ArticleLiterature Review

The Genetic Basis of Seborrheic Dermatitis: A Review

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Abstract

Seborrheic Dermatitis (SD) is a common inflammatory skin disease that presents as itchy, flaking skin in the seborrheic areas. Various environmental and intrinsic factors have been identified as predisposing factors for SD, but its etiology remains poorly understood. Although it was recognized that genetic factors play a role in SD etiology, there have not been studies that systematically review the literature specifically for causal mutations or protein deficiencies in SD. In this review, we searched various databases for gene mutations and protein deficiencies that cause SD or SD-like phenotype in humans and experimental animals, and summarize 11 gene mutations or protein deficiencies that were described in the literature. Most of the encoded proteins play a role either in the immune response (ACT1, C5, IKBKG/NEMO, STK4, 2C TCR) or epidermal differentiation (ZNF750, MPZL3). Understanding the genetic basis of SD can impart knowledge of the pathobiology of the disease and help identify novel therapeutic targets. This article is protected by copyright. All rights reserved.

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... Seborrheic dermatitis (SD) is a chronic, recurrent inflammatory condition that affects approximately 1-3% of individuals worldwide. Its pathogenesis involves an interplay between several factors, such as genetic predisposition, altered skin barrier, excessive secretion of sebaceous glands, skin microbiome, and immune response [1,2]. A systematic review that analyzed the genetic basis of SD identified 11 gene mutations or protein deficiencies that induced an SD or SD-like phenotype in humans or mice. ...
... A systematic review that analyzed the genetic basis of SD identified 11 gene mutations or protein deficiencies that induced an SD or SD-like phenotype in humans or mice. The majority of encoded proteins are involved in epidermal differentiation or immunity [1]. The innate immune response seems to play a critical role in the pathogenesis of SD. ...
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Seborrheic dermatitis (SD) is a relapsing inflammatory skin disorder that affects the seborrheic areas of the body. Its etiology is not completely elucidated; however, the link between disease exacerbations and the proliferation of Malassezia spp., along with the good response to antifungal agents, indicate the role of fungi in its pathophysiology. Sertaconazole nitrate is a relatively new imidazole antifungal agent with a particular structure, consisting in a benzothiophene ring similar to the indole ring of tryptophan, and it acts mainly through the inhibition of ergosterol synthesis and the formation of pores in the fungal cell membrane. The aim of our study was to evaluate the efficiency of sertaconazole 2% cream compared with other topical treatments in patients with SD. We performed an extensive literature search by browsing the PubMed database with the keyword combination “sertaconazole AND seborrheic dermatitis AND clinical trial”, which retrieved eight controlled clinical trials evaluating the effects of sertaconazole in SD. All of the clinical trials included a standard scoring index (SI). At 28 days since the beginning of the treatment, the sertaconazole regimen was associated with a significantly higher percentage of patients with mild SI and a lower percentage of patients with moderate or severe SI (odds ratio 0.51) than the other investigated treatments—hydrocortisone, ketoconazole, clotrimazole, metronidazole, pimecrolimus, and tacrolimus (odds ratio 1.95). In conclusion, treatment with sertaconazole 2% cream may represent an efficient alternative therapy for patients with SD.
... Although the picture of microbial dysbiosis is currently incomplete (particularly whether it is a cause or consequence of disease [77]), work thus far indicates that microbe biodiversity and abundance, influenced by host or intrinsic factors (e.g., age, gender, immunity and hormonal status) [78,79] and environmental or extrinsic factors (e.g., climate, physical activity, diet, grooming products or even face mask wearing as highlighted during the recent COVID-19 pandemic) [14,80], are important in maintaining skin health or driving disease. The microbial component of disease has therefore been an important target in treatment with anti-fungal therapies such as the commercially popular ZnPT available over-the-counter. ...
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Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10–15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.
... Not all patients with a high density of Malassezia develop the disease, so it may be possible that dysregulation of the immune system is required for their detrimental action [11]. Genetic studies have found up to 11 gene mutations and protein deficiencies linked to FSD or FSD-like phenotype in humans or mice, suggesting a genetic susceptibility [12]. ...
