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

With an ultrasensitive noncompetitive enzyme-linked immunosorbent assay (ELISA), we tested the hypothesis that the presence of insulin autoantibodies in nondiabetic individuals is a normal event. Plasma and peripheral blood mononuclear cells were obtained from 50 nondiabetic whites for determination of insulin autoantibodies by ELISA and radioimmunoassay (anti-insulin IgG [AI-IgG] and 125I-labeled insulin bound [%]), islet cell antibodies, anti-nuclear antibodies and rheumatoid factor, and HLA class II-type antigens (DR, DRw, and DQ). The range of 125I-insulin binding was significantly less than was seen in pretreatment sera from individuals with diabetes (from -0.4 to 0.4% vs. -0.8 to 7.7%, respectively, P = 0.001). Eighty-eight percent of these nondiabetic individuals had significant levels of AI-IgG with preferential binding to human insulin. The geometric mean of AI-IgG concentrations in individuals with significant levels was 180 pM. Binding to human insulin was seen in 88%, to pork insulin in 42%, and to beef insulin in 24% of individuals (P less than 0.001 overall; P less than 0.05 where more bound to pork than beef insulin). Binding of AI-IgG to human insulin-coated plates was substantially inhibited by preincubation with human insulin (median inhibition 57.6%) with little if any inhibition by glucagon, C-peptide, albumin, or IgG. Four individuals had highly specific human AI-IgG as shown by immunoaffinity studies. AI-IgGs were significantly higher in individuals with the HLA haplotype DR4,DRw53,DQ3 and lower in individuals with DR5,DRw52,DQ1 (P = 0.03 for both).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Sep
PMID:Presence of insulin autoantibodies as regular feature of nondiabetic repertoire of immunity. 193 23

The association of certain HLA-D alleles with insulin-dependent diabetes mellitus (IDDM) is well known. One hundred and sixty-one non-related diabetic individuals and 142 non-related healthy controls were typed for the HLA DR-DQw-Dw association, using a restriction fragment length polymorphism (RFLP) typing method that combines three probe/enzyme systems: DRB/Taq I, DQB/Taq I, and DQB/Bam HI. Comparison of frequencies in both diabetics and controls confirms previous results in terms of HLA class II and IDDM association. Moreover, we have found that DR3/3 heterozygous individuals are more susceptible to IDDM when they are also Dw25 (associated with B18) than when they are Dw24 (associated with B8). Using oligonucleotide dot-blot hybridizations we analyzed the HLA-DQB1 sequence of DR3,Dw24 and DR3,Dw25 homozygous individuals, and we found no difference at position 57 between these two DR3-carrying haplotypes. This observation points to the heterogeneity of HLA genetic factors in IDDM susceptibility.
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PMID:Heterogeneity of HLA genetic factors in IDDM susceptibility. 197 Mar 33

The human leukocyte antigens (HLA) are implicated in the genetic susceptibility to a large number of diseases. Some of the diseases associated with HLA class II are related to specific amino acids or epitopes of the domain of the HLA class II molecule that is distal to the membrane. In man, selective immunoglobulin A deficiency is the most common immunodeficiency, frequently resulting in recurrent sino-pulmonary infections and gastro-intestinal disorders. Associations have been described with HLA class I, and to a lesser extent with different class II alleles, which might indicate that they share some common feature. Here we study 95 IgA-D patients and find positive associations with three DR-DQ haplotypes and a strong negative association with a fourth haplotype. Comparison of the sequences of the polymorphic amino-terminal domain of the DQ beta chain showed that the three 'susceptibility' haplotypes all had a neutral alanine or valine at position 57. The 'protective' allele had the negatively charged aspartic acid at this position (Asp57). Codon 57 of the HLA-DQ beta chain has been implicated in the susceptibility to insulin-dependent diabetes mellitus. Our data suggest that the same amino acid position could possibly also influence susceptibility and resistance to selective immunoglobulin A deficiency.
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PMID:Different amino acids at position 57 of the HLA-DQ beta chain associated with susceptibility and resistance to IgA deficiency. 197 29

Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) is associated with the HLA-DR3 and DR4 haplotypes. The HLA-DR2 haplotype is negatively associated with IDDM, an association that has been interpreted as dominant protection. Here, we describe the molecular analysis of the HLA class II genes in an unusual family with three HLA-DR1/2 siblings, all of whom have IDDM. With polymerase chain reaction amplification and sequence analysis to characterize the class II alleles, we identified a novel DQB1 allele on the DR1 haplotype and an unusual DQB1 allele on the DR2 haplotype. However, the DRB1 alleles on these DR1 and DR2 haplotypes are the conventional alleles (*0101 and *1501, respectively). These results suggest that it is the conventional DQB1 allele (*0602) not the DRB1 allele (*1501) on the protective DR2 haplotype that confers protection in the general population and, furthermore, that these unusual DQB1 alleles may confer susceptibility to IDDM in this family. The unusual DQB1 allele on this DR2 haplotype encodes Asp at position 57, indicating that it is the allele DQB1*0602 and not simply the presence of this residue that is responsible for the protective effect.
Diabetes 1991 Apr
PMID:Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. 201 48

Transracial analysis provides a method of distinguishing primary associations between insulin-dependent diabetes mellitus (IDDM) and HLA class II alleles from those secondary to linkage disequilibrium. Blacks show DR-DQ relationships that are different from other races and are a useful group in which to investigate HLA-D region associations with IDDM. In this study, the frequencies of HLA-DQA1 and -DQB1 alleles in Afro-Caribbean IDDM and control subjects were compared. Alleles were identified with sequence-specific oligonucleotide probing. The DQA1 allele A3 was positively associated with IDDM (relative risk [RR] = 25.3, corrected P [Pc] less than 7.0 x 10(-6). The DQB1 alleles DQw2 and DQw8 were also positively associated (RR = 4.7, Pc less than 6.5 x 10(-3) and RR = 12.3, Pc = 3.4 x 10(-3), respectively). The A1.2 and DQw6 alleles were negatively associated (RR = 0.16, Pc less than 3.5 x 10(-3) and RR = 0.15, Pc = 2.4 x 10(-2), respectively). These findings were compared to data from other races. The positive associations with A3 and DQw2 are consistent with all racial groups investigated. The negative association with DQw6 is present in all racial groups in which it is a common allele. These findings suggest that DQ alleles, and hence DQ molecules, may directly affect predisposition to IDDM.
Diabetes 1991 Jun
PMID:HLA-DQA1 and -DQB1 alleles associated with genetic susceptibility to IDDM in a black population. 204 Mar 90

The main principles of this hypothesis are very general: (i) signal-detection from background noise is one central issue in electronics; (ii) an important source of misunderstanding at different levels of communication is the fact that a given signal may have different meanings in different contexts; (iii) the unique role of chance in developmental biology is generally appreciated (37). In AIDS the basic defect would be the human specific inability to distinguish between the amino acid sequence of neuroleukin and peptides derived from the gp120 envelope protein of HIV, resulting in a slowly progressing failure of the CD4+ T cell-mediated immunity. In IDDM the postulated HLA class II-dependent hypersensitivity to immunological noise could predispose to random contacts between cells with a different signalling language. In the ensuing dialogue neuroleukin secreted by T cells would imply a continuous demand for insulin secretion to pancreatic beta cells resulting in diabetes. This hypothesis does not contradict with the provocative ideas proposed by Duesberg concerning the relationships between HIV and AIDS (24) and the known data on the genesis of IDDM.
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PMID:Are syntax errors due to the amino acid sequence of neuroleukin involved in the pathogenesis of the acquired immunodeficiency syndrome (AIDS) and insulin dependent diabetes mellitus (IDDM)? 204 84

