Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This brief review is focused on those heavy metals (cadmium, gold and mercury) that have strong associations with autoimmunity. Cadmium treatment of rats and mice results in autoimmune responses that vary with species and inbred strain of animals. However, there is no solid evidence demonstrating that the renal pathology observed in humans exposed to cadmium has an autoimmune pathogenesis. More clear-cut are the autoimmune effects of preparations containing gold salts, that have been widely used in the treatment of rheumatoid arthritis. Gold may cause autoimmune thrombocytopenia, immune complex-mediated glomerulonephritis and other autoimmune disorders. Similarly, there is solid evidence that mercury can induce autoimmune disease both in humans and experimental animals. The lessons to be derived from metal-induced autoimmunity relate to structure-activity relationship, pathogenesis, etiology and genetics. They probably apply to xenobiotic-induced autoimmune disease in general.
Lupus 1994 Dec
PMID:Autoimmunity and heavy metals. 770

The cause of toxic oil syndrome (TOS) has not yet been definitively determined, but some genetic susceptibility factors (certain HLA antigens and female sex) have been identified in 236 patients. Similarities with genetic factors for scleroderma and hydralazine-induced lupus (i.e. in TOS female sex and HLA-A24, Pcorrected = 0.00001 and DR4, Pcorrected = 0.04, respectively) may provide a clue to the responsible xenobiotic and its pathogenesis, and may also help in understanding the basis of the related eosinophilia-myalgia syndrome associated with tryptophan ingestion. In this paper it is also established that a human class I antigen (HLA-A24) and, independently, an HLA class II haplotype (DR4-DQ8, Pcorrected = 0.04) and arginine 52 in the alpha-DQ chains (Pcorrected = 0.03) are associated with TOS susceptibility, similarly to insulin-dependent diabetes. This further supports the classification of TOS as an autoimmune disease. Also, the increased frequency of a particular set of low-frequency HLA class I antigens in chronic TOS patients (i.e. B27, B37, B38 and B49) and the probable decrease in the frequency of HLA-B homozygotes in surviving patients (Pcorrected = 0.008) may provide an objective model to explain the maintenance of the HLA polymorphism: less frequent HLA alleles may be more advantageous in the event of unexpected human contact with unusual xenobiotics (not only microbes); however, other mechanisms working together to preserve and generate HLA polymorphism may coexist.
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PMID:Frequencies of HLA-A24 and HLA-DR4-DQ8 are increased and that of HLA-B blank is decreased in chronic toxic oil syndrome. 880 34

An unprecedented arsenal of new xenobiotic immunosuppressive agents has been developed recently. Most of the new immunosuppressants have been tested primarily in the treatment of allograft rejection in experimental models of transplantation, and some of the new drugs have already proven their safety and efficiency in extensive clinical trials on transplant patients. Another field for their potential application is the treatment of autoimmune diseases. This review will give an overview of the therapeutic potential of the new xenobiotic drugs in different animal models of rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, diabetes mellitus, thyroiditis and uveoretinitis. The new xenobiotics are either inhibitors of the de novo synthesis of nucleotides, for example mycophenolate mofetil, mizoribine, leflunomide, and brequinar, or are immunophilin-binding agents (cyclosporin, FK506 and rapamycin) that inhibit signal transduction and cell cycle progression in lymphocytes. A different mode of action is likely to account for the immunosuppressive effects of deoxyspergualin, which may interfere with intracellular chaperoning by the heat shock protein HSP70 and the activation of transcription factor NF-kappa B.
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PMID:Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases. 935 1

