UMLS:C0011854 - FACTA Search

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Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the CD5 mRNA expression and VH gene family usage in Epstein-Barr virus (EBV)-immortalized B-cell lines derived from the blood of patients with type 1 diabetes (IDDM) of recent onset and of patients with polyneuritis cranialis multiplex (cranial neuritis; CN). After immortalization with EBV, at least 10 cell lines from each subject were tested for surface CD5 and CD20. mRNA expression was studied using cDNA probes for the six VH families as well as for CD5. The EBV lines from the IDDM patients used the VHIV family more frequently and VHI and VHII families less frequently than lines from controls. EBV lines from CN patients expressed the VHI and VHII families more often than those of the controls. When the IDDM and CN lines were compared, the lines derived from IDDM patients were found to use VH families I and II less frequently and VH families IV and V more frequently than lines from CN patients. There were no significant differences in the mean numbers of CD5+ B cells in the cell lines tested. More than half of the lines from each patient expressed CD5 at the mRNA level. No correlation was seen between the expression of surface CD5 and the level of CD5 mRNA expression. There was, however, a positive correlation between the usage of VH families III, V and VI, and the CD5 mRNA expression. In conclusion, the usage of VH families I to VI seemed to differ in patients with IDDM and CN. No differences were seen in the surface CD5 expression, but the lines expressing CD5 mRNA preferentially used the VH families III, V and VI.
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PMID:CD5 and immunoglobulin VH gene expression in B-cell lines from patients with autoimmune diseases. 128 53

The autoimmune phenomena associated with destruction of the beta cell in pancreatic islets and development of type 1 (insulin-dependent) diabetes mellitus (IDDM) include circulating islet cell antibodies. We have immortalized peripheral blood lymphocytes from prediabetic individuals and patients with newly diagnosed IDDM by Epstein-Barr virus transformation. IgG-positive cells were selected by anti-human IgG-coupled magnetic beads and expanded in cell culture. Supernatants were screened for cytoplasmic islet cell antibodies using the conventional indirect immunofluorescence test on cryostat sections of human pancreas. Six islet cell-specific B-cell lines, originating from a patient with newly diagnosed IDDM, could be stabilized on a monoclonal level. All six monoclonal islet cell antibodies (MICA 1-6) were of the IgG class. None of the MICA reacted with human thyroid, adrenal gland, anterior pituitary, liver, lung, stomach, and intestine tissues but all six reacted with pancreatic islets of different mammalian species and, in addition, with neurons of rat cerebellar cortex. MICA 1-6 were shown to recognize four distinct antigenic epitopes in islets. Islet cell antibody-positive diabetic sera but not normal human sera blocked the binding of the monoclonal antibodies to their target epitopes. Immunoprecipitation of 35S-labeled human islet cell extracts revealed that a protein of identical size to the enzyme glutamate decarboxylase (EC 4.1.1.15) was a target of all MICA. Furthermore, antigen immunotrapped by the MICA from brain homogenates showed glutamate decarboxylase enzyme activity. MICA 1-6 therefore reveal glutamate decarboxylase as the predominant target antigen of cytoplasmic islet cell autoantibodies in a patient with newly diagnosed IDDM.
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PMID:Human monoclonal islet cell antibodies from a patient with insulin-dependent diabetes mellitus reveal glutamate decarboxylase as the target antigen. 138 89

Several studies have demonstrated abnormalities of T cell regulation of Epstein-Barr virus-induced B cell activation in systemic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, and systemic sclerosis. However, a normal suppressive peripheral T cell function was observed in Graves' disease. To investigate whether this abnormality is a common feature to other autoimmune diseases, we studied T cell regulation of Epstein-Barr virus induced B cell activation in 15 newly diagnosed type 1 (insulin dependent) diabetes mellitus patients and 10 normal control subjects. Peripheral B lymphocytes infected with Epstein-Barr virus were cultured for 20 days in the presence or absence of autologous T cells at different ratios (1:1 and 1:4). IgM and IgG secretions into the supernatants were determined using an enzyme-linked immunosorbent assay. The extent of suppression when T cells were added, as measured by a suppression ratio, was not significantly different in type 1 (insulin dependent) diabetes mellitus patients and normal subjects. We conclude that in type 1 (insulin dependent) diabetes mellitus, the autoimmune reactivity is not dependent upon a generalized suppression defect. It can be hypothesized, therefore, that in type 1 diabetes mellitus as well as in Graves' disease, a local or organ specific suppressor deficit may induce the autoimmune phenomena.
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PMID:Normal suppressive T cell function of Epstein-Barr virus induced B cell activation in type 1 (insulin dependent) diabetes mellitus. 196 82