Notable progress was achieved by the investigations on the immunology of diabetes. Studies of immunogenetics have demonstrated that Type 1 (insulin-dependent) diabetes shows a primary association with the HLA class II genes (e.g., with HLA-DR3 and DR4 in Caucasoid populations), a determining features of this type of the disease. Besides, it presents a wide variety of autoantibodies, such as islet-cell cytoplasmic antibodies (ICA), islet-cell surface antibodies (ICSA), complement-fixing islet-cell antibodies (CF-ICA), antibodies to a Mr-64000 islet-cell protein, and many studies are trying to evaluate their pathogenic and predictive role. Various changes of cell-mediated immunity have been also described. The proportion of activated T cells in circulation is increased in patients with Type 1 diabetes. It was assumed that the T cells are the main cause of pancreatic beta-cell damage. Type 1 diabetes is actually considered as a chronic autoimmune disease, with several stages of evolution leading to the destruction of the pancreatic beta-cells, with a consecutive gradual decrease of insulin secretion. From the therapeutic point of view, many problems are raised by insulin immunogenicity, mainly depending on the so-called "contaminants". To avoid phenomena of allergic reactions, immunological insulin-resistance, lipodistrophy, a.o., highly purified and human type insulins have been prepared. The insulin autoantibodies (IAA) detected before the clinical onset of Type 1 diabetes are considered a new marker of autoimmunity. New hopeful prospects are opened by diabetes immunotherapy, in which Cyclosporin A detains a particular role, although it should be used only in special conditions, under strict clinical observation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunological aspects of diabetes. 219 11

Insulin induced proliferation of blood mononuclear cells, numbers of blood B and T cells, of blood lymphocytes bearing interleukin 2 receptors or HLA class II molecules were assayed at diagnosis and one year later in children with insulin-dependent diabetes mellitus (IDDM) and in healthy children. Insulin and islet cell antibodies were also studied. The numbers of lymphocytes expressing HLA class II molecules and NK cells were increased at diagnosis. T cells of the helper/inducer (CD4+) phenotype and interleukin 2 receptor positive lymphocytes were increased both at diagnosis and one year later. At diagnosis, insulin induced proliferation of blood mononuclear cells in 65% and one year later in 50% of the patients. Insulin antibodies were detected in 10% and islet cell antibodies in 90% of patients at diagnosis, and in 67% and 78%, respectively, one year later.
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PMID:Immune responses to insulin and lymphocyte subclasses at diagnosis of insulin-dependent diabetes and one year later. 220 2

Family and population studies indicate that predisposition to insulin-dependent (type I) diabetes mellitus (IDDM) is polygenic. It has been shown that the absence of the aspartic acid in position 57 (Asp57) of the DQ beta chain is positively correlated to IDDM. However, Asp57-negative haplotypes do not always confer susceptibility and conversely, some Asp57-positive haplotypes seem to be disease associated. It has been suggested that other HLA class II sequences, probably belonging to the HLA DQA1 gene, confer susceptibility to IDDM. This report, based on extensive oligonucleotide dot blot hybridization of PCR-amplified DQA1 and DQB1 genes, reinforces the importance of the Asp57-negative DQ beta chain, but also introduces the possibility that a DQ alpha chain bearing an arginine in position 52 (Arg52) confers susceptibility to IDDM. A molecular model of susceptibility to IDDM is proposed. This model strongly suggests that the disease susceptibility correlates quantitatively with the expression at the cell surface of a heterodimer, composed of a DQ alpha-chain bearing an Arg52 and a DQ beta chain lacking an Asp57. In view of the respective positions of the two residues and their charge, we might anticipate that both residues DQ beta Asp57 and DQ alpha Arg52 are critical for modulation of susceptibility, presumably via viral-antigenic peptide and/or autoantigen presentation.
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PMID:A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. 231 83

A major part of the T lymphocyte response to mumps and Coxsackie B4 virus appears to be restricted by HLA-DR associated restriction elements. This was further corroborated in inhibition experiments using monoclonal antibodies reactive with different HLA class II molecules. Only antibodies reactive with DR molecules significantly inhibited the response. The frequencies of DR restricted antigen-reactive T lymphocytes (ARTL) to mumps and Coxsackie B4 virus were then investigated, using a limiting dilution assay. A decreased frequency of DR3 restricted ARTL to mumps and Coxsackie B4 was found compared to ARTL restricted by other DR associated elements. In contrast, an increased frequency of DR4 restricted ARTL to mumps and Coxsackie B4 was found. The results were similar for healthy individuals and Type 1 diabetic patients. No correlation was found between DR restriction elements and the frequencies of ARTL to varicella-zoster or PPD. The studies indicate that HLA-DR3 and DR4, which are associated with Type 1 diabetes, have a different regulatory function on the proliferative T lymphocyte response to mumps and Coxsackie B4.
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PMID:T lymphocyte responses to Coxsackie B4 and mumps virus. II. Immunoregulation by HLA-DR3 and -DR4 associated restriction elements. 241 85


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