Short- and long-term effects of T-cell modulating agents in experimental autoimmunity

Mellergård, Johan; Havarinasab, Said; Hultman, Per

doi:10.1016/j.tox.2003.10.004

Cited by 10 publications

(5 citation statements)

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“…immune system, for which both autoimmunity and immune suppression have been reported [7][8][9]. Detection of mercury in the environment is thus of high relevance for public health and in the framework of sustainable development.…”

Section: Databasementioning

confidence: 99%

“…Nephrotoxicity [4] and genotoxicity [5] have been demonstrated. Other adverse effects occur in neural tissues, where the targeting of enzymes and receptors involved in nerve impulse transmission is probably involved [6], as well as in the immune system, for which both autoimmunity and immune suppression have been reported [7–9]. Detection of mercury in the environment is thus of high relevance for public health and in the framework of sustainable development.…”

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confidence: 99%

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Mechanisms of cholinesterase inhibition by inorganic mercury

et al. 2007

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The poorly known mechanism of inhibition of cholinesterases by inorganic mercury (HgCl2) has been studied with a view to using these enzymes as biomarkers or as biological components of biosensors to survey polluted areas. The inhibition of a variety of cholinesterases by HgCl2 was investigated by kinetic studies, X‐ray crystallography, and dynamic light scattering. Our results show that when a free sensitive sulfhydryl group is present in the enzyme, as in Torpedo californica acetylcholinesterase, inhibition is irreversible and follows pseudo‐first‐order kinetics that are completed within 1 h in the micromolar range. When the free sulfhydryl group is not sensitive to mercury (Drosophila melanogaster acetylcholinesterase and human butyrylcholinesterase) or is otherwise absent (Electrophorus electricus acetylcholinesterase), then inhibition occurs in the millimolar range. Inhibition follows a slow binding model, with successive binding of two mercury ions to the enzyme surface. Binding of mercury ions has several consequences: reversible inhibition, enzyme denaturation, and protein aggregation, protecting the enzyme from denaturation. Mercury‐induced inactivation of cholinesterases is thus a rather complex process. Our results indicate that among the various cholinesterases that we have studied, only Torpedo californica acetylcholinesterase is suitable for mercury detection using biosensors, and that a careful study of cholinesterase inhibition in a species is a prerequisite before using it as a biomarker to survey mercury in the environment.

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Section: Databasementioning

confidence: 99%

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confidence: 99%

Mechanisms of cholinesterase inhibition by inorganic mercury

et al. 2007

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“…In HgIA, the levels of ACA with ELISA, measured at OD 405 nm are extremely low, and most papers do not show the data. ACA is significantly increased in HgIA in A.SW (ethyl mercury) [166], C57BL/6 (HgCl2) [167] and B10.S (6 mg Hg/L) [168]. In this thesis, F2 exposed to Hg had a significantly higher (p < 0.05) ACA compared to control but the levels were modest (0.03 -0.24, measured at OD 405 nm).…”

Section: In the First Experimental Study For Gwasmentioning

confidence: 59%

Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity

Alkaissi¹

2018

Linköping University Medical Dissertations

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BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well-established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg. OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion. METHODS: MHC II (H-2 s) mice were paired (A.SW x B10.S) to achieve F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Petra Cassel, thank you for being there whenever I needed help. I know that there were many things that had nothing to do with you, but you still helped me and I appreciate that a lot. I sit in the corridor were no one else sits (except for when Said and students were there). So you and Camilla Janefjord were my daily colleagues I met every day and more or less the first that I said hi/good morning to. In some way, when I think of AIR, I actually think of you. You are the ones that represents it, how does that feel? . Sandra Hellberg, You are a very smart and kind person. We have always bumped in to each other in different occasions: being host in PhD party or being base group tutors together. You always take initiativ...

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“…As treatment of CD40L tg mice with low dosages of FK506 that have been successfully used in other models (Muraoka et al, 1996) did not result in a significant amelioration of autoimmune dermatitis (unpublished data), in this study tg mice were injected with 10 mg/kg FK506 to analyze whether this concentration is able to reduce dermatitis in the CD40L mouse model without causing severe side effects. A similar dose of FK506 has been shown to inhibit the induction of autoantibodies in mercury-induced autoimmunity in rodents (Mellergard et al, 2004).…”

Section: Resultsmentioning

confidence: 96%

FK506 Controls CD40L-Induced Systemic Autoimmunity in Mice

Loser

Balkow

Higuchi

et al. 2006

Journal of Investigative Dermatology

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Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.

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Short- and long-term effects of T-cell modulating agents in experimental autoimmunity

Cited by 10 publications

References 36 publications

Mechanisms of cholinesterase inhibition by inorganic mercury

Mechanisms of cholinesterase inhibition by inorganic mercury

Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity

FK506 Controls CD40L-Induced Systemic Autoimmunity in Mice

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