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)

Due to their high immunostimulatory ability as well as the critical role they play in the maintenance of self-tolerance, dendritic cells have been implicated in the pathogenesis of autoimmune diseases. The non-obese diabetic (NOD) mouse is an animal model of autoimmune type 1 diabetes, in which pancreatic beta cells are selectively destroyed mainly by T cell-mediated immune responses. To elucidate initiation mechanisms of beta cell-specific autoimmunity, we attempted to generate bone marrow-derived dendritic cells from NOD mice. However, our results showed low proliferative response of NOD bone marrow cells and some defects in the differentiation into the myeloid dendritic cells. NOD dendritic cells showed lower expressions of MHC class II, B7-1, B7-2 and CD40, compared with C57BL/6 dendritic cells. In mixed lymphocyte reactions, stimulatory activities of NOD dendritic cells were also weak. Treatment with LPS, INF-gamma and anti-CD40 stimulated NOD dendritic cells to produce IL-12p70. The amount of IL-12, however, appeared to be lower than that of C57BL/6. Results of the present study indicated that there may be some defects in the development of NOD dendritic cells in the bone marrow, which might have an impact on the breakdown of self tolerance.
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PMID:Defects in the differentiation and function of bone marrow-derived dendritic cells in non-obese diabetic mice. 1080 1

Although MHC class II genes have a stronger association with type 1 diabetes than MHC class I genes, studies have shown that MHC class I molecules play an independent role in the etiology of type 1 diabetes, and the existence of susceptibility genes within a segment of MHC between the HLA-B and TNF genes has been predicted, where MHC class I chain-related gene A (MICA) resides. MICA has a triplet repeat polymorphism in the transmembrane region consisting of five alleles. We analyzed this polymorphism in 162 unrelated children (82 boys) with type 1 diabetes (age at diagnosis 7.01 +/- 3.76 yr) and 154 randomly selected unrelated children (87 boys), age 2.81 +/- 2.12 yr. Phenotype frequency of allele A9 in children with type 1 diabetes was significantly higher than in controls (RR = 2.42, 95% CI = 1.52-3.85, p = 0.000162, pc = 0.00081). Gene frequency of allele A9 was also significantly higher in children with type 1 diabetes when compared with control children (RR = 2.73, 95% CI = 1.85-4.03, p = 2.62 x 10(-7), pc = 1.31 x 10(-6)). This study demonstrates that MICA allele A9 confers risk of type 1 diabetes.
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PMID:Polymorphism in the transmembrane region of the MICA gene and type 1 diabetes. 1080 66

Qualitative and/or quantitative alterations in the expression of the MHC class II molecules affect the onset and maintenance of the immune response and may be the basis of a wide variety of disease states, such as autoimmunity and immunodeficiency.CIITA is a major physiological regulator of the expression of MHC class II genes. The availability of CIITA ap- pears generally essential for MHC class II gene expression, and hence its own transcriptional regulatory mechanisms result of fundamental importance for a correct homeostasis of the immune response. Therefore, it is possible to hypothesize that variability at the CIITA-encoding locus, AIR-1, could constitute an additional source of susceptible traits to autoimmune diseases. Mutations at AIR-1/CIITA promoters could modulate expression of CIITA. Variations in CIITA expression could influence the qualitative and quantitative expression of MHC class II molecules at cell surface. We have analyzed sequence variation at AIR-1/CIITA promoters by PCR-SSCP in 23 IDDM and 30 RA patients compared to a sample of 19 unaffected normal controls and 16 unaffected IDDM family members, for a total of 88 Caucasian subjects from the Northeast of Italy. No sequence difference was found at the four AIR-1/CIITA promoters between autoimmune patients and normal controls. Moreover, the promoters resulted invariant within the entire group of 88 subjects analyzed, comprising patients and controls. This finding suggests a possible selective advantage in maintaining CIITA upstream regulatory sequences invariant.
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PMID:Analysis of CIITA encoding AIR-1 gene promoters in insulin-dependent diabetes mellitus and rheumatoid arthritis patients from the northeast of Italy: absence of sequence variability. 1082 88