This study demonstrates that extramedullary hematopoiesis occurs in livers of adult lpr mice and, after treatment with each of three xenobiotic compounds--phenobarbital, cyproterone acetate, and nafenopin--it includes granulopoiesis. lpr mice are used as a model of the human disease systemic lupus erythematosus (SLE). The develop a syndrome very similar to that of human sufferers. In untreated lpr mice, mononuclear white blood cells were discernible in hepatic sinusoidal foci; T and B lymphocytes were distinguished from each other by immunocytochemistry at light microscope level. After treatment with any of the xenobiotic compounds, immunolabeling demonstrated the additional presence of granulocytes in foci, and, at electron microscope level neutrophils, eosinophils and their precursors were clearly recognizable.
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PMID:Hepatic extramedullary granulopoiesis after treatment with liver-stimulatory xenobiotics, in lpr mice. 989 23

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.
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PMID:Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity. 1050 38

Environmental and other xenobiotic agents can cause autoimmunity. Examples include drug-induced lupus, toxic oil syndrome, and contaminated l-tryptophan ingestion. Numerous mechanisms, based on (italic)in vitro(/italic) evidence and animal models, have been proposed to explain how xenobiotics induce or accelerate autoimmunity. The majority of these can be divided into three general categories. The first is those inhibiting the processes involved in establishing tolerance by deletion. Inhibiting deletion can result in the release of newly generated autoreactive cells into the periphery. The second mechanism is the modification of gene expression in the cells participating in the immune response, permitting lymphocytes to respond to signals normally insufficient to initiate a response or allowing the antigen-presenting cells to abnormally stimulate a response. Abnormal gene expression can thus disrupt tolerance maintained by suppression or anergy, permitting activation of autoreactive cells. The third is the modification of self-molecules such that they are recognized by the immune system as foreign. Examples illustrating these concepts are presented, and related mechanisms that have the potential to similarly affect the immune system are noted. Some mechanisms appear to be common to a variety of agents, and different mechanisms appear to produce similar diseases. However, evidence that any of these mechanisms are actually responsible for xenobiotic-induced human autoimmune disease is still largely lacking, and the potential for numerous and as yet unidentified mechanisms also exists.
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PMID:Environmentally induced autoimmune diseases: potential mechanisms. 1050 39

The etiology of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several cases, however, xenobiotics (i.e. drugs and occupational agents) were identified as etiologic agents and associations with certain polymorphic alleles of xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1) and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1- and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other chemicals to reactive metabolites. NAT-2 is the most important enzyme in acetylation of aromatic amines, and thus may be responsible for detoxification of many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point mutation in the 3' flanking region of the gene (Msp1) and a mutation in exon 7 leading to an isoleucine-valine-exchange in the heme-binding region of the enzyme, have been described and may lead to a higher basal and inducible enzyme activity. With respect to NAT-2, several alleles which combine for the two phenotypes "fast" and "slow" acetylators have been described. We analyzed the gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed in genomic DNA by PCR, whereas NAT-2 phenotypes were measured by the caffeine method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE group (n = 68) exhibited a significant increase (p < 0.05) in the mutant Val-allele (OR = 2.59) when compared to controls (n = 184). However, no significant differences in allele frequencies for MspI in the SLE group and for both CYP1A1 polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype, patients suffering from SLE (n = 88) 75% and SSc (n = 26) 80.2%, respectively, were slow acetylators compared to 55% slow acetylators in the healthy German population (p < 0.05). The observed increased frequencies of the CYP1A1 mutant Val-allele and the slow actylator phenotype in idiopathic autoimmune disease support our concept that in slow acetylators non-acetylated xenobiotics may accumulate and are subsequently metabolized by other enzymes into reactive intermediates. Thus, enhanced formation of reactive metabolites could alter self-proteins presented to the immune system thus stimulating autoreactive T cells which induce autoimmunity.
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PMID:Polymorphisms of the xenobiotic-metabolizing enzymes CYP1A1 and NAT-2 in systemic sclerosis and lupus erythematosus. 1059 36