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Facial seborrheic dermatitis (FSD) is a chronic and relapsing inflammatory skin disorder occurring in areas of the face rich in sebaceous glands. It clinically manifests as erythematous scaly macules or plaques, often associated with pruritus. Although the pathogenesis of seborrheic dermatitis is not yet fully understood, Malassezia yeast, hormones, sebum levels, and immune response are known to play important roles. Additional factors including drugs, cold temperatures, and stress may exacerbate the condition. Currently, the available treatments do not cure the disease but relieve symptoms. Various pharmacological treatments are available, including antifungal agents, keratolytics, topical low-potency steroids, and calcineurin inhibitors. All of them provide several benefits, but they also have potential side effects. Seborrheic dermatitis tends to have a chronic, recurrent course. To avoid the long-term use of drugs, topical non-pharmacological products such as cosmetics or medical devices may improve clinical outcomes. Products with antimicrobial and anti-inflammatory ingredients such as zinc, piroctone olamine, dihydroavenanthramide, biosaccharide gum-2, and stearyl glycyrrhetinate may speed FSD recovery and avoid flare-ups. Finally, the use of specific cleansers, moisturizers, and sunscreens formulated as light creams or gel/creams should be strongly recommended to all FSD patients. We provide a brief review of the most used non-pharmacological cleansers, topical gel/creams, and specific sunscreens in the management of FSD.
... Skin regions rich in sebaceous glands are commonly affected. SD often presents as pink to red greasy-looking skin with yellowish scales in seborrheic areas such as the nasolabial folds, upper lip, eyelids and eyebrows, scalp, retro-auricular areas and the upper chest [2][3][4]. Despite the high prevalence, the pathogenesis of SD is not well understood. ...
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Introduction The pathogenesis of seborrheic dermatitis (SD) is multifactorial and traditional treatments may not target all aspects of it. The aim of this study was to evaluate short-term anti-fungal, anti-microbial, anti-inflammatory and anti-pruritus properties of a novel non-steroidal cream (NSC) containing piroctone olamine, zinc salt of l-pyrrolidone carboxylate (PCA), hydroxyphenyl propamidobenzoic acid, biosaccharide gum-2 and stearyl glycyrrhetinate in patients with face and chest SD. Methods Twelve male subjects affected by SD, presenting face and chest manifestations, were enrolled. Patients were instructed to apply NSC twice a day, performing regular visits at baseline (W0), after 7 (W1) and 14 (W2) days of treatment. A limitation of the study was that no control group treated with the vehicle without active ingredients was enrolled. To evaluate the efficacy of the NSC, investigator’s assessments were represented by scoring index (SI) and investigator’s global assessment score (IGA). In order to assess NSC anti-fungal and anti-microbial effects, skin scale scrapings were collected and used for Malassezia furfur (MF) and Staphylococcus epidermidis (SE) cultures. In parallel, in order to assess NSC anti-inflammatory effects, gene expression of IL-1α, IL-1β, IL-6, IL-8, and TNF-α was assessed. In addition, anti-pruritus effects were also evaluated through gene expression of cathepsin S and l-histidine decarboxylase. Results SI mean scores significantly decreased at W1 and, to a greater extent, at W2 compared with W0. The IGA score registered an important improvement efficacy both for face and chest, from W1 to W2. MF and SE growth was already inhibited at W1, with a more pronounced decrease at W2. Gene expression of all analyzed mediators was significantly reduced at W1 compared to W0. Conclusion In conclusion, our assessment is that NSC is an effective and well tolerated treatment option for SD with anti-fungal, anti-microbial and anti-inflammatory properties. Trial Registration ISRCTN registry, ISRCTN77871064 (retrospectively registered October 17, 2019). EudraCT number, 2019-003813-32. Funding ISDIN.
... Toxic metabolites released by Malassezia yeasts activate the host's immune response by irritating the skin, which leads to deterioration of epidermal differentiation. [4,5] However, whether its presence is incidental or causative is not known. In addition, it has been suggested that inflammatory responses in SD are initiated by personal tendency, nonimmunogenic irritations and oxidative stress. ...
