Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Like human insulin-dependent diabetes, autoimmune diabetes in BB rats and NOD mice is under control of Class II genes of the major histocompatibility complex. The mechanisms of expression of these genes is still unclear. No aberrant expression of Class II antigens was found in BB rats at the onset of diabetes. The putative role of inadequate Class II-linked suppressor control is suggested, however, by the observation that in vivo treatment with anti-Class II monoclonal antibody prevents the onset of diabetes in NOD mice, and that this protection can be transfer by CD4+ T cells.
 ...
PMID:The role of class II major histocompatibility complex antigens in autoimmune diabetes: animal models. 278 59

The predominant genetic elements contributing to HLA-associated disease susceptibility have been localized within the HLA-D, or class II, region of the major histocompatibility complex for a large number of autoimmune diseases. Two likely candidate susceptibility genes in this region have been identified: the DQ beta 3.2 gene is the single allele most highly associated with type I diabetes (IDDM) and accounts for the HLA-DR4 association with that disease. DNA sequence analysis and mutagenesis studies implicate a small set of key residues within the DQ3.2 molecule as critical polymorphic residues likely contributing to disease-associated immune mechanisms. Different class II genes, Dw4 and Dw14, specific alleles at the DR beta locus, account for the HLA-DR4 association with rheumatoid arthritis (RA). A single cluster of polymorphic residues within the DR beta molecule may be sufficient to account for nearly all of the structural and genetic contributions of the HLA complex to the pathogenesis of RA.
 ...
PMID:Determinants of genetic susceptibility in HLA-associated autoimmune disease. 279 47

Viruses are implicated in the pathogenesis of beta-cell destruction in type I (insulin-dependent) diabetes. The aim of our study was to investigate whether reovirus 1 or reovirus 3, which are known to infect beta-cells and induce autoimmunity in susceptible mice, could alter the expression of the major histocompatibility complex (MHC) proteins by human beta-cells and rat insulinoma RINm5F cells. Forty-eight hours after infection of either human beta-cells or RINm5F cells with reovirus 1 or reovirus 3, cytopathic effects were noted. By flow-cytofluorometric analysis, infected RINm5F cells exhibited a seven- to eightfold increase in the surface expression of class I MHC proteins. Upregulation of class I MHC proteins on reovirus 3-infected RINm5F cells was inhibited by 80% after preexposure of the virus to reovirus 3 antiserum. When analyzed by double-indirect immunofluorescence microscopy, human beta-cells infected with reoviruses 1 or 3 also exhibited markedly increased levels of class I MHC proteins. Reovirus infection of human beta-cells or RINm5F cells was not accompanied by the induction of class II MHC proteins. These findings suggest that 1) in addition to direct cytopathic effects, reovirus infection may contribute to beta-cell destruction by increasing expression of class I MHC proteins and therefore reactivity with cytotoxic T-lymphocytes; and 2) some viruses may increase MHC protein expression independent of and before the action of cytokines (e.g., interferon-gamma and tumor necrosis factor) released by immunoinflammatory cells.
Diabetes 1988 Mar
PMID:Reovirus infection enhances expression of class I MHC proteins on human beta-cell and rat RINm5F cell. 283 51

The ability of recombinant interferon-gamma (rIFN-gamma) to induce major histocompatibility complex (MHC) antigen expression in the rat insulinoma cell line RINm5F was investigated. The cells were stained with monoclonal antibodies specific for rat class I and class II MHC antigens. RINm5F cells endogenously expressed class I antigens; this was enhanced by rIFN-gamma. Class II antigens could not be detected on RINm5F cells, but both I-A and I-E were induced by rIFN-gamma.
Diabetes 1988 Feb
PMID:Interferon-gamma induces class II MHC antigens on RINm5F cells. 283 86

Analysis of sequence variation in the polymorphic second exon of the major histocompatibility complex genes HLA-DQ alpha and -DQ beta has revealed 8 allelic variants at the alpha locus and 13 variants at the beta locus. Correlation of sequence variation with serologic typing suggests that the DQw2, DQw3, and DQ(blank) types are determined by the DQ beta subunit, while the DQw1 specificity is determined by DQ alpha. The nature of the amino acid at position 57 in the DQ beta subunit is correlated with susceptibility to insulin-dependent diabetes mellitus. This region of the DQ beta chain contains shared peptides with Epstein-Barr virus and rubella virus.
 ...
PMID:Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. 284 56

