Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This pilot study evaluated the effects of immunostimulatory liposome-plasmid-DNA complexes combined with specific allergens for immunotherapy of refractory canine atopic dermatitis. Seven dogs with previously diagnosed atopic dermatitis and unsatisfactory response to at least 12 months of conventional allergen-specific immunotherapy underwent a series of six intradermal injections (weeks 0, 2, 4, 6, 10 and 14), with patient-specific allergen extracts contained in cationic liposome-DNA complexes. Degree of pruritus was assessed on a visual analogue scale. Lesion scores were determined using the Canine Atopic Dermatitis Extent and Severity Index (CADESI) and medication usage was recorded at weeks 0 and 14. Canine cytokine mRNA expression in peripheral blood mononuclear cells collected prior to treatment and at the completion of the study was determined for IFN-gamma, IL-4, TNF and IL-10 genes using quantitative reverse transcription competitive polymerase chain reaction. Repeated intradermal injections of specific allergens incorporated into liposome-nucleic acid complexes were well tolerated in all seven dogs. There was a significant improvement in pruritus scores (P = 0.0277) and concurrent significant decrease in IL-4 production (P = 0.0428) at the completion of the trial compared to pretreatment values. Medication scores, CADESI and production of other cytokines did not change significantly with treatment. These early results suggest that antigen-specific immunotherapy using a novel liposome-nucleic acid complex vaccine may be beneficial for treatment of established atopic dermatitis in dogs using lower antigen doses. Further investigations in larger numbers of dogs with earlier stages of disease are warranted.
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PMID:Use of immunostimulatory liposome-nucleic acid complexes in allergen-specific immunotherapy of dogs with refractory atopic dermatitis - a pilot study. 1572 7

Atopic eczema/dermatitis syndrome is a term that covers different subtypes of atopic dermatitis. The "intrinsic" type of atopic dermatitis is non-IgE-associated, and the "extrinsic" type is IgE-associated atopic eczema/dermatitis syndrome. In the etiopathogenesis of atopic dermatitis there are well known interactions among genetic, environmental, skin barrier, immune factors, and stress. Genetic factors determine the expression of atopic dermatitis as pure or mixed with concomitant respiratory or intestinal allergy, depending on genetic susceptibility. Immunologic abnormalities of type I and type IV reactions have been described in patients with atopic dermatitis. Immunologic triggers are aeroallergens, food allergens, microbial products, autoallergens and contact allergens. Immune reactions determine many features of atopic dermatitis. These immune reactions also include cell mediated or delayed hypersensitivity. The currently accepted model proposes a predominant Th2 cytokine milieu in the initiating stages of acute atopic dermatitis lesions, and a mixed Th1 and Th2 pattern in chronic lesions. A two-phase model includes Th2 initiation with attraction of macrophages and eosinophils, which in turn produce interleukin 12 that is the activator of Th1 type response. Atopic dermatitis skin contains an increased number of IgE-bearing Langerhans cells which bind allergens via the high-affinity IgE receptor (FcepsilonRI). Langerhans cells play an important role in cutaneous allergen presentation to Th2 cells via major histocompatibility molecules. Eosinophilia and IgE production are influenced by type 2 cytokines. Degranulation of eosinophils occurs in the dermis with the release of toxic proteins such as major basic protein and could account for much of the inflammation. Mast cells are increased in number and produce mediators other than histamine that induce pruritus and may have an effect on interferon gamma expression. Mast cells produce a number of proinflammatory cytokines. There is an elevated production of prostaglandin E2 by peripheral monocytes. Prostaglandin E2 has at least two potential roles in the initiation of atopic dermatitis. Firstly, it reduces interferon-gamma production by T helper cells, thereby favoring the initial, dominant Th2 immune response; and secondly, it directly enhances IgE production by B lymphocytes with an increased secretion of interleukin 4, interleukin 5 and interleukin 13. Many lesions of atopic dermatitis result from scratching, thus it is tempting to speculate that immune perturbations in genetically predisposed individuals provoke the release of local pruritogens and keratinocyte-derived cytokines, which then further exacerbate the previously described immune response.
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PMID:Etiopathogenesis of atopic dermatitis--an overview. 1578 48