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Background: Seborrheic dermatitis is a chronic, inflammatory skin disease, in which many endogenous and exogenous factors play a role. Recent studies have shown that oxidative stress increases in these patients. The role of the dynamic thiol/disulfide homeostasis, an important component of the oxidative stress, in the pathogenesis of seborrheic dermatitis has not yet been investigated. Objectives: The objective was to investigate the relationship between the dynamic thiol/disulfide balance in the plasma of seborrheic dermatitis patients and disease severity. Methods: In this case–control study, 70 seborrheic dermatitis patients and 61 age- and sex-matched healthy controls were included. Thiol/disulfide homeostasis was calculated from venous blood samples, and tests were performed by automated spectrophotometric method. The thiol/disulfide balance between the patient and control groups was compared. In addition, disease severity and other demographic characteristics and thiol/disulfide balance parameters were compared. Results: Native and total thiols were significantly higher in the patient group than that in the control group (P < 0.001). Disulfide levels were nonsignificantly lower in the patient group than controls (P = 0.821). Patients' age and age at the onset of disease were found to have a negative correlation with native and total thiol levels. Conclusion: Higher levels of thiols in the serum may be responsible for the increased proliferation of seborrheic dermatitis lesions. To the best of the authors' knowledge, this is the first report on the correlation between thiol/disulfide homeostasis in patients with seborrheic dermatitis.
... The scalp has a high follicular density and an enhanced sebum production rate compared to other human skin areas [1]. Dandruff begins with puberty with a peak incidence at 20 years of age and is less prevalent over 50 years [2], linked with sebaceous gland activity [3]. Dandruff has been considered as a less severe form of scalp seborrheic dermatitis, characterized by skin flacking, subinflammation, pruritus, and absence of erythema. ...
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The critical CO2 hydration reaction to bicarbonate and protons is catalyzed by carbonic anhydrases (CAs, EC 4.2.1.1). Their physiological role is to assist the transport of the CO2 and HCO3− at the cellular level, which will not be ensured by the low velocity of the uncatalyzed reaction. CA inhibition may impair the growth of microorganisms. In the yeasts, Candida albicans and Malassezia globosa, the activity of the unique β-CA identified in their genomes was demonstrated to be essential for growth of the pathogen. Here, we decided to investigate the sulfonamide inhibition profile of the homologous β-CA (MreCA) identified in the genome of Malassezia restricta, an opportunistic pathogen triggering dandruff and seborrheic dermatitis. Among 40 investigated derivatives, the best MreCA sulfonamide inhibitors were dorzolamide, brinzolamide, indisulam, valdecoxib, sulthiam, and acetazolamide (KI < 1.0 μM). The MreCA inhibition profile was different from those of the homologous enzyme from Malassezia globosa (MgCA) and the human isoenzymes (hCA I and hCA II). These results might be useful to for designing CA inhibitor scaffolds that may selectively inhibit the dandruff-producing fungi.
... The mechanisms of individual susceptibility to D and SD remains unclear, but host genetics implicate immune response (ACT1, C5, IKBKG/NEMO, STK4) and epidermal differentiation (ZNF750). However, it is still not known how disruption to these genetic factors is related to the clinical presentation of D and SD (Jacobs and Miller, 1972;Evans et al., 1977;Mancini et al., 2008;Abdollahpour et al., 2012;Crequer et al., 2012;Nehme et al., 2012;Boisson et al., 2013;Halacli et al., 2015;Karakadze et al., 2018). ...