Our understanding of HLA class II polymorphism has undergone a rapid evolution in the last few years. As in so many areas of modern biology, this progress has depended largely on the application of recombinant DNA techniques to the study of this gene family. In particular, the recent development of methods of gene amplification by means of the polymerase chain reaction has allowed for the rapid assessment of polymorphism in the human population. In addition, the elucidation by x-ray crystallographic analysis of the three-dimensional structure of an HLA molecule has been a major step. These areas of progress have now begun to converge to allow a more detailed approach to the problem of class II polymorphism and disease susceptibility. As discussed in this review, the data so far indicate that a few amino acid substitutions in class II molecules may exert a critical influence on susceptibility to autoimmune diseases such as RA and IDDM. The mechanism by which these class II polymorphisms predispose to autoimmune disease is still unknown. It is tempting to speculate that differences in the binding affinity of HLA molecules for autoantigens might be involved; however, as yet no specific autoantigen has been identified for either RA or IDDM. Intriguingly, sequence similarities have been observed between some viral proteins and class II molecules, raising the possibility that these infectious agents might induce autoimmunity by "molecular mimicry." Examples include the human cytomegalovirus protein, IE2 as well as the Epstein Barr virus gp110 protein. Other possible mechanisms involve more complex immunoregulatory effects, such as the absence of suppressor functions that appear to be under the influence of the HLA genes. To some extent, the persistent ignorance about the cause of autoimmunity reflects a general lack of knowledge concerning exactly how HLA polymorphisms exert immunoregulatory effects. For example, in addition to influencing antigen presentation, MHC molecules also affect the overall T cell repertoire during thymic selection. The relative importance of HLA class II polymorphism in exerting immunoregulatory effects by means of thymic selection of the T cell repertoire is unknown. For autoimmune diseases such as RA and IDDM, there is a need to identify a specific functional abnormality that is causing the disease before the etiological significance of the emerging associations with class II polymorphisms become clear.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:HLA class II polymorphism: implications for genetic susceptibility to autoimmune disease. 266 47

A five amino acids-long sequence (GPPAA) in the region of the 57th amino acid of HLA-DQ8 beta chain, which seems to be important in defining the risk for type 1 diabetes, occurs also in the BERF4-encoded EBNA3C protein of Epstein-Barr virus (EBV) in six successive repeats. The antigenicity of this region was analysed using synthetic peptides containing different modifications of the GPPAA sequence. Two of the seven individuals who had acute EBV infection produced antibodies against an EBV-derived peptide (GPPAAGPPAAGPPAA) paralleling the EBNA2 antibodies. These two cases also contracted type 1 diabetes immediately after the infection. High antibody levels against this peptide were found in a total of 12% of EBV+ individuals, and in most cases antibodies remained at high levels for several years. Human sera as well as affinity-purified antibodies specific for the GPPAAGPPAAGPPAA peptide reacted also with shorter peptide analogues (GPPAAGPPAA and GPPAA), as well as with peptides containing the surrounding motifs from DQ8 beta chains. However, none of these antibodies bound to denatured DQ8 beta chains in immunoblotting. The charge of the 57th amino acid modulated the antigenicity of this epitope, as peptides from Asp-57-negative DQ molecules were reactive, while peptides from Asp-57-positive DQ molecules were not. The responsiveness was seen in both HLA-DQ8-positive and -negative subjects as well as in type 1 diabetic individuals. The results suggest that some individuals who carry the GPPAA sequence in their HLA-DQ molecule recognize this epitope in EBV. This phenomenon may have potential importance in EBV-induced immune abnormalities, although cross-reactivity against DQ molecules could not be demonstrated in the present study.
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PMID:Antibody reactivity to an Epstein-Barr virus BERF4-encoded epitope occurring also in Asp-57 region of HLA-DQ8 beta chain. Childhood Diabetes in Finland Study Group. 750 47

