in self-antigen presentation is present on prediabetic and diabetic APC, and this presumably delivers abnormal or lack of signals to T cells to allow self tolerance. Since most autoimmune diseases have strong genetic linkage to MHC class II region, our recent results additionally demonstrating low MHC class I expression on lymphoid cells in a diversity of autoimmune diseases (hypothyroidism, rheumatoid arthritis, lupus, etc.) suggest that this pathway of abnormal class I presentation of self epitopes may be important for tolerance to many tissue-specific antigens (40). Certainly, the unanswered genetic questions will address the role of the specific genes controlling self-antigen presentation through MHC class I followed by T-cell education to self.
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PMID:Mechanisms of autoimmunity in type I diabetes. 844 41

Lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), a chronic autoimmune disease, have recently been shown to have decreased surface expression of MHC class I antigens. Since IDDM and other autoimmune diseases share a strong genetic association with MHC class II genes, which may in turn be linked to genes that affect MHC class I expression, we studied other autoimmune diseases to determine whether MHC class I expression is abnormal. Fresh PBLs were isolated from patients with IDDM, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosis, rheumatoid arthritis, and Sjogren's syndrome. Nondiabetic and non-insulin-dependent diabetes mellitus patients served as controls. MHC class I expression was measured with a conformationally dependent monoclonal antibody, W6/32. Freshly prepared PBLs from the autoimmune diseases studied and the corresponding fresh EBV-transformed B cell lines had decreased MHC class I expression compared with PBLs from normal volunteers and non-insulin-dependent (nonautoimmune) diabetic patients. Only 3 of more than 180 donors without IDDM or other clinically recognized autoimmune disease had persistently decreased MHC class I expression; one patient was treated with immunosuppressive drugs, and subsequent screening of the other two patients revealed high titers of autoantibodies, revealing clinically occult autoimmunity. Patients with nonautoimmune inflammation (osteomyelitis or tuberculosis) had normal MHC class I expression. Autoimmune diseases are characterized by decreased expression of MHC class I on lymphocytes. MHC class I expression may be necessary for self-tolerance, and abnormalities in such expression may lead to autoimmunity.
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PMID:Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity. 848 90

Rheumatoid arthritis (RA), one of the most common autoimmune disorders, is believed to be mediated via. T lymphocytes and genetic studies have shown that it is strongly associated with HLA-DR4. The DR4 subtypes DR4Dw4, DR4Dw14 and DR4Dw15 represent increased risk factors for RA, whereas DR4Dw10 is not associated with the disorder. Our study determines and compares the natural ligand motifs of these MHC class II molecules and identifies 60 natural ligands. At relative position 4 (P4), only the RA-associated DR4 molecules allow, or even prefer, negatively charged amino acids, but do not allow those which are positively charged (Arg, Lys). In the case of DR4Dw10 the preference for these amino acids is reversed. The results predict features of the putative RA-inducing peptide(s). A remarkable specificity, almost exclusively for negative charges (Asp, Glu), is found at P9 of the DR4Dw15 motif. This specificity can be ascribed to amino acid beta57 of the DR beta chain, and gives an important insight into the beta57-association of another autoimmune disease, insulin-dependent diabetes mellitus type I.
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PMID:Natural ligand motifs of closely related HLA-DR4 molecules predict features of rheumatoid arthritis associated peptides. 867 55


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