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Nick J Reynolds

Publications and source records attributed to Nick J Reynolds.

9 recordsLinked to original sources
PubMed2025

Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modelling in vitro.

BACKGROUND: Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. RESULTS: The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. CONCLUSIONS: Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.

Atopic eczema↗
PubMed2006

Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial.

BACKGROUND: Atopic eczema affects 1-2% of adults, and can cause considerable morbidity. We aimed to assess the safety and efficacy of azathioprine as systemic monotherapy for moderate-to-severe atopic eczema, and the therapeutic importance of the thiopurine methyltransferase (TPMT) polymorphism (a key determinant of azathioprine-induced myelotoxicity) by using TPMT enzyme activity to establish azathioprine dose. METHODS: We did a parallel-group, double-blind, placebo-controlled trial in an outpatient setting. Minimisation was used to assign 63 patients with active disease despite optimum topical therapy to treatment with azathioprine (n=42) or placebo (n=21) for 12 weeks. As maintenance treatment, patients with heterozygous range TPMT activity received azathioprine 1.0 mg/kg daily, compared with 2.5 mg/kg daily in patients with normal TPMT activity. For the first 4 weeks, all participants received lower azathioprine doses (0.5 and 1.0 mg/kg daily, respectively) to reduce gastrointestinal side-effects. The primary measure of clinical response was disease activity assessed by the SASSAD (six area six sign atopic dermatitis) score. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN58943280. FINDINGS: 54 (86%) participants completed the study; two (3%) withdrew from the placebo group and seven (11%) from the azathioprine group. At week 12, there was a 37% (12.0 unit) improvement in mean disease activity with azathioprine compared with a 20% (6.6 unit) improvement with placebo (17% [5.4 unit] difference, 95% CI 4.3-29%). This finding was accompanied by significant improvements in patient-reported itch, area of involvement, global assessment, and quality of life. Between participants there was a wide variation in response to the drug. Generally, azathioprine was well tolerated, although two individuals developed drug hypersensitivity. Participants with heterozygous range TPMT activity responded to azathioprine in similar proportions to other participants, but none developed bone-marrow toxicity. TPMT-based dosing seemed to reduce predicted toxicity, and drug efficacy was maintained. INTERPRETATION: Treatment with azathioprine as systemic monotherapy produces clinically relevant improvement in moderate-to-severe atopic eczema that remains active despite optimum therapy with topical corticosteriods. We believe the study of azathioprine as systemic monotherapy for atopic eczema has major advantages, which should allow clarification of the relation between azathioprine effectiveness and metabolite profiles in other inflammatory diseases.

Adolescent↗
PubMed2005

The anti-psoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria.

Anthralin is a potent topical drug, inducing clearance of psoriatic plaques. Anthralin disrupts mitochondrial function and structure, but its mechanism of action remains undefined. This study aimed to determine whether anthralin induced keratinocyte apoptosis as well as to investigate molecular mechanisms and the role of mitochondria. We studied human keratinocytes and human 143B rho(0) cells, which lack mitochondrial DNA and a functional respiratory chain. We show that anthralin disrupts mitochondrial membrane potential (DeltaPsim) and causes endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis. Disruption of DeltaPsim and cytochrome c release were independent of mitochondrial permeability transition or caspase activation. Human 143B rho(0) cells were resistant to anthralin-induced cell death, disruption of DeltaPsim, and cytochrome c release compared with the isogenic 143B rho+ cell line. Using the intrinsic fluorescence of anthralin, rapid accumulation within mitochondria was observed independent of DeltaPsim. Using assays that measure individual respiratory chain complexes, we show that anthralin specifically interacts with ubiquinone pool. These data indicate that anthralin induces apoptosis through a novel mitochondrial pathway dependent on oxidative respiration and involving electron transfer with the ubiquinone pool. These studies identify keratinocyte apoptosis as a potentially important mechanism involved in the clearance of psoriasis.

Anthralin↗
PubMed2002

Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A.

Systemic cyclosporin A and tacrolimus are effective treatments for psoriasis. Cyclosporin A and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor nuclear factor of activated T cells (NFAT). Inhibition of T cell activation is thought to account for their therapeutic action in psoriasis. We investigated whether nonimmune cells in human skin express calcineurin and NFAT1 and whether cyclosporin A and tacrolimus block activation of calcineurin/NFAT in epidermal keratinocytes. The expression patterns of the principal components of calcineurin/NFAT signaling pathway in normal human skin and psoriasis were determined by immunohistochemistry. We assessed calcineurin/NFAT activation in cultured keratinocytes by measuring the degree of nuclear localization of calcineurin and NFAT1 using immunofluorescence/confocal microscopy and assessed if cyclosporin A and tacrolimus blocked nuclear translocation of these proteins. A variety of cell types in normal and psoriatic skin expressed calcineurin and NFAT1, but expression was particularly prominent in keratinocytes. The principal cyclosporin A and tacrolimus binding proteins cyclophilin A and FKBP12 were also expressed by keratinocytes and nonimmune cells in skin. NFAT1 was predominantly nuclear in normal basal epidermal keratinocytes. Increased nuclear localization of NFAT1 was observed in suprabasal keratinocytes within lesional and to a lesser extent nonlesional psoriatic epidermis compared to normal skin (p = 0.001 and p = 0.03, respectively), suggesting increased activation of calcineurin in psoriatic epidermal keratinocytes. Agonists that induce keratinocyte differentiation, specifically 12-0-tetradecanoyl-phorbol-13-acetate (TPA) plus ionomycin, TPA, and raised extracellular calcium, induced nuclear translocation of NFAT1 and calcineurin in keratinocytes that was inhibited by pretreatment with cyclosporin A or tacrolimus. In contrast in human dermal fibroblasts, TPA plus ionomycin or TPA did not significantly alter the proportion of nuclear-associated NFAT1. These data provide the first evidence that calcineurin is functionally active in human keratinocytes inducing nuclear translocation of NFAT1 and also indicate that regulation of NFAT1 nuclear translocation in skin is cell type specific. Inhibition of this pathway in epidermal keratinocytes may account, in part, for the therapeutic effect of cyclosporin A and tacrolimus in skin diseases such as psoriasis.

Biological Transport↗
PubMed2002

Phototherapy and systemic treatments.

A proportion of children and adults with moderate to severe atopic eczema are not adequately controlled with emollients and topical steroids, resulting in significant morbidity and disability. Studies indicate a significant placebo response, so randomized controlled trials of new treatments are vital. This article reviews the evidence for phototherapy and systemic treatments in atopic eczema.

Adjuvants, Immunologic↗