The identification and characterization of autoantigens associated with autoimmune IDDM (insulin dependent diabetes mellitus) would help to elucidate the pathogenic mechanism of this disease as well as to design antigen-based immunotherapy. Non-obese diabetic (NOD) mice have been used as the best model for studying the pathogenesis of human IDDM. To identify new autoantigens associated with IDDM, the lambda gt11-cDNA library from MIN6N8a, NOD-derived pancreatic beta cell line, was constructed and then candidate autoantigen clones were screened with prediabetic NOD sera. Nine positive clones were selected from 2x10(5)phage plaques. The nucleotide sequencing and homology searching showed that six of the nine positive clones had part of the endogenous ecotropic murine leukemia viral (MuLV) envelope gene. Nested deletion of this envelope gene revealed that the leucine zipper region in the transmembrane domain of MuLV envelope protein was the target epitope(s) reactive with prediabetic NOD mice sera. The prevalence of MuLV envelope protein-positive antibody in NOD mice was around 46%, while the non-NOD mice strains including BALB/c, ICR, C57BL/6, and SJL/J mice did not produce this envelope protein-reactive antibody. The expression of endogenous ecotropic MuLV envelope gene in NOD mouse pancreas was distinct in those with severe insulitis. However, both prediabetic and diabetic NOD mice did not show the MHC class II-restrictive cellular autoimmunity against our purified recombinant envelope protein. In this study, we showed that the endogenous ecotropic MuLV envelope protein was a new autoantigen reactive with the activated NOD humoral immune system.
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PMID:Endogenous ecotropic murine leukemia viral (MuLV) envelope protein as a new autoantigen reactive with non-obese diabetic mice sera. 1104 75

The genetic factors that contribute to the etiology of type 1 diabetes are still largely uncharacterized. However, the genes of the MHC (HLA in humans) have been consistently associated with susceptibility to disease. We have used several transgenic mice generated in our laboratory, bearing susceptible or resistant HLA alleles, in the absence of endogenous MHC class II (Abetao), to study immune responses to the autoantigen glutamic acid decarboxylase (GAD) 65 and its relevance in determining the association between autoreactivity and disease pathogenesis. Mice bearing diabetes-susceptible haplotypes, HLA DR3 (DRB1*0301) or DQ8 (DQB1*0302), singly or in combination showed spontaneous T cell reactivity to rat GAD 65, which is highly homologous to the self Ag, mouse GAD 65. The presence of diabetes-resistant or neutral alleles, such as HLA DQ6 (DQB1*0602) and DR2 (DRB1*1502) prevented the generation of any self-reactive responses to rat GAD. In addition, unmanipulated Abetao/DR3, Abetao/DQ8, and Abetao/DR3/DQ8 mice recognized specific peptides, mainly from the N-terminal region of the GAD 65 molecule. Most of these regions are conserved between human, mouse, and rat GAD 65. Further analysis revealed that the reactivity was mediated primarily by CD4(+) T cells. Stimulation of these T cells by rat GAD 65 resulted in the generation of a mixed Th1/Th2 cytokine profile in the Abetao/DR3/DQ8, Abetao/DR3, and Abetao/DQ8 mice. Thus, the presence of diabetes-associated genes determines whether immune tolerance is maintained to islet autoantigens, but autoreactivity in itself is not sufficient to induce diabetes.
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PMID:Type 1 diabetes-predisposing MHC alleles influence the selection of glutamic acid decarboxylase (GAD) 65-specific T cells in a transgenic model. 1114 22

