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)

Free radical-mediated oxidative damage and consequent protein modification by the end products of oxidative damage are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Oxidative modification of proteins has been shown to elicit antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM), and rheumatoid arthritis (RA). Oxidatively modified DNA (8-oxodeoxyguanine) and low-density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE)-modified 60-kDa Ro autoantigen elicits an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE-modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma-specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. In the face of overwhelming evidence for the involvement of oxidative damage in autoimmunity the administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, although results in cardiovascular disease are disappointing.
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PMID:Oxidatively modified autoantigens in autoimmune diseases. 1686 87

Although potentially autoreactive T cells are present even in healthy subjects, most individuals do not develop autoimmune disease. It has been well demonstrated that CD4+ CD25+ regulatory T cells play a significant role in controlling the expansion of autoreactive T cells in the periphery. However, some healthy individuals exhibit measurable responses to self peptide even in the presence of CD4+ CD25+ regulatory cells. This article describes the regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65 (GAD65), an autoantigen implicated in type-1 diabetes, by autologous CD8+ suppressor T cells. In cells cultured from healthy individuals, the inclusion of autologous CD8+ T cells at physiological levels resulted in a dramatic decrease in the magnitude of in vitro CD4+ T cell responses to GAD65 peptide. Based on transwell experiments, the observed suppression was cell contact-dependent. However, antibody blocking studies indicated that suppression was mediated by IL-10. Cell fractionation studies suggested that CD8+ suppressor T cells originate from the CD45RA+ CD27- population. The suppression of CD4+ T cell responses to GAD65 in healthy individuals raises the possibility that CD8+ suppressor T cells play an important role in controlling potentially autoreactive T cells in the general population.
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PMID:CD8+ suppressor-mediated regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65. 1716 50

Systemic administration of islet-derived antigens has been shown to protect against diabetes in the non-obese diabetic (NOD) mouse by the induction of antigen-specific regulatory T cells. Bystander regulation to related and unrelated islet-derived antigens (intramolecular and intermolecular recognition) in this context is recognized. We tested if intranasal administration of glutamic acid decarboxylase 65 (GAD 65)-derived peptides could protect against both autoimmune and, through bystander regulation, alloimmune responses in a NOD mouse model. Spontaneously diabetic female NOD mice underwent islet transplantation from either C57Bl/6 or NOD islet donors. Islet recipients were treated with intranasal GAD 65-derived peptides or control (ovalbumin) peptide pre- and post-transplantation. In-vitro analysis of the effect of inhalation was defined using lymph node proliferation assays and supernatant analysis for cytokines. GAD 65-derived peptide inhalation resulted in significant protection against recurrent autoimmune disease, with the generation of an interleukin (IL)-10-producing immune phenotype in a syngeneic islet transplant model. This phenotype, however, was not robust enough to protect against alloimmune responses. Inhalation of GAD-derived peptides induces an immunoregulatory response that protects against recurrent autoimmune, but not alloimmune responses in the NOD mouse.
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PMID:Inhalation of glutamic acid decarboxylase 65-derived peptides can protect against recurrent autoimmune but not alloimmune responses in the non-obese diabetic mouse. 1743 24

Type I diabetes is a chronic autoimmune disease resulting in the destruction of insulin-producing beta cells in the pancreas. In humans, disease incidence is linked to expression of specific MHC class II alleles and in mice type I diabetes is associated with the class II allele I-A(g7). I-A(g7) contains a polymorphism that is shared by human class II alleles associated with the disease, at position 57 in the beta chain, in which aspartic acid is changed to a serine. The P9 pocket in the peptide-binding groove is in part shaped by beta57, and therefore the structure of this pocket is modified in I-A(g7). Using mAbs, we have previously determined that alternative conformations of I-A(g7) form in response to peptide binding. In this study, we have extended these findings by examining how peptides induce I-A(g7) molecules to adopt different conformations. By mutating the amino acid in the P9 position of either class II-associated invariant chain peptide (CLIP) or glutamic acid decarboxylase (GAD) 65 (207-220), we have determined that the chemical nature of the P9 anchor amino acid, either acidic or small hydrophobic, affects the overall conformation of the I-A(g7) class II molecule. T cell hybridomas specific for GAD 65 (207-220) in the context of I-A(g7) were also examined for recognition of I-A(g7) bound to GAD 65 (207-220), in which Glu(217) in the P9 position was changed to alanine. We found that although some TCRs were able to recognize both peptides in the context of I-A(g7), and thus both class II conformations, approximately one-third of the T cells tested were not able to recognize the alternate class II conformation formed with the mutated peptide. These results indicate that the I-A(g7) conformations may affect functional activation of T cells, and thus may play a role in autoimmunity.
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PMID:Conformation of MHC class II I-A(g7) is sensitive to the P9 anchor amino acid in bound peptide. 1785 34