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The skin microbial community is a multifunctional ecosystem aiding prevention of infections from transient pathogens, maintenance of host immune homeostasis, and skin health. A better understanding of the complex milieu of microbe-microbe and host-microbe interactions will be required to define the ecosystem’s optimal function and enable rational design of microbiome targeted interventions. Malassezia, a fungal genus currently comprising 18 species and numerous functionally distinct strains, are lipid-dependent basidiomycetous yeasts and integral components of the skin microbiome. The high proportion of Malassezia in the skin microbiome makes understanding their role in healthy and diseased skin crucial to development of functional skin health knowledge and understanding of normal, healthy skin homeostasis. Over the last decade, new tools for Malassezia culture, detection, and genetic manipulation have revealed not only the ubiquity of Malassezia on skin but new pathogenic roles in seborrheic dermatitis, psoriasis, Crohn’s disease, and pancreatic ductal carcinoma. Application of these tools continues to peel back the layers of Malassezia/skin interactions, including clear examples of pathogenicity, commensalism, and potential protective or beneficial activities creating mutualism. Our increased understanding of host- and microbe-specific interactions should lead to identification of key factors that maintain skin in a state of healthy mutualism or, in turn, initiate pathogenic changes. These approaches are leading toward development of new therapeutic targets and treatment options. This review discusses recent developments that have expanded our understanding of Malassezia’s role in the skin microbiome, with a focus on its multiple roles in health and disease as commensal, pathogen, and protector.
Chapter
Eczema is an inflammatory skin disease which is characterized by itching and scaling plaques and patches on different skin sites. Histopathologically, a characteristic feature is the presence of epidermal edema or spongiosis. Eczema can develop at any age and may be associated with skin inflammation caused by irritation or allergy. Some forms of eczema have no apparent trigger although as our understanding of the molecular basis of skin disease grows, new pathways, such as the role of mutations in the filaggrin gene in atopic eczema, have been found to have a role in pathogenesis, in some individuals. This section will concentrate on two common forms of eczema, atopic dermatitis and contact dermatitis. It will also consider seborrhoeic dermatitis which, although not strictly speaking a form of eczema, shares some common features. This scaly inflammatory dermatosis is largely caused by an inflammatory response triggered by a member of the normal skin microbiome, the yeast Malassezia.
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The underlying mechanism of Seborrheic dermatitis (SD) is poorly understood but major scientific progress has been made in recent years related to microbiology, immunology and genetics. In light of this, the major goal of this article was to summarize the most recent articles on SD, specifically related to underlying pathophysiology. SD results from Malassezia hydrolyzation of free fatty acids with activation of the immune system by the way of pattern recognition receptors, inflammasome, IL‐1β and NF‐kB. M. restricta and M. globosa are likely the most virulent subspecies, producing large quantities of irritating oleic acids, leading to IL‐8 and IL‐17 activation. IL‐17 and IL‐4 might play a big role in pathogenesis, but this needs to be further studied using novel biologics. No clear genetic predisposition has been established; however, recent studies implicated certain increased‐risk human leukocyte antigen (HLA) alleles, such as A*32, DQB1*05 and DRB1*01 as well as possible associations with psoriasis and atopic dermatitis (AD) through the LCE3 gene cluster while SD, and SD‐like syndromes, share genetic mutations that appear to impair the ability of the immune system to restrict Malassezia growth, partially due to complement system dysfunction. A paucity of studies exists looking at the relationship between SD and systemic disease. In HIV, SD is thought to be secondary to a combination of immune dysregulation and disruption in skin microbiota with unhindered Malassezia proliferation. In Parkinson’s disease, SD is most likely secondary to parasympathetic hyperactivity with increased sebum production as well as facial immobility which leads to sebum accumulation.
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Das seborrhoische Ekzem ist eine mehrheitlich chronisch-rezidivierend verlaufende Dermatose mit erythematosquamösen Hautveränderungen im Gesicht (v. a. Stirn, perinasal, Glabella, Augenbrauen) sowie der behaarten Kopfhaut und dem Brustbereich. Die äußerliche Behandlung erfolgt antimykotisch bzw. kombiniert antimykotisch-antientzündlich.
Chapter
The conditions included in this chapter are acne keloidalis nuchae, keloids, some pigmentary disorders, as well as a couple hair disorders prevalent in patients of African descent. Management of cutaneous disease should be nuanced to account for differences in skin pigmentation, hair care practices, and psychosocial impact. When educating patients about preventative techniques in hair disorders, for example, special care should be taken to address differences in hair texture and hair care practices. Our therapies should be tailored appropriately with these nuances in mind as well. In the realm of pigmentary disorders, while procedural therapies such as the use of lasers have shown promise, care should still be taken to minimize new ones such as post-inflammatory hyperpigmentation. The study of cutaneous diseases in patients with skin of color demands further investigation to better understand the prevalence of these conditions in ethnic populations and develop therapies specifically tailored toward these populations.