Specific and major histocompatibility complex (MHC)-restricted T-cell recognition of antigenic peptides is based on interactions of the T-cell receptor (TCR) with the MHC alpha helices and solvent exposed peptide residues termed TCR contacts. In the case of MHC class II-presented peptides, the latter are located in the positions p2/3, p5 and p7/8 between MHC anchor residues. For numerous epitopes, peptide substitution studies have identified the central residue p5 as primary TCR contact characterized by very low permissiveness for peptide substitution, while the more peripheral positions generally represent auxiliary TCR contacts. In structural studies of TCR/peptide/MHC complexes, this has been shown to be due to intimate contact between the TCR complementarity determining region (CDR) three loops and the central peptide residue. We asked whether this model also applied to two HLA-DR presented epitopes derived from an antigen targeted in type 1 diabetes. Large panels of epitope variants with mainly conservative single substitutions were tested for human leukocyte antigen (HLA) class II binding affinity and T cell stimulation. Both epitopes bind with high affinity to the presenting HLA-DR molecules. However, in striking contrast to the standard distribution of TCR contacts, recognition of the central p5 residue displayed high permissiveness even for non-conservative substitutions, while the more peripheral p2 and p8 TCR contacts showed very low permissiveness for substitution. This suggests that intimate TCR interaction with the central peptide residue is not always required for specific antigen recognition and can be compensated by interactions with positions normally acting as auxiliary contacts.
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PMID:Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition. 1125 3

MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic beta cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.
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PMID:The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. 1128 96

Type 1 diabetes mellitus is strongly associated with HLA-DQ8 in humans and I-A(g7) in the NOD mouse. The disease is characterized by loss of tolerance to auto-antigens such as GAD, insulin, and the protein tyrosine phosphatase-like molecule, IA-2. We identified T cell epitopes on the intracytoplasmic region of IA-2 by immunizing DQ8/NOD, DQ8/B10, and NOD mice with overlapping 18 mer peptides in CFA. We identified four peptides presented both by DQ8 and NOD, five DQ8 specific peptides, and six NOD specific peptides. Both mouse lines failed to respond to ten peptides. We demonstrated MHC class II and CD4 restriction of proliferative responses using appropriate blocking antibodies. To understand the role of non-MHC genes in the generation of immune response to the islet auto-antigen, we evaluated cytokine secretion following immunization of DQ8 transgenic mice with strongly immunogenic peptides. The NOD background resulted in increased secretion of cytokines. In conclusion, we have identified IA-2 peptides that induce lymphoproliferative responses in DQ8 transgenic and NOD mice and shown that these peptides stimulate production of Th1 and Th2 cytokines.
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PMID:HLA-DQ8 transgenic and NOD mice recognize different epitopes within the cytoplasmic region of the tyrosine phosphatase-like molecule, IA-2. 1160 Feb 16

The structural and functional properties of HLA-DQ and -DR molecules that confer susceptibility to several common autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis, have been defined. The relevant polymorphisms directly affect interaction with peptides, which provides strong support for the hypothesis that these diseases are peptide-antigen driven. Several studies indicate that structural modifications of peptides can affect MHC class II binding and/or TCR recognition and should be considered in the analysis of T cell responses in autoimmune diseases.
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PMID:Insights into autoimmunity gained from structural analysis of MHC-peptide complexes. 1167 85

Numerous studies have associated carriage of HLA-DRB1*1501, DQA1*0102 and DQB1*0602 (DR15, DQ6) with dominant resistance to type 1 diabetes and have concluded that one or more of the component HLA class II molecules mediate this effect. Mechanisms for MHC class II-mediated resistance to diabetes have been proposed from studies of transgenic mice, usually using the diabetes-prone non-obese diabetic (NOD) strain. However, these studies have not reached any consensus on a plausible mechanism. In this study we question why the role of central MHC genes in resistance to diabetes has not been addressed, as the central MHC carries markers of susceptibility to diabetes in linkage disequilibrium with several genes with known or putative immunoregulatory functions. To illustrate the type of studies required to address this issue, we selected diabetes patients and control subjects for carriage of HLA-DR15 and the C allele at position +738 in the inhibitor of kappa B-like gene (IKBL). These alleles mark the 7.1 haplotype (HLA-A3, B7, IKBL738*C, DR15, DQ6). HLA-DR15 was the most effective marker of resistance, but an effect may be evident with IKBL738*C in a larger study. Moreover, carriage of the entire haplotype was particularly rare in patients. The best explanation for this is that the critical gene lies between IKBL and HLA-DRB1, and is more closely linked to HLA-DRB1. Candidate genes at the centromeric end of the central MHC are reviewed, highlighting the need for further study.
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PMID:Can MHC class II genes mediate resistance to type 1 diabetes? 1190 20


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