Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Molecular mimicry between viral antigens and host proteins was often suggested to be involved in induction of autoimmune diseases. In type 1 diabetes where pancreatic beta cells are destroyed by autoimmune phenomena, a linear sequence homology between a major autoantigen, glutamate decarboxylase (GAD), and the 2C protein of coxsackie B4 was identified. In addition, a sequence homology between GAD and the mycobacterial heat shock protein 60 was described and the suggestions were made that molecular mimicry between GAD, coxsackievirus B4-2C protein, and/or heat shock protein 60 (hsp60) may be actively involved in an autoimmune reaction towards the pancreatic beta-cells. Our group was the first to isolate human monoclonal autoantibodies to GAD (MICA 1-6) from a patient with newly diagnosed type 1 diabetes. The MICA allowed a detailed characterization of the diabetes associated self-epitopes in GAD and represent a set of GAD autoantibodies present in sera from patients with type 1 diabetes. Using deletion mutants of GAD we demonstrated that the regions of GAD covering the homology sequences to coxsackievirus B4 and to the hsp60 were absolutely required for binding of the MICA to GAD. We now designed an antibody-based analysis to ask whether molecular mimicry between GAD and coxsackie B4-2C or hsp60 is relevant in type 1 diabetes. Since part of the MICA recognize conformational epitopes, they allow to test for conformational molecular mimicry in viruses that have been incriminated in the development of type 1 diabetes. Our data reveal no crossreactivity between the diabetes associated GAD epitopes defined by the MICA and hsp60, rubellavirus, cytomegalovirus, and coxsackie B1-B6 virus antigens. Neither coxsackie B4-specific antibodies in sera from normal individuals nor GAD-positive sera from patients with type 1 diabetes indicated a crossreactivity between coxsackie B4-2C and GAD. Although the regions in GAD homologous to coxsackie B4-2C and hsp60 represented parts of GAD indispensible for binding of diabetes associated autoantibodies they did not mediate a crossreactivity of autoantibodies between GAD and these two proteins. No evidence for molecular mimicry between GAD and a whole panel of foreign antigens was detected by autoantibodies in type 1 diabetes.
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PMID:Sequence homology of the diabetes-associated autoantigen glutamate decarboxylase with coxsackie B4-2C protein and heat shock protein 60 mediates no molecular mimicry of autoantibodies. 791 51

To test the role of glutamic acid decarboxylase (GAD65) or bovine serum albumin (BSA) autoimmunity in the pathogenesis of diabetes, GAD65 or BSA was injected intraperitoneally into neonatal female NOD mice (100 micrograms/mouse of each protein). Treatment with GAD65, but not with BSA, significantly delayed the onset of diabetes compared with control mice (P < 0.05). At 18 weeks, 6 of 10 control mice compared with 0 of 10 GAD65-treated mice (P = 0.005) and 7 of 14 BSA-treated mice had developed diabetes. However, after 79 weeks, 6 of 10 of the GAD65-treated mice were diabetic compared with 9 of 10 of the control mice and 12 of 14 of the BSA-treated mice. In GAD65-treated mice without diabetes, insulitis was markedly reduced compared with control or BSA-treated mice (P < 10(-4)). To further elucidate why GAD becomes an autoantigen, the expression in NOD mice islets was studied. Quantitative immunohistochemistry revealed that islet cell expression of GAD was increased in 5-week-old NOD mice compared with BALB/c mice (P = 0.02). With the occurrence of insulitis (9-15 weeks), the GAD expression was further increased relative to 5-week-old NOD mice (P < 0.02). In conclusion, GAD, but not BSA, autoimmunity is important for the development of diabetes in NOD mice. Furthermore, concordant with the appearance of insulitis, the GAD expression increased in NOD mouse islets, which could possibly potentiate the beta-cell-directed autoimmunity.
Diabetes 1994 Dec
PMID:Neonatal tolerization with glutamic acid decarboxylase but not with bovine serum albumin delays the onset of diabetes in NOD mice. 795 2

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS, taking part in processes which are now relatively well understood but also in processes which are remarkable progress has been achieved. The most thoroughly studied field of GABA operation is its role of inhibitory neurotransmitter realized through the mediation of GABA-A and GABA-B receptors. There are at least 40 per cent of synaptic inhibitory events in the CNS in which the neurotransmitter action of GABA is involved. The action of GABA on GABA-A receptor, a Cl- channel, is influenced by benzodiazepines, barbiturates and other substances, suggesting that some neurological and psychiatric diseases are connected with the function of GABA-A receptor. In addition to synaptic inhibition, GABA has several metabolic regulatory functions. GABA is produced not only in neurons but also in beta cells of the pancreas and in tubular cells of the kidney cortex. Its role in these parenchymatous cells is not sufficiently understood. Similarly as GABA, glutamic acid decarboxylase (GAD), an enzyme catalysing GABA formation from glutamate, has also been intensively studied. GAD structure, its function in various parts of the CNS and in some parenchymatous cells, and the regulation of GAD activity are still in the focus of interest. Recently GAD has been demonstrated to act as autoantigen in the rare neurological disease "stiff man syndrome" (SMS) and in insulin-dependent diabetes mellitus (IDDM). In the presented paper a short review of GABA functions, GAD properties and of the antigenic feature of GAD are given. (Fig. 7, Ref. 41.)
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PMID:[Gamma-aminobutyric acid and glutamate decarboxylase]. 800 82

Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. Thus it may not be necessary to identify the target autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity.
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PMID:Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. 801 Dec 98

T lymphocytes are implicated in the pathogenesis of Type 1 (insulin dependent) diabetes. Activated T lymphocytes expressing IL-2 receptors are found at increased levels in the peripheral blood in the prediabetic period, at diagnosis and for several months after the onset of the disease, but their role in the pathogenesis of the disease is not known. We have used co-culture of peripheral blood lymphocytes with IL-2 alone to selectively generate T cell clones from the in vivo activated T cell population, and examined the phenotype and antigen specificity of the clones derived. From 3 patients with newly-diagnosed Type 1 diabetes 184 clones were generated, the majority of which (39%) were CD4+TCR alpha beta+, whilst 31% were CD8+TCR alpha beta+. From 2 healthy control subjects 90 clones were obtained, of which 62% were CD4+TCR alpha beta+ and 33% were CD8+TCR alpha beta+. Antigen specificity was examined in 46 clones from the patients and 44 from the control subjects in proliferation assays, using as antigens homogenate of human islets of Langerhans, human islet membrane preparation and human liver membrane preparation. Three clones (all CD4+TCR alpha beta+) from the patients, but none from the control subjects, proliferated in a dose dependent fashion in response to stimulation with human islet homogenate presented by autologous APCs, but to neither of the other autoantigen preparations. Our results demonstrate that a relatively high proportion (7%) of T lymphocytes activated in vivo recognise human islet antigens, indicating that they may have a role in the pathogenesis of the disease.
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PMID:T cell clones generated from patients with type 1 diabetes using interleukin-2 proliferate to human islet antigens. 802 12

The mechanisms involved in the targeting of proteins to different cytosolic compartments are still largely unknown. In this study we have investigated the targeting signal of the 65-kD isoform of glutamic acid decarboxylase (GAD65), a major autoantigen in two autoimmune diseases: Stiff-Man syndrome and insulin-dependent diabetes mellitus. GAD65 is expressed in neurons and in pancreatic beta-cells, where it is concentrated in the Golgi complex region and in proximity to GABA-containing vesicles. GAD65, but not the similar isoform GAD67 which has a more diffuse cytosolic distribution, is palmitoylated within its first 100 amino acids (a.a.). We have previously demonstrated that the domain corresponding to a.a. 1-83 of GAD65 is required for the targeting of GAD65 to the Golgi complex region. Here we show that this domain is sufficient to target an unrelated protein, beta-galactosidase, to the same region. Site-directed mutagenesis of all the putative acceptor sites for thiopalmitoylation within this domain did not abolish targeting of GAD65 to the Golgi complex region. The replacement of a.a. 1-29 of GAD67 with the corresponding a.a. 1-27 of GAD65 was sufficient to target the otherwise soluble GAD67 to the Golgi complex region. Conversely, the replacement of a.a. 1-27 of GAD65 with a.a. 1-29 of GAD67 resulted in a GAD65 protein that had a diffuse cytosolic distribution and was primarily hydrophilic, suggesting that targeting to the Golgi complex region is required for palmitoylation of GAD65. We propose that the domain corresponding to a.a. 1-27 of GAD65, contains a signal required for the targeting of GAD65 to the Golgi complex region.
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PMID:A signal located within amino acids 1-27 of GAD65 is required for its targeting to the Golgi complex region. 803 38

Glutamic acid decarboxylase (GAD) is an autoantigen of the islet cell antibodies (ICAs) present in type I diabetes. GAD autoantibodies are also found in patients with stiffman syndrome and in certain ICA-positive individuals who rarely develop diabetes on long-term follow-up. This latter subset of ICA has been termed restricted or beta-cell-specific ICA because the antibodies react with only the beta-cells of the islet. By immunoprecipitation of recombinant GAD65 and GAD67 protein and protein fragments, 83% of sera from individuals with new-onset diabetes or prediabetes (n = 30) had GAD65 autoantibodies, but only 26% had GAD67 autoantibodies. In contrast, all restricted ICA sera (n = 6) had both GAD65 and GAD67 autoantibodies. In both types of sera, the binding of GAD67 autoantibodies could be blocked by preincubation of the serum with GAD65 and GAD67, but the binding of GAD65 autoantibodies could not be blocked by preincubation with GAD67. The titer of GAD65 autoantibodies was much higher in the restricted ICA sera (titer > 1:1,000) than in the sera from individuals with new-onset diabetes or prediabetes (titer < 1:100) and was reflected by the greater amount of GAD65 protein immunoprecipitated by restricted ICA sera (2.61 +/- 1.39 U) compared with sera from individuals with new-onset diabetes (0.51 +/- 0.34 U). The restricted ICA sera immunoprecipitated equimolar amounts of GAD65 protein fragments, suggesting a non-conformational or linear epitope; epitope mapping localized the major epitope region to amino acids 361-442 and a second minor epitope region to amino acids 1-195.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Aug
PMID:Identification of glutamic acid decarboxylase autoantibody heterogeneity and epitope regions in type I diabetes. 803 4