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Puntos para una lectura rápida •La genética y el hongo Malassezia son los principales responsables de la enfermedad. •En la dermatitis seborreica no esperamos ver ningún signo que no sea eritema y/o descamación; estos signos adicionales (alopecia, pústulas o folículos en penacho) nos obligan a descartar otras enfermedades. •El diagnóstico es clínico, pero la dermatoscopia nos resultará muy útil para descartar otras patologías que pueden imitar una dermatitis seborreica. •El Ministerio de Sanidad recomienda solicitar una serología VIH a las personas con dermatitis seborreica, independientemente de la severidad de la enfermedad. •El tratamiento tiene el objetivo de reducir la inflamación (corticoides, pimecrolimus y tacrolimus), reducir la cantidad de Malassezia (antifúngicos) y eliminar la descamación (queratolíticos). •Los corticoides tópicos no solo no deben evitarse, sino que son totalmente válidos y recomendables para el tratamiento de los brotes (menos de 4 semanas), pero no son aconsejables como tratamiento preventivo (periodos entre brotes).
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Background/aim: Malassezia colonization, sebaceous gland activity, hormones, immune system defects, environmental factors, and the interactions between these factors are thought to contribute to the pathogenesis of seborrheic dermatitis (SD). Zinc, an essential element, is involved in many biological processes including the ones that contribute to the development of SD. The aim of this study is to evaluate serum zinc levels in patients with SD. Materials and methods: Forty-three patients with SD and 41 healthy controls were enrolled in the study. Disease activity was assessed by the Seborrheic Dermatitis Area and Severity Index by a single dermatologist. Serum zinc levels of all subjects were evaluated. Results: Statistically significantly lower serum zinc levels were noted in SD patients than in the control group (79.16 ± 12.17 vs. 84.88 ± 13.59, respectively; P = 0.045). Conclusion: The results of the study demonstrated that patients who had SD had lower levels of serum zinc levels than healthy subjects.
Chapter
Seborrheic dermatitis (SD) is a chronic relapsing erythematous scaly disease with a prevalence of 1–3% in the general population. The exact etiology is unknown and multifactorial; the most accepted theory suggests that yeast of Malassezia spp. causes skin irritation and inflammation on the seborrheic areas in susceptible individuals. The clinical diagnosis is based on the location and appearance of the lesions. Treatment objective is to clear the signs of the disease, ameliorate the symptoms, and maintain remission with long-term therapy. Topical antifungal and anti-inflammatory agents are the first-line therapy. Systemic therapy is reserved only for severe or refractory cases, and alternative therapies have also been reported.
Chapter
Papulosquamous diseases are a group of disorders whose etiology is not known. They are characterized by scaly papules and plaques. The resemblance of these diseases to similar disorders makes it difficult to identify, thereby leading to misdiagnosis.
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Seborrheic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models—with particularly interesting insights from examining the Mpzl3 knockout mice and their SD‐like skin phenotype, and patients carrying a ZNF750 mutation—highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favorable conditions for the commensal Malassezia to over‐colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia‐centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD. This article is protected by copyright. All rights reserved.