The diverse genetic backgrounds of lupus-prone murine models, which produce both quantitative and qualitative differences in disease expression, may be a valuable resource for studying the influence of environmental exposure on autoimmune disease in sensitive populations. We tested this premise by exposing autoimmune-prone BXSB and the nonautoimmune C57BL/6 mice to the heavy metal mercury. Although both strains express a nonsusceptible H-2 haplotype, exposure to mercury accelerated systemic autoimmunity in both male and female BXSB mice, whereas the C57BL/6 mice were resistant. The subclasses of antichromatin antibodies elicited in BXSB mice by mercury exposure were more consistent with the predominant Th1-type response of idiopathic disease than with the Th2-type response found in mercury-induced autoimmunity (HgIA). The appearance and magnitude of both humoral and cellular features of systemic autoimmunity correlated with the mercury dose. Furthermore, environmentally relevant tissue levels of mercury were associated with exacerbated systemic autoimmunity. These studies demonstrate that xenobiotic exposure can accelerate spontaneous systemic autoimmunity, and they support the possibility that low-level xenobiotic exposure enhances susceptibility to systemic autoimmunity in genetically susceptible individuals.
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PMID:Xenobiotic acceleration of idiopathic systemic autoimmunity in lupus-prone bxsb mice. 1117 21

The cell nucleus is a prominent target of autoantibodies in systemic autoimmune disorders. Approximately 2% of the population in Europe and North America suffers from systemic rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and scleroderma. The molecular mechanisms of systemic autoimmunity are largely unknown despite its high prevalence. Contributing factors that have been considered include (1) genetic predisposition, (2) influence of hormones, and (3) environmental factors. The latter are mainly correlated with the generation of scleroderma, as xenobiotic-induced subsets of this disease have been observed in individuals exposed to silica (SiO(2)) dusts, organic solvents, heavy metals, and certain drugs. In addition to the epidemiological relevance, animal models of xenobiotic-induced autoimmunity serve as elegant tools for controlled induction of antigen-driven autoimmune responses. Because antigen processing and presentation constitute the basis for every antigen-driven autoimmune response, effects of xenobiotics on degradation of nuclear autoantigens have been characterized to elucidate molecular mechanisms of autoimmunity that target the cell nucleus. By means of a cell-based disease model, it has been shown that xenobiotics such as mercuric chloride, platinum salts, and silica (nano)particles specifically alter structure, function, and proteolysis in the cell nucleus. Signature proteins of the cell nucleus redistribute to aberrant, nucleoplasmic clusters, where they colocalize with proteasomes and are subjected to proteasomal proteolysis. Recruitment of nuclear autoantigens to proteasomal degradation is correlated with autoimmune responses that specifically target these antigens in both animal models of xenobiotic-induced autoimmunity and patients with idiopathic scleroderma.
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PMID:Xenobiotic-induced recruitment of autoantigens to nuclear proteasomes suggests a role for altered antigen processing in scleroderma. 1612 80

The immune system in higher organisms is under integrated control and has the capacity to rapidly respond to the environment. Recently, there has been a significant increase in the prevalence of allergic diseases. Environmental factors likely play a major role in the explosion of allergy. Although the "hygiene hypothesis" may explain the increase in allergic diseases which are prone to T helper 2 (Th2) immune responses, recent findings highlight the possible involvement of environmental xenobiotic chemicals which can modulate normal immune function. Interestingly, several reports suggest that the prevalence of systemic lupus erythematosus, a Th2-type autoimmune disease, is also increasing, although the development of high-sensitivity immunological tests may be a possible cause. The increased prevalence of autoimmune disease in women, the sexual dimorphism of the immune response, and the immunomodulatory effects of sex steroids, have focused attention on the role of chemicals which influence sex steroids in the development of immune diseases. Moreover, recent reports indicate that some environmental chemicals can work on nuclear hormone receptors, other than sex hormone receptors, and modulate immune reactions. This review focuses on the impact of environmental chemicals on immune system function and pathogenesis of immune diseases, including allergy and autoimmune diseases.
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PMID:The immune system as a target for environmental chemicals: Xenoestrogens and other compounds. 1669 29


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