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)

The diversity of HLA antigens frequencies associated with Insulin Dependent Diabetes Mellitus (IDDM) reported in different populations raised the importance of determining HLA-A, -B and -C specificities in patients with IDDM in the Egyptian population. The study has been carried out on thirty patients with IDDM and thirty healthy control subjects matched for age and sex as patients included in the study. The results of the present work showed that patients with IDDM showed a significant increase in frequency of HLA-A2, HLA-B8 and HLA-B15. These findings are in accordance with the genetic heterogeneity of IDDM which is in turn in harmony with the modern concept on the complex aetiology of the disease. On the other hand, HLA-A3, HLA-B5 and HLA-B7 have been found significantly decreased in patients with IDDM, thus suggesting that these alleles may confer a protective effect from acquiring the disease. When HLA specificities have been studied in relation to the age of onset of the disease, HLA-A29 have been found in higher frequency in the age group after 15 years, while HLA-B15 in that before 15 years. This variability may be related to variation in the viral agents responsible for the infectious mechanism.
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PMID:HLA-A, -B and -C specificities in insulin dependent diabetes mellitus in the Egyptian population. 387 1

For a preliminary estimation of the prevalence and significance of HLA antigens, tests were carried out on the A and B loci in an unselected group of 107 patients with type 1 diabetes in Bucharest. Monospecific antisera furnished by NIH, Bethesda were used. For HLA-A the following data were obtained: A2 (20.3% of the total specificities); A1 (18.4%); A3 (14.0%); A28 (10.1%). Provisional estimations in the healthy population also indicated HLA-A2 as being more frequent than followed by A30/31, A1, A9, A3. For HLA-B: B7 (38.2%); B5, B12 and B14 (14.0% each); B8 (11.1%). In the healthy subjects, the order was B12, B35, B5, B8 the same as B18, then B7 (which did not exceed 11%). The most frequently encountered haplotypes in the diabetic patients were: A2/B7 (8.4% of the total haplotypes); A3/B7 (6.9%); A1/B7 (6.6%); A10/B7 (3.8%); A9/B7 and A11/B7 (3.6% each). An unexpectedly high frequency of the HLA-B7 antigen was found in group of diabetic patients investigated, contrasting with its assumed "protector" role in the Caucasian population. The frequency of antigen HLA-A3 and haplotype HLA-A3/B7 infringes their listing in the "resistance axis" to diabetes.
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PMID:Testing histocompatibility antigens (loci A and B) in a group of type 1 (insulin-dependent) diabetic patients in Bucharest. 404 1

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

Particular major histocompatibility complex (MHC) class II alleles clearly contribute to T cell-mediated autoimmune type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice. However, studies in NOD mice indicate MHC class I-restricted T cell responses are also essential to T1D development. In humans, epidemiological studies have suggested that some common class I alleles, including HLA-A2.1 (A*02011), may confer increased susceptibility to T1D when expressed in conjunction with certain class II alleles. We show here that when HLA-A2.1 molecules are transgenically expressed in NOD mice, A2-restricted T cell responses arise against pancreatic beta cells, leading to an earlier onset of T1D. The accelerated onset of T1D in the NOD.HLA-A2.1 transgenic mice is not due to nonspecific effects of expressing a third class I molecule, because a stock of NOD mice transgenically expressing HLA-B27 class I molecules showed no such acceleration of T1D, but rather were significantly protected from disease. These findings provide the first functional evidence that certain human MHC class I molecules can contribute to the development of T1D.
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PMID:Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. 1236 80

The adaptive immune system generates CD8 cytotoxic T lymphocytes (CTLs) as a major component of the protective response against viruses. Knowledge regarding the nature of the peptide sequences presented by HLA class I molecules and recognized by CTLs is thus important for understanding host-pathogen interactions. In this study, we focused on identification of a CTL epitope generated from coxsackievirus B4 (CVB4), a member of the enterovirus group responsible for several inflammatory diseases in humans and often implicated in the triggering and/or acceleration of the autoimmune disease type 1 diabetes. We identified a 9-mer peptide epitope that can be generated from the P2C nonstructural protein of CVB4 (P2C(1137-1145)) and from whole virus by antigen-presenting cells and presented by HLA-A2.1. This epitope is recognized by effector memory (gamma interferon [IFN-gamma]-producing) CD8 T cells in the peripheral blood at a frequency of responders that suggests that it is a major focus of the anti-CVB4 response. Short-term CD8 T-cell lines generated against P2C(1137-1145) are cytotoxic against peptide-loaded target cells. Of particular interest, the epitope lies within a region of viral homology with the diabetes-related autoantigen, glutamic acid decarboxylase-65 (GAD(65)). However, P2C(1137-1145)-specific cytotoxic T lymphocyte (CTL) lines were not activated to produce IFN-gamma by the GAD(65) peptide homologue and did not show cytotoxic activity in the presence of appropriately labeled targets. These results describe the first CD8 T-cell epitope of CVB4 that will prove useful in the study of CVB4-associated disease.
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PMID:Identification of a naturally processed cytotoxic CD8 T-cell epitope of coxsackievirus B4, presented by HLA-A2.1 and located in the PEVKEK region of the P2C nonstructural protein. 1556 50