Tacrolimus ointment (Protopic) is a topically applied macrolide lactone immunomodulator effective in the treatment of atopic dermatitis. Its mechanism of action primarily involves calcineurin inhibition, which interrupts cytokine gene expression and leads to the downregulation of T-cell activity. Tacrolimus ointment (0.03% and 0.1% for adults and 0.03% for children) is an effective treatment for atopic dermatitis of the trunk and limbs, as well as sensitive skin areas such as the face. Its efficacy is similar to or greater than that of hydrocortisone acetate 1%, hydrocortisone butyrate 0.1% and betamethsone valerate 0.12% ointments and pimecrolimus 1% cream. Systemic absorption of tacrolimus from the ointment is minimal, and adverse events, which are mostly associated with the application site and include skin burning and pruritus, tend to resolve early in treatment. Unlike topical corticosteroids, tacrolimus ointment is not associated with skin atrophy, and it is a well tolerated treatment for adults or children with atopic dermatitis, particularly when long-term treatment is indicated or the face or skin-fold regions are involved.
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PMID:Tacrolimus ointment: a review of its use in atopic dermatitis and its clinical potential in other inflammatory skin conditions. 1581 96

Epilepsy and onchocerciasis (river blindness) constitute serious public health problems in several tropical countries. There are four main mechanisms that might explain a relationship between these two diseases: (i) the presence of Onchocerca volvulus in the central nervous system; (ii) the pathogenicity of various O. volvulus strains; (iii) immunological mechanisms involving cross-reactive immunization or cytokine production during infection; and (iv) the triggering role of insomnia due to itching.
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PMID:Onchocerciasis-related epilepsy? Prospects at a time of uncertainty. 1630 6

Pruritic Papular Eruption with Human Immunodeficiency Virus infection (PPE-HIV) is characterized by symmetrically distributed papules with pruritus in the skin of patients suffering advanced HIV infection. Although known since 1985, the etiology of this symptomatic dermatitis is unclear. We set out to characterize the phenotype of the infiltrating cells and the cytokine profile in the lesions, as an attempt to contribute to determining its etiopathogenesis. Clinical data and histological, immunohistochemical, and ultrastructural features of skin biopsies from 20 HIV patients with PPE were studied. The histopathological aspects, cell immunophenotypes, and cytokine expressions in the lesions where quantified and compared to perilesional skin, and to those in the clinically normal skin of HIV patients without PPE-HIV (n=11) and those in normal skin samples from HIV negative individuals (n=10). PPE-HIV occurred mainly in HIV patients with mean CD4+ counts of 124.6 +/- 104 lymphocytes/mm3. Furthermore, their eosinophil counts were significantly increased. The skin lesions were characterized by a predominantly perivascular dermal lymphohistiocytic inflammatory infiltrate. Langerhans cells were normally distributed in the epidermis and seen among the cellular components of dermal infiltrates. The density of CD8+ lymphocytes was elevated and the density of CD4+ cells was reduced in dermal infiltrates. Interleukin 5 was the predominant cytokine in the lesions. Electron microscopic analysis didn't disclose HIV or other infectious agents in the lesions. These results refute the hypothesis of an infectious etiology of PPE-HIV. CD8+ lymphocytes and Langerhans cells seem to have roles in the pathogenesis of PPE-HIV. The increased frequency of IL5 was associated with abundant eosinophils in the lesions, suggesting a type Th2 response in this dermatitis.
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PMID:Pruritic papular eruption associated with HIV-etiopathogenesis evaluated by clinical, immunohistochemical, and ultrastructural analysis. 1633 70

The E3 ubiquitin (Ub) ligase Itch is a critical regulator of T helper 2 (Th2) cytokine production through its ability to induce Ub-dependent JunB degradation. After T cell receptor engagement, Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222, which are located within a Pro-rich region. Phosphorylation of these sites is necessary and sufficient for disrupting an inhibitory interaction between the WW domain of Itch and its catalytic HECT (Homologous to E6-AP C Terminus) domain and induces a conformational change that greatly enhances the catalytic activity of Itch, a HECT E3 ligase found to be directly activated upon its phosphorylation.
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PMID:Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. 1644 28

The proinflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNFalpha treatment is determined by the balance between NF-kappaB and Jun kinase (JNK) signaling; NF-kappaB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding. Here we show that TNFalpha-mediated JNK activation accelerates turnover of the NF-kappaB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK inhibitor renders mice resistant in three distinct models of TNFalpha-induced acute liver failure, and cells from these mice do not display inducible c-FLIP(L) ubiquitination and degradation. Thus, JNK antagonizes NF-kappaB during TNFalpha signaling by promoting the proteasomal elimination of c-FLIP(L).
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PMID:The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. 1646 5