The nonobese diabetic (NOD) mouse represents probably the best spontaneous model for a human autoimmune disease. It has provided not only essential information on type 1 diabetes (T1D) pathogenesis, but also valuable insights into mechanisms of immunoregulation and tolerance. Importantly, it allows testing of immunointervention strategies potentially applicable to man. The fact that T1D incidence in the NOD mouse is sensitive to environmental conditions, and responds, sometimes dramatically, to immunomanipulation, does not represent a limit of the model, but is likely to render it even more similar to its human counterpart. In both cases, macrophages, dendritic cells, CD4+, CD8+, and B cells are present in the diseased islets. T1D is a polygenic disease, but, both in human and in NOD mouse T1D, the primary susceptibility gene is located within the MHC. On the other hand, T1D incidence is significantly higher in NOD females, although insulitis is similar in both sexes, whereas in humans, T1D occurs with about equal frequency in males and females. In addition, NOD mice have a more widespread autoimmune disorder, which is not the case in the majority of human T1D cases. Despite these differences, the NOD mouse remains the most representative model of human T1D, with similarities also in the putative target autoantigens, including glutamic acid decarboxylase IA-2, and insulin.
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PMID:Animal models of spontaneous autoimmune disease: type 1 diabetes in the nonobese diabetic mouse. 1787

Stiff-person syndrome is an autoimmune disease characterized by muscle rigidity accompanied by decreased respiratory function. We report a patient with this syndrome who underwent thymectomy under general anesthesia. A 79-year-old woman complaining of increasing muscle rigidity over the past four months was transferred to this hospital. Marked speech disturbance and dysphagia were observed on admission. The diagnosis of stiff-person syndrome was made based on an increase in serum anti-glutamic acid decarboxylase antibody level and thymoma in the anterior mediastinum. Following alleviation of muscle rigidity by high-dose gamma-globulin, thymectomy was scheduled. General anesthesia was given with propofol, fentanyl and epidural ropivacaine. Propofol was continuously infused to maintain BIS below 60 and vecuronium was intermittently administered when muscle contraction was observed in response to electrical stimulation of the ulnar nerve. Despite full recovery of muscle contractility following surgery, tidal volume was too low to remove the tracheal tube, and mechanical ventilation was continued in ICU. One hour after admission to ICU, the tracheal tube was removed, with no marked changes in respiratory condition thereafter. Since many anesthetics are respiratory suppressants that can delay the recovery of respiratory function, careful monitoring of respiratory condition is required postoperatively.
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PMID:[Anesthetic management for thymectomy in a patient with stiff-person syndrome]. 1796 28

Successful transplantation requires the prevention of allograft rejection and, in the case of transplantation to treat autoimmune disease, the suppression of autoimmune responses. The standard immunosuppressive treatment regimen given to patients with autoimmune type 1 diabetes who have received an islet transplant results in the loss of T cells. In many other situations, the immune system responds to T cell loss through cytokine-dependant homeostatic proliferation of any remaining T cells. Here we show that T cell loss after islet transplantation in patients with autoimmune type 1 diabetes was associated with both increased serum concentrations of IL-7 and IL-15 and in vivo proliferation of memory CD45RO(+) T cells, highly enriched in autoreactive glutamic acid decarboxylase 65-specific T cell clones. Immunosuppression with FK506 and rapamycin after transplantation resulted in a chronic homeostatic expansion of T cells, which acquired effector function after immunosuppression was removed. In contrast, the cytostatic drug mycophenolate mofetil efficiently blocked homeostatic T cell expansion. We propose that the increased production of cytokines that induce homeostatic expansion could contribute to recurrent autoimmunity in transplanted patients with autoimmune disease and that therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet transplantation.
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PMID:Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. 1843 11

Stiff Person Syndrome (SPS) is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD-Ab), the key enzyme in gamma-aminobutyric acid synthesis (GABA). In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [(11)C]flumazenil (FMZ) positron emission tomography (PET) in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS.
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PMID:11C-flumazenil positron emission tomography demonstrates reduction of both global and local cerebral benzodiazepine receptor binding in a patient with Stiff Person Syndrome. 1857 17

Oxidative damage mediated by reactive oxygen species results in the generation of deleterious by-products. The oxidation process itself and the proteins modified by these molecules are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Proteins modified in this manner have been shown to induce pathogenic antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM) and rheumatoid arthritis (RA). 8-oxodeoxyguanine (oxidatively modified DNA) and oxidized low-density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE) modified 60 kD Ro autoantigen induces an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. The administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, particularly on account of the overwhelming evidence for the involvement of oxidative damage in autoimmunity. However, this should be viewed in the light of disappointing results obtained with the use of antioxidants in cardiovascular disease.
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PMID:Autoimmunity and oxidatively modified autoantigens. 1862 46

Celiac disease (CD) is a T-cell-mediated enteropathy, triggered in genetically susceptible individuals by the ingestion of wheat gluten or related rye and barley proteins, whose clinical picture disease is considerably heterologous. Patients with CD are at high risk of autoimmune disorders; similarly, CD is frequent in patients with type 1 diabetes mellitus (T1DM), a disorder characterized by the immune-mediated beta-cell destruction, with the cooperation of environmental factors in genetically susceptible individuals. The immunological markers of beta-cell destruction are the autoantibodies to insulin, glutamic acid decarboxylase, and the protein tyrosine phosphatase. In absence of these markers, incidental hyperglycemia in children and adolescents appears unlikely to be associated with the progression to T1DM. We report a girl with CD and incidental hyperglycemia, without immunological markers of T1DM, with a family history for hyperglycemia, and diagnosed as maturity-onset diabetes of the young. We present this case as evidence that the possibility of monogenic forms of diabetes must be suspected in children with incidental hyperglycemia, a family history for mild hyperglycemia or diabetes, and absence of markers of beta-cell destruction, even if the patients are affected by an autoimmune disease.
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PMID:Hyperglycemia in celiac disease: not always pretype 1 diabetes? 1876 37


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