Article
Background Seborrhoeic dermatitis (SD) is a common but epidemiologically poorly researched chronic skin disease. Objectives To characterise the prevalence and dermatological comorbidity of SD in Germany. Methods In the course of voluntary company skin checks, full body examinations were carried out in more than 500 companies by experienced dermatologists and documented electronically. Results 161,269 participants were included (55.5% male, mean age 43.2+10.9 years). SD was identified in 3.2% (men: 4.6%, women 1.4%). A significant difference was found between age groups (2.0% in < 35; 3.6% in 35‐64; 4.4% ≥ 65 years). Most frequent concomitant skin conditions were: folliculitis (17.0%, 95% CI 15.9‐18.1), onychomycosis (9.1%, 95% CI 8.3‐10.0), tinea pedis (7.1%, 95% CI 6.3‐7.8), rosacea (4.1%, 95% CI 3.6‐4.7), acne (4.0%, 95% CI 3.4‐4.5) and psoriasis (2.7%, 95% CI 2.3‐3.2). Regression analysis revealed the following relative dermatological comorbidity when controlling for age and gender: folliculitis (OR 2.1, 95% CI 2.0‐2.3), contact dermatitis (OR 1.8, 95% CI 1.1‐2.8), intertriginous dermatitis (OR 1.8, 95% CI 1.4‐2.2), rosacea (OR 1.6, 95% CI 1.4‐1.8), acne (OR 1.4, 95% CI 1.2‐1.7), pyoderma (OR 1.4, 95% CI 1.1‐1.8), tinea corporis (OR 1.4, 95% CI 1.0‐2.0), pityriasis versicolor (OR 1.3, 95% CI 1.0‐1.7) and psoriasis (OR 1.2, 95% CI 1.0‐1.4). Conclusions SD is a common disease which is more prevalent in men and older people and has an increased rate of dermatological comorbidity. However, absolute differences in prevalence of comorbidities are mostly small and negligible. Nevertheless, the findings underline the necessity of integrated, complete dermatological diagnostics and therapy. This article is protected by copyright. All rights reserved.
Chapter
Seborrheic dermatitis (SD) is a common chronic inflammatory skin disorder, with an incidence of 1–3% of the adult population. Clinically, SD presents as erythematous plaques with greasy‐looking, yellowish scales distributed on areas rich in sebaceous glands such as the scalp, the face, the upper back, and body folds. There is a large variation in extent and morphologic characteristics of the disease, depending on areas affected and age of incidence. It has two incidence peaks, the first in the first three months of life and the second beginning at puberty and reaching its peak at 40–60 years of age. Affected individuals are usually healthy, although seborrheic dermatitis has been associated with human immunodeficiency virus (HIV) infection, Parkinson's disease, a number of other neurologic disorders, and use of certain medications. Both antifungal and anti‐inflammatory preparations have been used to treat SD effectively and safely. In this chapter, we summarize the current knowledge on SD, including epidemiology, burden of disease, clinical presentations, diagnosis and management.
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Seborrheic Dermatitis (SD) is a common inflammatory skin disorder, but its molecular pathogenesis remains elusive. Previously, we have established the Mpzl3 knockout (‐/‐) mice as a model for SD. In this study, we focused on early phases of skin inflammation and determined the cytokine profiles and identified immune cell types in the lesional skin in the Mpzl3 ‐/‐ mice. Using flow cytometry, we detected significant increase of CD45+ leukocytes, CD3+ T lymphocytes and especially γδ T cells but not αβ T cells in the lesional skin compared to control. We also detected high levels of IL‐17 and determined that the γδ T cells were a major contributing source. CD3+ and γδ T cell localization in the skin was verified by indirect immunofluorescent staining. Since neither γδ T cells nor IL‐17 had been implicated in SD, our study provides novel insights into the role of MPZL3 in the pathogenesis of SD‐like skin inflammation. This article is protected by copyright. All rights reserved.
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Background: The recessive rough fur mutation (ruf)―named for the unkempt, greasy appearance of the hair coat in homozygotes―has previously been mapped on mouse Chromosome 9. However, the assignment of ruf to a particular gene is needed to facilitate a complete molecular analysis of the mutant phenotype. Results: To establish a more refined location for ruf (as a basis for positional cloning) DNA isolated from a large backcross family was typed for microsatellite and single-nucleotide markers on Chromosome 9. This analysis restricted the location of ruf between sites that flank only four genes known to be expressed in skin, one of which―Mpzl3, for myelin protein zero-like 3―generates a similar hair phenotype in mice homozygous for engineered and spontaneous null-alleles. A cross between ruf mutants and mice heterozygous for the Mpzl3rc mutation (which controls a recessive phenotype called rough coat) produced offspring that displayed matted, damp-looking fur, indicating that ruf is a mutant allele of Mpzl3. However, sequence analysis of the Mpzl3 promoter, exons and splice junctions revealed no mutant-specific DNA defect. Conclusion: The results presented indicate that ruf is a mutant allele of Mpzl3. With a genetic assignment in hand, the rough fur variant can now be more fully characterized to advance our understanding of Mpzl3’s role in normal skin development and function, hepatic triglyceride synthesis, weight regulation, energy and glucose homeostasis; and to model-related human disorders.
