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)

Oxygen free radicals and other oxygen derived species (Superoxide, O2-; Hydroperoxide, HOO; Singlet oxygen, 1O2-; Hydroxyl radical, OH; and Hydrogen peroxide, H2O2) including lipid peroxides have been suggested as important causative agents of aging and several human diseases, including cancer, multiple sclerosis, Parkinson's disease, autoimmune disease, ischemia, anemia, senile dementia, asbestosis and in thalassemia. This paper aims to communicate some of the theories and rationales in aging process and thalassemia.
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PMID:Role of lipid peroxidation and antioxidants in aging process and thalassemia. 134 11

A long-term side effect of therapy with a variety of drugs is a syndrome resembling the idiopathic autoimmune disease, systemic lupus erythematosus. Essentially all patients with drug-induced lupus display autoantibodies to nuclear histone components whose specificity appears to be related to the higher order structure of histones existing in chromatin. IgG antibodies to H1 and the (H2A-H2B)-DNA complex were observed in most patients with lupus induced by procainamide, hydralazine, and quinidine, whereas the H3-H4 tetramer, comprising half the mass of the nucleosome core particle, was largely nonantigenic. IgM antibodies to (H2A-H2B)-containing chromatin subunits were common also. IgM reactivity was observed with the DNA-free H3-H4 tetramer and with H1, especially in hydralazine-induced lupus. These results suggest that IgM antihistone antibodies may result from autoimmunization with a nonnative form of chromatin, whereas IgG antibodies may be selected for reactivity with H1 and a native form of the (H2A-H2B)-DNA subunit of the nucleosome. The chemical basis for induction of autoimmunity by drugs is unclear because lupus-inducing drugs do not have a common structural feature or biological activity nor are they capable of specific reactions with histones, the principal target antigen. However, in the presence of activated neutrophils, procainamide is transformed metabolically to the cytotoxic procainamide-hydroxylamine. Mixing experiments and cell-free studies demonstrated that procainamide was cooxidized with H2O2 by myeloperoxidase released when neutrophils undergo the respiratory burst and degranulation reactions. Preliminary results indicate other lupus-inducing drugs are also biotransformed by this mechanism suggesting that a common denominator linking these drugs may be the capacity to be oxidized to reactive metabolites by the action of activated phagocytic cells.
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PMID:Autoantibody specificity in drug-induced lupus and neutrophil-mediated metabolism of lupus-inducing drugs. 163 38

Resident peritoneal macrophages from New Zealand Black (NZB) mice release O2- and H2O2 after adherence to a plastic surface without any chemical or particulate stimulant. This phenomenon is age dependent and more pronounced in animals with sever autoimmune disease. Significant differences were observed between the high and low breakage NZB sublines (HB and LB), which were previously developed by selective matings on the basis of chromosome breakage rates. The LB subline differs significantly from the HB subline with respect to autoimmune hemolytic anemia and tumor incidence. When the macrophages were stimulated with the tumor promoter TPA, the number of "responders" was higher in the HB than in the LB subline and correlated with the degree of splenomegaly, that is, with the severity of the disease. A negative response to agonist stimulation and very low spontaneous production of active oxygen species was observed in NZW and Swiss mice, which is the normal finding for resident macrophages according to data from the literature. The increased superoxide and hydrogen peroxide production by macrophages of NZB mice is discussed with respect to autoimmune disease and cancer.
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PMID:Superoxide and hydrogen peroxide production by macrophages of New Zealand black mice. 216 74

Suppression of oxidative injury by viral-mediated transfer of the human catalase gene was tested in the optic nerves of animals with experimental allergic encephalomyelitis (EAE). EAE is an inflammatory autoimmune disorder of primary central nervous system demyelination that has been frequently used as an animal model for the human disease multiple sclerosis (MS). The optic nerve is a frequent site of involvement common to both EAE and MS. Recombinant adeno-associated virus containing the human gene for catalase was injected over the right optic nerve heads of SJL/J mice that were simultaneously sensitized for EAE. After 1 month, cell-specific catalase activity, evaluated by quantitation of catalase immunogold, was increased approximately 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the optic nerve. Effects of catalase on the histologic lesions of EAE were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), extent of the cellular infiltrate, extravasated serum albumin labeled by immunogold (for blood-brain barrier disruption), and in vivo H2O2 reaction product. Relative to control, contralateral optic nerves injected with the recombinant virus without a therapeutic gene, catalase gene inoculation reduced demyelination by 38%, optic nerve head swelling by 29%, cellular infiltration by 34%, disruption of the blood-brain barrier by 64%, and in vivo levels of H2O2 by 61%. Because the efficacy of potential treatments for MS are usually initially tested in the EAE animal model, this study suggests that catalase gene delivery by using viral vectors may be a therapeutic strategy for suppression of MS.
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PMID:Adeno-associated viral-mediated catalase expression suppresses optic neuritis in experimental allergic encephalomyelitis. 981 89

