1,721,012 research outputs found
The pathogenesis of atopic eczema
No full textAtopic eczema is associated with a genetic predisposition to dysregulation of the immune system. T lymphocytes differentiate towards the Th2 type with promotion of immunoglobulin E antibodies. Allergic responses to environmental allergens develop and microbes, including staphylococci and pityrosporum yeasts, may contribute to the inflammatory process
Quantifying human susceptibility to contact sensitization; risk assessments now and in the future
No full textAssessment and quantification of the risk that a chemical will induce allergic contact sensitization presently depend heavily on background data from animal tests. Following the banning of animal testing of chemicals used in cosmetics and personal products in Europe after 2013, alternative approaches will be required. The chemical properties likely to make a given compound a sensitizer can be determined in vitro with reasonable certainty, but confirmation that it is a sensitizer comes only from in vivo exposure to it. Assessment of the sensitization risks involves consideration of how much of the compound will be applied to skin, for how long, and at which sites. However, the in vivo interactions of the chemical with the skin, with regard to its permeability, and biochemical and immune defences, cannot be predicted from a theoretical position. The xenobiotic-metabolizing enzymes and antioxidant defences may degrade chemicals or may generate potentially immunogenic haptens. Many factors can modify the skin and the immune response, including sex, race, age, genetic programming of epidermal permeability, and/or antioxidant and drug-metabolizing pathways. The only certain way to evaluate whether a chemical will sensitize is in vivo exposure, and the nature of the hazard is revealed by determination of the dose-response relationship. This review shows there is still a serious gap in our understanding of the biological factors and variables involved in conferring resistance or susceptibility to the development of allergic sensitization by chemicals. We are not yet in a position to predict sensitization by chemicals from a theoretical starting point
Patch testing in drug allergy
No full textPurpose of review: The review intends to clarify understanding of when and how skin patch tests can be used to help drug allergy diagnosis and identify causally relevant drugs. It aims to give an understanding of which clinical patterns of drug reaction are produced by T-lymphocyte-mediated pathomechanisms since these are what are detected by patch tests. It also covers fundamental principles underlying patch test methodology and summarizes clinical patterns and causal drugs for which patch tests have reasonable value to diagnose culprit drugs.Recent findings: A number of recent studies have consolidated evidence that the use of patch tests in drug hypersensitivity diagnosis is not a robust science. The field is bedeviled by the lack of standardized approach to ascertain and define clinical entities in a sufficiently clear way that allows researchers to be confident that patch tests are used appropriately in T-cell-mediated clinical conditions. The literature is confounded by case series including patch tests from conditions which may be the wrong type of test causing the sensitivity of the test system to be measured incorrectly.Summary: For certain drug eruptions mediated by T cells (exanthemata, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, erythema multiforme/toxic epidermal necrolysis, fixed drug eruption and symmetrical drug-related intertriginous and flexural exanthem) patch tests can elicit positive responses in a proportion of cases. The test works best with aromatic anticonvulsants and various antibiotics but does not appear to work consistently with a wide range of drugs. A coordinated and systematic research effort is required to resolve inconsistencies to encourage greater utilization of this potentially important diagnostic methodology
Skin manifestations of drug allergy
No full textCutaneous adverse drug reactions range from mild to severe and from those localized only to skin to those associated with systemic disease. It is important to distinguish features of cutaneous drug reactions which help classify the underlying mechanism and likely prognosis as both of these influence management decisions, some of which necessarily have to be taken rapidly. Severe cutaneous reactions are generally T cell-mediated, yet this immunological process is frequently poorly understood and principles for identification of the culprit drug are different to those of IgE mediated allergic reactions. Furthermore, intervention in severe skin manifestations of drug allergy is frequently necessary. However, a substantial literature reports on success or otherwise of glucocorticoids, cyclophsphamide, ciclosporin, intravenous immunoglobulin and anti-tumour necrosis factor therapy for the treatment of toxic epidermal necrolysis without clear consensus. As well as reviewing the recommended supportive measures and evidence base for interventions, this review aims to provide a mechanistic overview relating to a proposed clinical classification to assist the assessment and management of these complex patients
Peroxisome proliferator-activated receptors and their relevance to dermatology
