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:C0004364 (autoimmune disease)
24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type I diabetes (TID) is an autoimmune disease characterized in part by the presence of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65), among other pancreatic islet antigens. We investigated the independent epitope specificities of these GAD65 antibodies (GAD65Ab) and their combinations in the sera of new onset TID patients and first-degree relatives positive for GAD65Ab. For our analysis, we used four GAD65-specific recombinant Fabs (rFabs) that recognize different conformational determinants of GAD65 located throughout the molecule, including the N-terminal, the middle and the C-terminal regions. We used these epitope-specific rFabs in competition assays to determine the binding specificity of the autoantibodies found in patient sera. Among the 61 sera from newly diagnosed GAD65Ab-positive TID patients GAD65 binding was competed for 23 sera by all four rFabs, 29 by at least two rFabs, and in nine sera were displaced by one or no rFab. In contrast, none of the 24 sera from GAD65Ab-positive first-degree relatives of TID patients were displaced by all four rFabs. When using all four rFabs simultaneously to compete with GAD65Ab binding, binding of sera from TID patients was reduced by an average of 70%. A significantly weaker competition was observed when evaluating sera of GAD65Ab-positive first-degree relatives (P < 0.0001).
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PMID:Multiplicity of the antibody response to GAD65 in Type I diabetes. 1549 46

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

As an autoimmune disease, type 1 diabetes mellitus (DM) can be associated with other autoimmune disorders. The aim of this study was to detect subclinically associated autoimmune thyroid disease, coeliac disease, and Addison's disease. The presence of autoantibodies was evaluated with special regard to the control of diabetes and to the clinical status of the patient. Fifty-one type 1 diabetic patients (22 men, 29 women, mean age 37+/-11 years, mean duration of diabetes 16+/-13 years) were included into this study. Specific antibodies to islet antigens--glutamic acid decarboxylase (GAD65), protein thyrosine phosphatase IA-2alpha, and to thyroid autoantigens--thyroid microsomal peroxidase (TPO) and thyroglobulin (TG) and also thyroid stimulating hormone (TSH) were measured by RIA. Autoantigens of the small intestine--tissue transglutaminase autoantibodies (ATTG), IgA and IgG antibodies to gliadin (AGA-IgA, AGA-IgG) were evaluated by ELISA. Endomysial autoantibodies (EMA) and adrenal cortex antibodies (ACA) were detected by indirect immunofluorescence microscopy. Eleven new cases of thyreopathy (22 % of patients) were detected by the assessment of thyroid autoantibodies and TSH. Two new cases of thyreotoxicosis were diagnosed during the study. Coeliac disease was diagnosed in at least two cases. Addison's disease was not diagnosed, although the ACA were positive in two patients. No influence of single or combined autoantibody positivity on the control of diabetes was found if normal organ function was preserved. In both patients with thyreotoxicosis the control of diabetes was worsened and improved after treatment. The screening of autoantibodies in type 1 diabetic patients could reveal subclinical cases of AITD or coeliac disease. Subclinical forms of these disorders have no influence on diabetes control. However, impaired organ function may be associated with the worsened control of diabetes as we demonstrated on two newly diagnosed cases of thyreotoxicosis. We suggest the need for the follow-up of patients with positive autoantibodies because further deterioration of the respective organs can be expected.
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PMID:Screening for associated autoimmunity in type 1 diabetes mellitus with respect to diabetes control. 1571 40

Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing beta cells in the islets of Langerhans. From studies in animal models, CD8(+) T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of beta cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8(+) clones isolated from spleens of NOD mice that had been immunized with GAD65(515-524) or insulin B-chain(15-23) peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous beta cells, they differed in the expression of IFN-gamma-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.p. injection into neonatal mice, only the insulin B-chain(15-23)-reactive CD8(+) T clone accelerated diabetes in all recipients after 4 wk, although both insulin- and GAD-reactive clones homed to pancreas and pancreatic lymph nodes with similar kinetics. Diabetes was associated with increased pancreatic T cell infiltration and, in particular, recruitment of macrophages. Thus, secretion of IFN-gamma-inducible protein-10 by autoaggressive CD8(+) lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.
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PMID:Different diabetogenic potential of autoaggressive CD8+ clones associated with IFN-gamma-inducible protein 10 (CXC chemokine ligand 10) production but not cytokine expression, cytolytic activity, or homing characteristics. 1572 83