Azaspiranes are novel macrophage-targeting agents with activity in preclinical animal models of autoimmune disease and transplantation. The purpose of this work was to determine the effects of atiprimod (SK&F 106615), an azaspirane being developed for the treatment of rheumatoid arthritis, on rat pulmonary alveolar macrophage (AM) function and immunocompetance in Candida-infected mice. AM from rats treated with 20 mg/kg/day of atiprimod for 15 days demonstrated enhanced killing of Candida albicans ex vivo. Concentration-dependent increases in candidacidal activity were also observed as early as one hour after exposure in vitro in AM from untreated normal rats. Treatment of AM with atiprimod in vitro did not increase particulate-stimulated superoxide production or phagocytosis of Candida but decreased their ability to concentrate acridine orange, indicating an increase in lysosomal pH. Increased candidacidal activity was inhibited by superoxide dismutase and catalase, suggesting a role for reactive oxygen intermediates (ROI). Atiprimod also increased free radical-mediated killing of Candida in the presence of H2O2, iron and iodide in a cell-free system. These findings indicated that treatment with atiprimod increased the candidacidal activity of rat AM in a free radical-dependent manner. The data also suggested that atiprimod did not increase ROI production by AM, but rather increased the efficiency of radical-mediated killing. This increase may be caused by cyclization of atiprimod, facilitating electron transfer and peroxidation of lipid membranes. In vivo studies in Candida-infected CBA mice showed that atiprimod (10 mg/kg/day), did not compromise immune function in the infected mice and could be differentiated from prototypical immunosuppressive compounds used for treatment of autoimmune diseases.
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PMID:Atiprimod (SK&F 106615), a novel macrophage targeting agent, enhances alveolar macrophage candidacidal activity and is not immunosuppressive in Candida-infected mice. 1034 66

Apart from the essential trace element iodine, which is the central constituent of thyroid hormones, a second essential trace element, selenium, is required for appropriate thyroid hormone synthesis, activation and metabolism. The human thyroid gland has the highest selenium content per gram of tissue among all organs. Several selenocysteine-containing proteins respectively enzymes are functionally expressed in the thyroid, mainly in thyrocytes themselves: three forms of glutathione peroxidases (cGPx, pGPx, and PH-GPx), the type I 5-deiodinase, thioredoxin reductase and selenoprotein P. The thyroidal expression of type II 5-deiodinase still is controversial. As thyrocytes produce H2O2 continuously throughout life an effective cell defense system against H2O2 and reactive oxygen intermediates derived thereof is essential for maintenance of normal thyroid function and protection of the gland. In experimental animal models long-term and strong selenium deficiency leads to necrosis and fibrosis after high iodide loads. Combined iodide and selenium deficiency such as in central Zaire is thought to cause the myxedematous form of endemic cretinism. Inadequate selenium supply and prediagnostically low serum selenium levels are significantly correlated with the development of thyroid carcinoma and other tumors. Though selenium supply controls expression and translation of selenocysteine-containing proteins no direct correlation is found between selenium tissue content and expression of various thyroidal selenoproteins, indicating that other regulatory factors contribute to or override selenium-dependent expression control, e.g., in thyroid adenoma, carcinoma or autoimmune disease. As both trace elements, iodine and selenium, were washed out from the upper layers of the soil during and after the ice ages in many regions of the world adequate supply with these essential compounds needs to be provided either by a balanced diet or supplementation.
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PMID:The trace element selenium and the thyroid gland. 1040 85

Several rodent models have been proposed for various forms of systemic vasculitis. The MRL-lpr mouse has been studied extensively as a model for systemic lupus erythematosus. Backcross experiments in combination with genetic linkage studies have firmly established that the phenotype of autoimmune disease is dependent on the combination of various background genes. It has also become apparent that environmental factors, particularly infections, modulate the disease phenotype. Specific interventions, such as the treatment of Brown Norway rats with agents resulting in polyclonal B cell stimulation or immunization with human myeloperoxidase and subsequent localized perfusion with neutrophil lysosomal extract and H2O2, have provided substantial insights into the cellular and molecular mechanisms leading to the development of vasculitis and glomerulonephritis. Even though the existing models may not exactly mirror any specific human disease, they offer reproducible, highly controlled conditions to answer specific questions about pathogenesis and novel therapeutic approaches.
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PMID:Are animal models of vasculitis suitable tools? 1064 49