Antibodies to glutamic acid decarboxylase-65 (GAD65) are present in a number of autoimmune disorders, such as insulin-dependent (type 1) diabetes mellitus (IDDM), stiff man syndrome, and polyendocrine autoimmune disease. Antibodies to GAD in IDDM patients usually recognize conformation-dependent regions on GAD65 and rarely bind to the second isoform, glutamic acid decarboxylase-67 (GAD67). In contrast, those present in stiff man syndrome and polyendocrine disease commonly target the second isoform (GAD67) and include antibodies that are less dependent on the conformation of the molecule. By immortalizing peripheral blood B cells with Epstein-Barr virus, we have generated three human IgG autoantibodies, termed b35, b78, and b96, to GAD65 from one patient with multiple autoantibodies to endocrine organs and Graves' disease. All three autoantibodies are of the IgG1 isotype, with islet cell activity, and do not react with GAD67. The regions on GAD65 recognized by the three autoantibodies have been investigated by immunoprecipitation with a series of chimeras, by binding to denatured and reduced antigens, and using protein footprinting techniques. Using chimeric GAD proteins, we have shown that b35 targets the IDDM-E1 region of GAD65 (amino acids 240-435) whereas both b78 and b96 target the IDDM-E2 region of GAD65 (amino acids 451-570). Furthermore, examination of binding to recombinant GAD65 and GAD67 by Western blotting revealed some differences in epitope recognition, where only b78 bound denatured and reduced GAD65. However, b35, b78, and b96 autoantibodies had different footprinting patterns after trypsin treatment of immune complexes with GAD65, again indicating different epitope recognition. Our results indicate that antibodies to GAD65 present in nondiabetic patients with multiple autoantibodies to endocrine organs show similarities to those in IDDM (by targeting IDDM-E1 and IDDM-E2 regions of GAD65) as well as subtle differences in epitope recognition (such as binding to denatured and reduced GAD65 and by protein footprinting). Thus, the GAD65 epitopes recognized by autoantibodies in different autoimmune diseases may overlap and be more heterogeneous than previously recognized.
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PMID:Human B cells secreting immunoglobulin G to glutamic acid decarboxylase-65 from a nondiabetic patient with multiple autoantibodies and Graves' disease: a comparison with those present in type 1 diabetes. 925 51

Approximately one-half of Caucasians with newly diagnosed insulin-dependent diabetes mellitus (IDDM) have autoantibodies to insulin, and the majority of those express the HLA-DR4 genotype [Ziegler, R., Alper, C. A., Awdeh, Z. L., Castano, L., Brink, S. J., Soeldner, J. S., Jackson, R. A. & Eisenbarth, G. S. (1991) Diabetes 40, 709-714]. However, it has been difficult to demonstrate T cell proliferative responses to human insulin in IDDM patients [Durinovic-Bello, I., Hummel, M. & Ziegler, A. G. (1996) Diabetes 45, 795-800]. We have immunized transgenic mice expressing the susceptible HLA-DR (alpha1*0101,beta1*0401) (hereafter called DRB1*0401) and human CD4 molecules on a murine major histocompatibility complex class II null background, with human preproinsulin (PPI), proinsulin (PI), and insulin and derived large panels of T cell hybridomas to determine the immunogenic epitopes of these proteins. These results show that the prohormones PI or PPI carry the major immunogenic T cell epitope in the DRB1*0401 transgenic mice. The PPI/PI immunodominant epitope LALEGSLQK was localized at the C-peptide/A-chain junction. This T cell epitope PPI/PI LALEGSLQK is unusual because, normally, it is proteolytically destroyed during the maturation of the insulin molecule. Additionally, this T cell epitope is both processed and presented by human DRB1*0401-positive Epstein-Barr virus transformed B cells, and it can also stimulate T cells from the peripheral blood of HLA-DR4-positive patients with type 1 diabetes. These findings may partly explain why susceptibility to type 1 diabetes is associated with HLA-DR4-positive individuals and why T cell responses to the mature insulin protein are rarely detected in IDDM patients.
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PMID:T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. 952 Apr 53