Type 1A diabetes is a chronic autoimmune disease usually preceded by a long prodrome during which autoantibodies to islet autoantigens are present. These antibodies are directed to a variety of antigens, but the best characterized are glutamic acid decarboxylase-65, insulinoma-associated antigen-2, and insulin. We hypothesize that the natural history of type 1A diabetes can be represented by several stages, starting from genetic susceptibility and ending in complete beta-cell destruction and overt diabetes. Type 1A diabetes probably results from a balance between genetic susceptibility and environmental influences. In both humans and animal models, the major determinants of the disease are genes within the major histocompatibility complex. The next best-characterized susceptibility locus is the insulin gene, the variable nucleotide tandem repeat locus. This gene affects the expression of insulin in the thymus and thus may play a role in the modulation of tolerance to this molecule. In a subset of genetically susceptible individuals, the activation of autoimmunity may be triggered by environmental factors such as viruses and/or diet. However, no conclusive association has been established between type 1A diabetes and specific environmental triggers. In this review, we provide evidence that insulin has a fundamental role in anti-islet autoimmunity.
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PMID:The stages of type 1A diabetes: 2005. 1579 Mar 62

Type 1A diabetes (T1D) is caused by autoimmune islet beta cell destruction precipitated by environmental triggers in genetically predisposed individuals. Islet beta cells produce insulin and are the primary target of this autoimmune disorder. Insulin, glutamic acid decarboxylase, and insulinoma associated-2 autoantibodies (IAA, GAD65, and IA-2) are the autoantibodies that have been associated most clearly with the development of T1D. Despite our current ability to predict T1D using genetic markers and detecting islet autoantibodies, we have yet to find a safe way to prevent the disease. However, there are more than 100 different therapies that prevent T1D in the nonobese diabetic (NOD) mouse model or the BioBreeding (BB) rats. This paper reviews a few select therapeutic approaches that have been or are being evaluated as possibilities for the prevention, amelioration, or cure of T1D.
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PMID:Immunotherapeutic approaches to prevent, ameliorate, and cure type 1 diabetes. 1628 Jun 41

Type 1 diabetes mellitus is an autoimmune disease caused by a culmination of noxious processes of autoimmunity composed of various components of the innate and adaptive immune systems. Current treatment of type 1 diabetes focuses on restraining the endocrine disease without affecting the autoimmune process that underlies it. Prevention of this disease requires immune modulation and early intervention. New therapeutic approaches can be classified on the basis of the immunological arm targeted, that is, T-cell immune modulation (using cytokines, anti-CD3 monoclonal antibodies, and peptide MHC class II dimers), innate immune system modulation (using alpha-galactosylceramide or peptide 277), or specific antigen vaccination (glutamic acid decarboxylase and insulin). Here we review the most promising therapies developed based on these targets and emphasize those that have reached human phase clinical investigation.
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PMID:Innovative immune-based therapeutic approaches for the treatment of type 1 diabetes mellitus. 1631 85

The discovery of islet cell antibodies (ICAs) was the prelude to the understanding that type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease. The issue regarding whether or not the measurement of ICAs should be completely replaced by biochemical markers detecting islet autoantibodies (AAs) for the prediction of T1DM has been the subject of endless international debates. In light of this controversy, we assessed the current role of ICAs as a predictive marker for T1DM progression. We examined a cohort of 1484 first-degree relatives (FDRs) of T1DM probands from the Children's Hospital of Pittsburgh Registry. These relatives were consecutively enrolled between 1979 through 1984 and followed up to 22 yr. Serum obtained at the time of enrollment was assayed for ICAs, glutamic acid decarboxylase (GAD)65, insulin A (IA)-2 AA, and insulin AAs (IAAs). In FDRs who had ICAs in addition to GAD65 and IA-2 AAs, the cumulative risk of developing insulin-requiring diabetes was 80% at 6.7 yr of follow-up, whereas this risk in those with GAD65 and IA-2 AAs without ICAs was only 14% at 10 yr of follow-up (log rank: P < 0.00001). Cox regression analysis showed that diabetes risk was significantly associated with the presence of ICAs in both subjects with low titer and high titer GAD65 and IA-2 AAs. The addition of IAAs in GAD65 and IA-2 AA-positive relatives did not increase the cumulative risk for conversion to insulin-treated diabetes. We provide evidence that a subgroup of ICAs predicts a more rapid progression to insulin-requiring diabetes in GAD65 and IA-2 AA-positive relatives and should remain part of the assessment of T1DM risk for intervention trials. In addition, these findings provide impetus for efforts to identify a novel islet autoantigen(s) reactive with this ICA subset.
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PMID:Cytoplasmic islet cell antibodies remain valuable in defining risk of progression to type 1 diabetes in subjects with other islet autoantibodies. 1639 Mar 85

