Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated previously that procainamide is metabolized to a hydroxylamine. The reactivities of this hydroxylamine and of the closely related nitroso derivative toward biological molecules were investigated with the objective of exploring possible mechanisms of procainamide-induced lupus. The hydroxylamine of procainamide was found to bind covalently to microsomal protein to a much greater degree than did procainamide and, in contrast to procainamide, it did not require metabolic activation. However, the hydroxylamine is readily converted nonenzymatically to the nitroso derivative, and reducing agents such as ascorbate and NADPH, which reduce the nitroso derivative to the hydroxylamine, blocked covalent binding. This suggests that the nitroso derivative is the reactive species for covalent binding. Furthermore, glutathione had been shown previously to block covalent binding of procainamide metabolites, and the nitroso derivative, but not the hydroxylamine, reacted rapidly with glutathione forming a sulfinamide derivative. The covalent binding of the nitroso derivative to microsomal protein appears to involve sulfydryl groups, because it, like the glutathione adduct, was readily cleaved by mild acid. In contrast, the nature of the covalent binding to albumin and histone protein appears different from that to microsomal protein in that most of the binding was stable to mild acid. The reactivity toward DNA was much less than that to protein. The observation that both the reactivity of nitrosoprocainamide and the specificity of antinuclear antibodies in procainamide-induced lupus are to histone protein rather than the DNA supports the hypothesis that this reactive metabolite plays a role in the etiology of procainamide-induced lupus.
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PMID:Reactivity and possible significance of hydroxylamine and nitroso metabolites of procainamide. 396 43

Induced mucosal tolerance has been shown to be beneficial in preventing or treating a number of murine and human autoimmune disorders. However, this particular form of therapy has not been thoroughly tested in systemic lupus erythematosus. In this study, we investigated the conditions for induction of nasal tolerance using a histone peptide named H471 expressing a dominant T cell epitope in the histone protein H4 of mononucleosome in lupus-prone SNF(1) female mice. We also tested the effect of chronic peptide nasal treatment on the development of autoimmune reactivities in these mice. Results demonstrated that a dose-dependent nasal tolerance to peptide H471 can be achieved before or after peptide sensitization in SNF(1) mice. In addition, tolerance to mononucleosomes was induced by nasal instillation of SNF(1) mice with H471. This was accompanied by an increase in IL-10 and suppression of IFN-gamma production by lymph node cells. Suppression of Th1-type cytokines was also observed in SNF(1) mice that were nasally administered with H471 before intradermal injection with the peptide. Finally, chronic nasal instillation of mice with the H471 peptide not only suppressed the development of autoantibodies, but also altered the severity of glomerulonephritis in lupus-prone SNF(1) mice.
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PMID:Histone peptide-induced nasal tolerance: suppression of murine lupus. 1209 22

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antinuclear antibodies (ANA) in association with protean clinic manifestations. ANA can bind to nuclear molecules, most prominently DNA and histones in nucleosomes, to form complexes to promote pathogenesis. Because of the intrinsic immunological activity of the nuclear components, these complexes can amplify responses by interacting with diverse pattern recognition receptors and internal sensing systems. Among molecules associated with nucleosomal components, HMGB1, a non-histone protein, can emanate from activated and dying cells; HMGB1's immune activity is determined by post-translational modifications, redox state, and binding to other immune mediators. Although ANAs form complexes that deposit in the kidney or induce type 1 interferon, ANAs may also block immune activity. Together, these studies highlight the importance of complexes in the pathogenesis of lupus and their role as antigens, immunogens, and adjuvants.
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PMID:The complex role of DNA, histones and HMGB1 in the pathogenesis of SLE. 2491 43

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that results in uncontrolled immune system activation and overproduction of autoantibodies. The pathogenesis of the disease is complex and not fully understood, nevertheless, genetic and environmental factors play an important role. So far, about 30 genes have been identified to be involved in the SLE pathomechanism. However, not all genetically predisposed individuals develop the disease. This phenomenon can be associated with epigenetic changes that occur under the influence of environmental factors. They can affect gene expression and are potentially hereditary, but do not lead to changes in the nucleotide sequence. Epigenetic dysfunctions, identified in the course of the disease, lead to changes in the expression of genes that play a key role in maintaining the body's immune tolerance. Major mechanisms of epigenetic variability are: DNA methylation, histone protein modification, non-coding RNA expression, as well as gene imprinting. The major epigenetic dysfunctions affecting the pathogenesis of the disease are global hypomethylation on CD4+ T cells resulting from ERK signaling pathway regulation, histone hypoacetylation, histone H3 lysine methylation, and reactivation of inactive chromosome X. In lupus patients, various epigenetic mechanisms interact with each other, enhancing the expression or silencing of genes responsible for the production of pro-inflammatory and anti-inflammatory cytokines and activation of autoreactive B-lymphocytes.
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PMID:[Epigenetic disturbances in systemic lupus erythematosus]. 2955 49