We tested the efficacy of biolistic-mediated gene transfer as a noninvasive therapy for type 1 diabetes (T1D) in nonobese diabetic (NOD) mice by expression of murine interleukin 4 (mIL-4) cDNA. Epidermal delivery of 2 microg of DNA yielded transient detection of serum mIL-4, using a conventional cDNA expression vector. A vector stabilized by incorporation of the Epstein-Barr virus (EBV) EBNA1/oriP episomal maintenance replicon produced higher levels of serum mIL-4 that persisted for 12 days after inoculation. Although biolistic inoculation of either vector reduced insulitis and prevented diabetes, the protracted mIL-4 expression afforded by the EBV vector resulted in Th2-type responses in the periphery and pancreas and more significant protection from the onset of diabetes. Our studies demonstrate the efficacy of biolistic gene delivery of stabilized cytokine expression as a viable therapeutic approach to prevent the onset of T1D.
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PMID:Biolistic-mediated interleukin 4 gene transfer prevents the onset of type 1 diabetes. 1095 99

Insulin-dependent diabetes mellitus in the NOD mouse model is caused by the T cell-mediated autoimmune destruction of pancreatic beta cells. Viral IL-10 (vIL-10), encoded in the Epstein-Barr virus genome, shares many of the anti-inflammatory properties of cellular IL-10, but lacks its immunostimulatory properties. In the present study, we generated transgenic (Tg) NOD mice in which vIL-10 was produced exclusively in pancreatic islets and investigated the effect of vIL-10 on the development of diabetes. The accumulation of lymphocytes around islets was more prominent, but the invasive insulitis decreased in the vIL-10 Tg mice. The incidence of diabetes was markedly reduced in the vIL-10 Tg mice, in clear contrast to the accelerated diabetes seen in the murine IL-10 Tg NOD mice. IL-12p40 and IFN-gamma mRNA levels were decreased in pancreata of the vIL-10 Tg mice, although CD4 mRNA level was markedly increased. These results suggest that locally produced vIL-10 induced leukocyte migration, but inhibited the activation of T(h)1, probably through suppressing the production of IL-12. They indicate that vIL-10 may well be superior to cellular IL-10 in the treatment of autoimmune diabetes. The vIL-10 Tg NOD mice should provide a useful tool for understanding the differential action of vIL-10 versus cellular IL-10.
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PMID:Suppression of T(h)1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10. 1131 56

Cytotoxic CD8 T lymphocytes (CTL) are effectors of pancreatic islet beta-cell destruction in type 1 diabetes but, with the exception of a single report, CTL to islet antigen peptides have not been identified. We used autologous blood monocyte-derived dendritic cells to elicit HLA-A2-restricted CTL to a peptide, MVWESGCTV (aa 797-805), that is contiguous with a dominant CD4 T-cell epitope in the islet antigen tyrosine phosphatase IA-2. IA-2 peptide-specific CTL activity measured as 51Cr release from autologous lymphoblasts was detected in 2/6 islet antibody-positive relatives at high risk for type 1 diabetes but also in 2/6 closely HLA-matched controls. All subjects had CTL activity to an HLA-A2-restricted Epstein-Barr virus peptide. CTL to the IA-2 self-peptide were therefore not disease-specific, consistent with other evidence that autoreactive T cells are present in healthy individuals.
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PMID:Cytotoxic T cells to an epitope in the islet autoantigen IA-2 are not disease-specific. 1135 32

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