Early therapy made possible by the predictive tests discussed above, using selective or even antigen-specific therapy, opens the way to more radical and much more innocuous therapeutic approaches of major AIDs. It should be realized, however, that before the putative autoantigens have been identified, immunotherapy must be based on nonantigen-specific agents. The results recently obtained in NOD mice indicate that the goal of nontoxic, long-lasting immune protection from the disease is feasible if treatment is started early enough. In some cases (anti-T cell monoclonal antibodies), it appears that specific unresponsiveness can be induced even in the absence of a concomitant administration of the autoantigen. In the case of IDDM, one must convince clinical diabetologists, patients, and their families that immunoprevention of the disease will only be achieved if research on both prediction and immunotherapy proceeds hand in hand: prediction programs are difficult to run without proposing access to preventive therapy, and the search for therapy cannot be successful without access to prediabetics or patients with preclinical diabetes and they can only be identified in prediction clinics. In brief, the two research approaches, prediction and specific therapy, have to be carried out in parallel until their convergence allows the final immunoprevention of the disease.
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PMID:Predictive medicine in autoimmune diseases: from the identification of genetic predisposition and environmental influence to precocious immunotherapy. 805 Jan 86

The diabetes syndrome of the BB rat resembles human Type 1 (insulin-dependent) diabetes including the prevalence of autoantibodies to the 64 kDa Beta-cell autoantigen, which has been identified as glutamate decarboxylase. This study aimed at detecting the prevalence and level of glutamate decarboxylase autoantibodies in 120-day-old diabetic and non-diabetic diabetes-prone BB/OK rats compared to those of sex- and age-matched diabetes-resistant LEW.1A rats. The antibodies were detected using semipurified glutamate decarboxylase from rat brain in two immunoassays, a direct and a sandwich enzyme-linked immunosorbent assay. For the last assay autoantibody-containing immunoglobulins of a serum from a patient with the stiff-man syndrome were used to bind specifically the enzyme as autoantigen in plastic wells. The antibody levels measured as optical density at 490 nm (x +/- SD)/prevalence of the diabetic group (120 +/- 29 days of age) of BB/OK rats 0.57 +/- 0.29 (n = 51)/88% as well as those of the nondiabetic group (121 +/- 26 days of age) with 0.51 +/- 0.29 (n = 32)/97% was significantly increased (p < 0.01) compared to those of the diabetes-resistant control group 0.15 +/- 0.06 (n = 29)/0%. Furthermore in a 209 +/- 27-day-old group (n = 21) of non-diabetic but diabetes-prone BB/OK rats the autoantibody levels of 1.21 +/- 0.39 vs 0.51 +/- 0.26 were further significantly enhanced (p < 0.01). These results were confirmed by a sandwich assay.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autoantibodies to glutamate decarboxylase detected in diabetes-prone BB/OK rats do not distinguish onset of diabetes. 805 59

Immune reactivity to the enzyme glutamic acid decarboxylase (GAD), a pancreatic islet autoantigen, is present at the diagnosis of insulin-dependent diabetes mellitus (IDDM). Because GAD is also highly expressed in the nervous system, we investigated the presence of autoantibodies to the isoform GAD65 in patients with diabetic neuropathy, which is a debilitating complication of the disease. We studied 39 patients with autonomic and somatic neuropathy, 28 patients matched for age and IDDM duration, and 13 patients with a shorter duration of IDDM, all with no diabetic complications, as well as 50 recently diagnosed diabetic patients, 23 neurologic patients with idiopathic autonomic failure unrelated to IDDM, and 72 healthy subjects. An immunoprecipitation radioligand assay was used to detect anti-GAD65 autoantibodies with in vitro transcribed and translated human islet GAD65 as antigen. Autoantibodies to GAD65 were present in 56% of the diabetic patients with neuropathy, 57% of the long-duration and 69% of the short-duration diabetic control subjects, 78% of the recently diagnosed patients, and 13% of the nondiabetic neuropathic patients. Among the diabetic patients with neuropathy, there was no correlation between the presence of anti-GAD65 antibodies and the presence of autoantibodies to sympathetic ganglia, vagus nerve, or adrenal medulla structures identified by immunofluorescence. Our study shows that anti-GAD65 antibodies are present in a high proportion of patients with diabetic neuropathy but are not exclusively associated with it, rendering it unlikely that they have a role as a disease marker or that they are pathogenetic.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Sep
PMID:High prevalence of autoantibodies to glutamic acid decarboxylase in long-standing IDDM is not a marker of symptomatic autonomic neuropathy. 807 Jun 15


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