No full textPeroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and are expressed in a variety of tissues including skin and cells of the immune system. They act as ligand-dependent transcription factors which heterodimerize with retinoid X receptors to allow binding to and activation of PPAR responsive genes. Through this mechanism, PPAR ligands can control a wide range of physiological processes. Based on their effects in vitro and in vivo PPAR agonists and antagonists have the potential to become important therapeutic agents for the treatment of various skin diseases. PPARs can also be activated directly by phosphorylation to have ligand-independent effects. This review will discuss the physiology of PPARs relating this to skin pathology and their role as a target for novel therapies, psoriasis, PPARs, wound healing, thiazolidinediones, transcription factor
Ultraviolet radiation causes less immunosuppression in patients with polymorphic light eruption than in controls
No full textIt is hypothesized that polymorphic light eruption is characterized by a partial failure of ultraviolet radiation-induced immunosuppression, resulting in a delayed-type hypersensitivity response to photo-induced antigens. We aimed to study the susceptibility of PLE patients to UVR-induced immunosuppression, by measuring the strength of sensitization to 2,4-dinitrochlorobenzene after UVR exposure, and to diphenylcyclopropenone without UVR exposure, in subjects with PLE and controls. Thirteen PLE patients and 11 controls were exposed to 1 minimum erythema dose (MED) of UVR delivered from Waldmann UV-6 bulbs to the upper inner arm. Twenty-four hours later at the same site they were exposed to a sensitizing dose of 2,4-dinitrochlorobenzene. One week later they were exposed to a sensitizing dose of diphenylcyclopropenone at a nonirradiated site. Three weeks later all subjects were challenged with four doses of 2,4-dinitrochlorobenzene and four doses of diphenylcyclopropenone. The resulting increase in skin thickness was measured with Harpenden callipers and summed over the four doses, to give a single value representing the reactivity of the subject to 2,4-dinitrochlorobenzene (ΣDN) and diphenylcyclopropenone (ΣDP). Among all subjects, there was a very strong correlation between ΣDN and ΣDP (Pearson correlation 0.56, p=0.004). The strength of the reaction to 2,4-dinitrochlorobenzene relative to the reaction to diphenylcyclopropenone was significantly greater among PLE patients than controls (p=0.04 independent samples t test of ΣDP–ΣDN). We conclude that induction of sensitization by 2,4-dinitrochlorobenzene is suppressed less by UVR in patients with PLE than in healthy controls
MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN)
No full textMicroRNA-155 (miR-155) has been involved in the response to inflammation in macrophages and lymphocytes. Here we show how miR-155 participates in the maturation of human dendritic cells (DC) and modulates pathogen binding by down-regulating DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), after directly targeting the transcription factor PU.1. During the maturation of DCs, miR-155 increases up to 130-fold, whereas PU.1 protein levels decrease accordingly. We establish that human PU.1 is a direct target for miR-155 and localize the target sequence for miR-155 in the 3'-untranslated region of PU.1. Also, overexpression of miR-155 in the THP1 monocytic cell line decreases PU.1 protein levels and DC-SIGN at both the mRNA and protein levels. We prove a link between the down-regulation of PU.1 and reduced transcriptional activity of the DC-SIGN promoter, which is likely to be the basis for its reduced mRNA expression, after miR-155 overexpression. Finally, we show that, by reducing DC-SIGN in the cellular membrane, miR-155 is involved in regulating pathogen binding as dendritic cells exhibited the lower binding capacity for fungi and HIV protein gp-120 when the levels of miR-155 were higher. Thus, our results suggest a mechanism by which miR-155 regulates proteins involved in the cellular immune response against pathogens that could have clinical implications in the way pathogens enter the human organism
Vaccination with DNA encoding a single-chain TCR fusion protein induces anticlonotypic immunity and protects against T-cell lymphoma
No full textThe clonotypic T-cell antigen receptor (TCR) provides unique V? and Vßsequences with potential as idiotypic targets for immunoregulation. For T-cell malignancies, vaccination with the TCR could induce therapeutic anti-idiotypic responses. To facilitate this approach, we have developed DNA vaccines that include the genes encoding TCR sequences from a T-cell lymphoma (TCL). To combine requirements for stable folding with a simple minimized single-chain construction, we used a three-domain V?VßCß sequence. To promote anti-TCR immunity, we fused a pathogen-derived sequence from tetanus toxin to the 3'-end of the single-chain TCR. The fusion gene vaccine induced anti-idiotypic antibodies and generated protection against the TCL. The critical requirement for the conformational integrity of the delivered TCR antigen was highlighted by the observation that DNA fusion vaccines containing either V?Vß or VßCß sequences failed to generate antibodies reactive with the native TCR or provide protection. This is the first report of a DNA vaccine able to induce anti-idiotypic immunity against TCL, and it presents a simple strategy for selectively eliminating T-cell clones in vivo
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