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL (adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1*0401 and HLA-DRB1*0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2,B44, DRB1*0401,DQB1*0301) and the 62.1AH (HLA-A2,B15(62),DRB1*0401,DQB1*0302). HLA-B15 marked susceptibility and HLA-B44 marked with resistance to T1DM in patients and controls preselected for HLA-DRB1*0401. A gene between TNFA and HLA-B on the 8.1AH (HLA-A1,B8,;DR3,DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL+446*T and HLA-A2,B15) were screened in donors preselected for HLA-DRB1*0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL+446*T and HLA-A2,B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA-DRB1*0401, DQB1*0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.
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PMID:Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes? 1585 1

Type 1 diabetes is thought to result from the destruction of beta-cells by autoantigen-specific T-cells. Observations in the NOD mouse model suggest that CD8+ cytotoxic T-cells play an essential role in both the initial triggering of insulitis and its destructive phase. However, little is known about the epitopes derived from human beta-cell autoantigens and presented by HLA class I molecules. We used a novel reverse immunology approach to identify HLA-A2-restricted, naturally processed epitopes derived from proinsulin, an autoantigen likely to play an important role in the pathogenesis of type 1 diabetes. Recombinant human proinsulin was digested with purified proteasome complexes to establish an inventory of potential COOH-terminals of HLA class I-presented epitopes. Cleavage data were then combined with epitope predictions based on the SYFPEITHI and BIMAS algorithms to select 10 candidate epitopes; 7 of these, including 3 with a sequence identical to murine proinsulin, were immunogenic in HLA-A2 transgenic mice. Moreover, six of six tested peptides were processed and presented by proinsulin-expressing cells. These results demonstrate the power of reverse immunology approaches. Moreover, the novel epitopes may be of significant interest in monitoring autoreactive T-cells in type 1 diabetes.
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PMID:Identification of naturally processed HLA-A2--restricted proinsulin epitopes by reverse immunology. 1598 6

Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with beta cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of beta cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLA-A2(insB10-18) tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with beta cell destruction in type 1 diabetes in humans.
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PMID:Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. 1633 97

Islet autoreactive CD8 T cells are plausible candidates for direct beta cell toxicity in type 1 diabetes (T1DM). In 2005, cellular studies in the pathogenesis of this disease have reached a new milestone. Autoreactive CD8 T cells have been defined and several target islet epitopes of these have been discovered and validated simultaneously in three independent studies. The insulin B10-B18 peptide that displays exceptional binding affinity for HLA-A2 has been reported in all three studies, and its recognition shows an association with autoimmune beta cell destruction and T1DM. These studies imply that CD8 T cell-based HLA tetramers and ELISPOT analyses can be useful to monitor T1DM as well as islet transplantation, and may provide useful tools to assess immunological efficacy of immune intervention trials.
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PMID:HLA class I epitope discovery in type 1 diabetes: independent and reproducible identification of proinsulin epitopes of CD8 T cells--report of the IDS T Cell Workshop Committee. 1713 May 27

Type 1 diabetes mellitus (T1DM) results from the destruction of beta cells by autoantigen-specific T cells. In the non-obese diabetic (NOD) mouse model, CD8+ T cells play an essential role in both the initial triggering of insulitis and its destructive phase, and proinsulin (PI) is one of the dominant target antigens (Ags). However, little is known about the beta cell epitopes presented by HLA class I molecules and recognized by human CD8+ T cells. We and other groups recently applied reverse immunology approaches to identify HLA class I-restricted PI epitopes. To establish an inventory of potential naturally processed epitopes, whole human PI or the transitional region between the B-chain and C-peptide were digested with purified proteasome complexes. By combining proteasome digestion data with epitope prediction algorithms, candidate epitopes restricted by HLA-A2.1 and other HLA class I molecules were identified. We validated immunogenicity and natural processing of the identified PI epitopes in HLA-A2.1-transgenic mice, while others demonstrated recognition of multiple PI epitopes by CD8+ T cells from T1DM and healthy subjects in the context of different HLA class I molecules. These results demonstrate the power of reverse immunology strategies for epitope discovery. DNA vaccination of HLA-transgenic mice may be another rapid and efficient reverse immunology approach to map additional epitopes derived from other T1DM Ags, such as IA-2 and glutamic acid decarboxylase 65 (GAD 65). Transfer of this information to Elispot- and MHC tetramer-based assay formats should allow to reliably detect and characterize autoreactive CD8+ T cell responses in T1DM, and may open new avenues for early T1DM diagnosis and immune intervention.
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PMID:HLA class I epitope discovery in type 1 diabetes. 1713 May 54


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