Goodpasture syndrome is an autoimmune disease of the kidneys and lungs mediated by antibodies and T-cells directed to cryptic epitopes hidden within basement membrane hexamers rich in alpha3 non-collagenous globular (NC1) domains of type IV collagen. These epitopes are normally invisible to the immune system, but this privilege can be obviated by chemical modification. Endogenous drivers of immune activation consequent to the loss of privilege have long been suspected. We have examined the ability of reactive oxygen species (ROS) to expose Goodpasture epitopes buried within NC1 hexamers obtained from renal glomeruli abundant in alpha3(IV) NC1 domains. For some hexameric epitopes, like the Goodpasture epitopes, exposure to ROS specifically enhanced recognition by Goodpasture antibodies in a sequential and time-dependent fashion; control binding of epitopes to alpha3(IV) alloantibodies from renal transplant recipients with Alport syndrome was decreased, whereas epitope binding to heterologous antibodies recognizing all alpha3 NC1 epitopes remained the same. Inhibitors of hydrogen peroxide and hydroxyl radical scavengers were capable of attenuating the effects of ROS in cells and kidney by 30-50%, respectively, thereby keeping the Goodpasture epitopes largely concealed when compared with a 70% maximum inhibition by iron chelators. Hydrogen peroxide administration to rodents was sufficient to expose Goodpasture epitope in vivo and initiate autoantibody production. Our findings collectively suggest that ROS can alter the hexameric structure of type IV collagen to expose or destroy selectively immunologic epitopes embedded in basement membrane. The reasons for autoimmunity in Goodpasture syndrome may lie in an age-dependent deterioration in inhibitor function modulating oxidative damage to structural molecules. ROS therefore may play an important role in shaping post-translational epitope diversity or neoantigen formation in organ tissues.
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PMID:Reactive oxygen species expose cryptic epitopes associated with autoimmune goodpasture syndrome. 1074 75

Relapsing polychondritis is a multisystem autoimmune disease involving cartilage destruction but no known causative antigen. HLA-DQ8 has been associated with various autoimmune diseases in humans. To study the role of DQ8 in autoimmune diseases, we have generated transgenic mice expressing DQ8 (DQA1*0301, DQB1*0302) in a NOD background lacking endogenous class II molecules (Abetao). Upon immunization with type II collagen (CII), 85% of NOD.DQ8 mice develop severe experimental polychondritis, auricular chondritis, and polyarthritis, with clinical and histological similarities to relapsing polychondritis (RP) in humans. CII-immunized mice mount a T cell response and produce Ab's to type IX collagen (CIX) and self-CII. Transgene-negative littermates do not develop any serological and clinical manifestations following immunization. B10.DQ8 transgenic mice develop polyarthritis and Ab's to CII only. The susceptibility to auricular chondritis in NOD.DQ8 mice can be attributed to response to CIX. A higher number of activated cells, CD4+CD44(hi)CD62L(lo), and lower regulatory cells CD4+CD152+CD25+ were observed in NOD.DQ8 mice compared with B10.DQ8 mice. The NOD.DQ8 mice provide a model of RP with a high disease incidence and multiple organ involvement to investigate putative autoantigen and regulatory cells involved in disease pathogenesis. An experimental model restricted by the human class II molecule will be valuable when studying the role of various collagens in immunologic and pathologic responses in human RP.
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PMID:Auricular chondritis in NOD.DQ8.Abetao (Ag7-/-) transgenic mice resembles human relapsing polychondritis. 1467 79

Except for a few diseases of molecular mimicry such as rheumatic fever, post-streptococcal glomerulonephritis in children, and gluten-sensitive enteropathy, the cause of autoimmune diseases is unknown. Most autoimmune diseases are remitting-relapsing and the pathophysiology of either the initial attack or subsequent relapses is a mystery. Migraine headaches in systemic lupus erythematosus patients are statistically associated with disease activity, i.e. the patients with bad lupus are the ones who get migraine. T lymphocytes reactive against self are normally suppressed by immunoregulatory T cells (Tregs), but suppression can be broken by CD28 ligation of Tregs. This raises intracellular levels of H2O2, which is a second messenger in the CD28 signaling cascade. Migraine headaches are often accompanied by systemic platelet activation and a brief but intense platelet oxidative burst which raises extracellular H2O2 levels to the point where H2O2 diffusing passively across lymphocyte cell membranes can raise intracellular H2O2 sufficiently to turn off regulatory T cell function via the CD28 signaling cascade. Passive diffusion of H2O2 mimics the effect of H2O2 formation triggered by CD28 ligation. This eliminates the immunosuppressive hold of Tregs on self-reactive T cells and the development or worsening of autoimmune disease ensues spontaneously.
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PMID:An explanation of how migraine headaches can trigger relapse in systemic lupus erythematosus. 2339


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