A study of Class I and II major histocompatibility complex gene product expression by a rat insulinoma cell line (RINm5F) was performed using monoclonal antibodies and immunoperoxidase techniques. RINm5F cells were incubated with different concentrations of gamma interferon. RINm5F cells exhibit low levels of Class I molecules and are normally devoid of Class II gene products. Upon exposure to gamma interferon, RINm5F cells showed a dramatic increase in Class I expression. This expression was homogenous and could be detected on all cells after 18 h of incubation with as little as 1 unit/ml of interferon. In contrast, de novo Class II expression was not homogeneous and required 36 h of incubation with 10 units/ml of interferon. The number of RINm5F cells expressing Class II antigens was dose- and time-dependent. Interferon treatment did not affect the morphology of RINm5F cells as determined by ultrastructural analysis. Withdrawal of interferon from the culture medium for as long as 78 h diminished but did not abolish the expression of Class I and Class II molecules already induced. The ability of interferon to enhance expression of Class I gene products and induce de novo expression of Class II molecules on B-cell-derived RINm5F cells supports the hypothesis that aberrant expression of major histocompatibility complex gene products on pancreatic B cells may be an important factor in triggering the immune response in Type 1 (insulin dependent) diabetes mellitus.
 ...
PMID:Class I and II major histocompatibility complex gene product expression by a rat insulinoma cell line in vitro following exposure to gamma interferon. 285 88

The nonobese diabetic mouse is recognized as an important animal model for human insulin-dependent diabetes mellitus. One of the components of susceptibility to this disease has been mapped to the major histocompatibility complex. In this study, full-length cDNA clones encoding the I-A alpha and beta chains from the nonobese diabetic mouse have been isolated and sequenced. They are identical to the sequences previously determined from the H-2d haplotype except for the sequence encoding the first external domain, the leader peptide, and the 5' untranslated region of the I-A beta chain molecule. Most strikingly, there are five consecutive nucleotide substitutions which lead to two radical amino acid changes in a region that is conserved between human and mouse. We suggest that the unique structure of the first external I-A beta chain domain is a major determinant in the disease susceptibility that maps to the major histocompatibility complex of the nonobese diabetic mouse.
 ...
PMID:The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. 288 18

A polygenic basis for susceptibility to insulin-dependent diabetes in nonobese diabetic (NOD) mice has been established by outcross to a related inbred strain, nonobese normal (NON). Analysis of first and second backcross progeny has shown that at least three recessive genes are required for development of overt diabetes. One, Idd-1s, is tightly linked to the H-2K locus on chromosome 17; another, Idd-2s, is localized proximal to the Thy-1/Alp-1 cluster on chromosome 9. Segregation of a third, Idd-3s, could be shown in a second backcross. Neither Idd-1s nor Idd-2s could individually be identified as the locus controlling insulitis; leukocytic infiltrates in pancreas were common in most asymptomatic BC1 mice. Both F1 and BC1 mice exhibited the unusually high percentage of splenic T lymphocytes characteristic of NOD, suggesting dominant inheritance of this trait. The polygenic control of diabetogenesis in NOD mice, in which a recessive gene linked to the major histocompatibility complex is but one of several controlling loci, suggests that similar polygenic interactions underlie this type of diabetes in humans.
 ...
PMID:Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. 288 18

This study was designed to map the diabetes susceptibility gene(s) associated with the rat major histocompatibility complex (MHC) RT1. We have crossed spontaneously diabetic male rats bearing the recombinant RT1r8 haplotype with female rats of the AC1.1r4 congenic strain. Three diabetic rats were determined to be homozygous for the r4 haplotype by serotyping. The absence of recombination within the MHC was confirmed by inspection of restriction-fragment-length patterns of the diabetic animals and the parental strains. In conjunction with previous breeding studies, this study maps the diabetes susceptibility gene to the right of the RT1-A locus and to the left of the RT1-C locus. A low incidence of diabetes in the F2 (4.5%) emphasizes the multifactorial nature of the susceptibility. The presence of depressed responsiveness of peripheral blood lymphocytes to concanavalin A stimulation increases the prevalence of the overt disease. An unusual feature of the diabetic syndrome in this study is the sparse or absent pancreatic lymphocytic inflammatory response, with true insulitis being a rare finding.
Diabetes 1988 Oct
PMID:Association of susceptibility to spontaneous diabetes in rat with genes of major histocompatibility complex. 290 75

Type I diabetes mellitus is strongly genetically linked to the major histocompatibility complex but relatively few potentially susceptible people, who are presumably frequently exposed to appropriate triggering factors (e.g. viral illness, environmental agents), develop overt disease. It is possible that some such individuals show latent disease (e.g. islet cell antibodies and perhaps local pancreatic pathology) that does not progress. On the basis of animal data and some clinical evidence we speculate that latent disease is controlled by suppressor cells. We suggest that physiological immunosuppression (e.g. with glucocorticoids) may selectively inactivate such T suppressor cells. Such immunomodulation may allow further islet cell destruction to occur and repeated episodes could eventually produce diabetes. Such episodes of altered immunoregulation may be due to intercurrent viral illness, stress, or therapy with low doses of immunosuppressive agents.
 ...
PMID:Low-dose immunosuppression may unmask type I diabetes mellitus by specific inactivation of suppressor cells. 294 Apr 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>