Type 1 diabetes (T1D) is an autoimmune disease suggested to be of a T helper (Th)1-like origin. This study aimed to investigate the Th1-like and Th2-like profile in high-risk individuals during the prediabetic phase and the immunologic effect of treatment with nicotinamide. High-risk first-degree relatives of T1D patients participating in the European Nicotinamide Diabetes Intervention Trial (ENDIT) were treated with either nicotinamide or placebo. Peripheral blood mononuclear cells (PBMC) were obtained during the prediabetic phase and close to the onset of manifest T1D and from nondiabetic high-risk individuals. Using the sensitive enzyme-linked immunospot (ELISPOT) technique to distinguish Th1-like from Th2-like lymphocytes, secretion of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) was analyzed from PBMCs spontaneously and after in vitro stimulation with the diabetes-associated autoantigens, glutamic acid decarboxylase 65 (GAD65, protein and peptide, aa 247-279), recombinant tyrosine phosphatase (IA-2), and heat shock protein (HSP, aa 437-460). High-risk individuals showed high spontaneous as well as autoantigen-induced IFN-gamma secretion. Secretion of IFN-gamma and the IFN-gamma/IL-4 ratio, induced by autoantigens, decreased in individuals developing T1D (p < 0.05), whereas nondiabetic individuals showed an increased IL-4 response (p < 0.05). Thus, a Th1-dominated cytokine profile observed in high-risk individuals inclined toward a diagnosis of diabetes. Nicotinamide caused decreased spontaneous (p = 0.05) and in vitro autoantigen-induced IFN-gamma secretion (p < 0.05) and may play a role in immune regulation, even though it has not been shown to prevent T1D.
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PMID:Nicotinamide reduces high secretion of IFN-gamma in high-risk relatives even though it does not prevent type 1 diabetes. 1670 96

DNA vaccination of autoimmune diabetes-prone NOD mice with unmodified target islet antigens, i.e., preproinsulin (PPIns) or glutamic acid decarboxylase 65 (GAD65), is poorly protective. However, in this study, we demonstrate protection against disease by covaccination with a mutant B7-1 molecule (B7-1wa) that binds the negative T cell regulator CTLA-4 (CD152), but not CD28. Codelivery of plasmids encoding a PPIns-GAD65 fusion construct and B7-1wa protected against both insulitis and diabetes. In vitro, the T cells of covaccinated mice had negative responses to both insulin and GAD65, and this was restored by adding blocking antibodies to transforming growth factor beta1 (TGF-beta1), suggesting a role for this cytokine. Adoptive transfer experiments revealed that DNA vaccination generated protective CD4(+) regulatory T cells (Tr) of either CD25(+) or CD25(-) phenotype. Furthermore, vaccinated mice had increased numbers of T cells with Tr-associated markers, such as CTLA-4, Foxp3, and membrane-bound TGF-beta1. Tr cells inhibited the responses of diabetogenic T cells to islet antigens, and depletion of T cells expressing membrane-bound TGF-beta1 abolished the suppressive effect. Thus, selective engagement of CTLA-4 during islet-antigen DNA vaccination induces Tr cells that protect against this autoimmune disease.
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PMID:Protective regulatory T cell generation in autoimmune diabetes by DNA covaccination with islet antigens and a selective CTLA-4 ligand. 1679 Mar 65


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