Pruritus is an important symptom in atopic dermatitis (AD), but the major pruritogen has not been identified. NC/Nga mice, spontaneously develop an eczematous AD-like skin lesion when kept under conventional conditions, but not under specific pathogen-free (SPF) conditions, have been thought to be an animal model for AD. In this study, to determine whether newly identified cytokine, IL-31, may be involved in pruritus of AD, we examined the IL-31 expression in spontaneous dermatitis model which showed itch-associated long-lasting (over 1.5 s duration) scratching behavior and compared with that of hapten-induced contact dermatitis model without itch-associated long-lasting scratching behavior, using NC/Nga mice. In NC/Nga mice cohabited with NC/Nga mice which developed severe dermatitis for 2 weeks (conventional NC/Nga mice), the numbers of long-lasting scratching counts were significantly increased. Yet in 2,4,6-trinitrochlorobenzene (TNCB)-sensitized and challenged mice (TNCB-applied NC/Nga mice), no significant increase in long-lasting scratching counts was observed. In conventional NC/Nga mice with long-lasting scratching behavior, expression of IL-31 mRNA was increased, while in TNCB-applied NC/Nga mice without long-lasting scratching behavior, the expression of IL-31 mRNA were unchanged. There was a good correlation between the scratching counts and expression of IL-31 mRNA in conventional NC/Nga mice, but not so in TNCB-applied NC/Nga mice. These results suggest that IL-31 causes the itch-associated scratching behavior in conventional NC/Nga mice, an experimental animal model for AD.
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PMID:Involvement of IL-31 on scratching behavior in NC/Nga mice with atopic-like dermatitis. 1648 Apr 23

Skin disfigurations and pruritus can pose severe threats to quality of life, and treatment options for patients with recalcitrant diseases are limited. Tumor necrosis factor alpha, a proinflammatory cytokine, appears to play a central role in mediating the symptoms of many skin disorders. We report cases in which etanercept (Enbrel; Immunex Corp, Thousand Oaks, Calif), a tumor necrosis factor alpha antagonist that is approved for the treatment of moderate to severe psoriasis, was administered to ameliorate the symptoms of acute and chronic dermatologic conditions, including Hailey-Hailey disease, severe psoriasis, dermatomyositis, and subacute cutaneous lupus erythematosus. Treatment with etanercept substantially improved the clinical symptoms and quality of life in these patients, and may offer a therapeutic option for some patients with severe skin disorders.
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PMID:Case reports of etanercept in inflammatory dermatoses. 1648 29

Patent lymphatic filariasis is characterized by a profound down-regulation of immune responses with both parasite Ag-specific tolerance and bystander suppression. Although this down-regulation is confined to the Th1 arm of the immune system in response to parasite Ag, we hypothesized a more generalized suppression in response to live parasites. Indeed, when we examined the cytokine profile of a cohort of filaria-infected (n = 10) and uninfected (n = 10) individuals in response to live infective-stage larvae or microfilariae of Brugia malayi, we found significant impairment of both Th1 and Th2 cytokines characterized by diminished production of IFN-gamma, TNF-alpha, IL-4, IL-5, and IL-10 in infected patients. The molecular basis of this impaired Th1/Th2 response was examined, and we identified three major networks of immunoregulation and tolerance. First, impaired induction of T-bet and GATA-3 mRNA underlies the Th1/Th2 deficiency in infected individuals. Second, regulatory networks, as evidenced by significantly increased expression of Foxp3 (natural regulatory T cell marker) and regulatory effectors such as TGF-beta, CTLA-4, PD-1, ICOS, and indoleamine 2,3-dioxygenase play an important role in immunosuppression. Third, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors cbl-b, c-cbl (cbl is abbreviation for Casitas B lymphoma), Itch, and Nedd4. Indeed, blocking CTLA-4 or neutralizing TGF-beta restored the ability to mount Th1/Th2 responses to live parasites and reversed the induction of anergy-inducing factors. Hence, we conclude that a profound impairment of live parasite-specific Th1 and Th2 immune responses occurs in lymphatic filariasis that is governed at the transcriptional level by a complex interplay of inhibitory mediators.
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PMID:Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence. 1649 86


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