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Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomised controlled trials (RCTs) makes choosing between them difficult for patients, clinicians and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase and Cochrane for RCTs of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics to one another, methotrexate or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity and inconsistency were evaluated. Direct comparisons from 41 RCTs (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3-4 months. Overall, cluster analysis showed adalimumab, secukinumab and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer-term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision-making. PROSPERO 2015:CRD42015017538.
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The complement system, which consists of three independent but interacting pathways, constitutes a powerful arm of innate immunity. Its major function is to recognize and destroy pathogenic microorganisms as well as eliminate modified self-antigens. Although it is a fine-tuned system with innate capacity to discriminate self from non-self as well as danger from non-danger signals, an unwarranted activation can nonetheless occur and cause tissue destruction. To prevent such activation, specific regulators present both in plasma and on the cell surface tightly control it. Data accumulated over the past four decades have also shown that the complement system is capable of not only cross-talk with the activation cascades of plasma––i.e. blood coagulation, contact activation, and the kinin/kallikrein system––but also serving as a bridge between innate and adaptive immunity. It is for these reasons that the various activation steps of the complement system have been recently targeted for therapy to treat diseases in which the role of complement is beyond doubt. This trend will certainly continue for years to come, especially as novel concepts guiding the field into areas never contemplated before are continuing to be discovered.
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Seborrheic Dermatitis (SD) and dandruff are of a continuous spectrum of the same disease that affects the seborrheic areas of the body. Dandruff is restricted to the scalp, and involves itchy, flaking skin without visible inflammation. SD can affect the scalp as well as other seborrheic areas, and involves itchy and flaking or scaling skin, inflammation and pruritus. Various intrinsic and environmental factors, such as sebaceous secretions, skin surface fungal colonization, individual susceptibility, and interactions between these factors, all contribute to the pathogenesis of SD and dandruff. In this review, we summarize the current knowledge on SD and dandruff, including epidemiology, burden of disease, clinical presentations and diagnosis, treatment, genetic studies in humans and animal models, and predisposing factors. Genetic and biochemical studies and investigations in animal models provide further insight on the pathophysiology and strategies for better treatment.
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Patients with genetically determined deficiency of complement component 5 are usually diagnosed because of recurrent invasive Neisseria meningitidis infections. Approximately 40 individual cases have been diagnosed worldwide. Nevertheless, reports of the responsible genetic defects have been sporadic, and we know of no previous reports of C5 deficiency being associated with a number of independent meningococcal disease cases in particular communities. Here we describe C5 deficiency in seven unrelated Western Cape, South African families.
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DNA methylation changes occur in animal models of calorie restriction, simulating human dieting, and in human subjects undergoing behavioral weight loss interventions. This suggests that obese individuals may possess unique epigenetic patterns that may vary with weight loss. Here, we examine whether methylation patterns in leukocytes differ in individuals who lost sufficient weight to go from obese to normal weight (successful weight loss maintainers; SWLM) vs currently obese (OB) or normal weight (NW) individuals. This study examined peripheral blood mononuclear cell (PBMC) methylation patterns in NW (n=16, current/lifetime BMI 18.5-24.9) and OB individuals (n=16, current BMI≥30), and SWLM (n=16, current BMI 18.5-24.9, lifetime maximum BMI ≥30, average weight loss 57.4 lbs) using an Illumina Infinium HumanMethylation450 BeadArray. No leukocyte population-adjusted epigenome-wide analyses were significant; however, potentially differentially methylated loci across groups were observed in RYR1 (p=1.54E-6), MPZL3 (p=4.70E-6), and TUBA3C (p=4.78E-6). In 32 obesity-related candidate genes, differential methylation patterns were found in BDNF (gene-wide p=0.00018). In RYR1, TUBA3C and BDNF, SWLM differed from OB but not NW. In this preliminary investigation, leukocyte SWLM DNA methylation patterns more closely resembled NW than OB individuals in three gene regions. These results suggest that PBMC methylation is associated with weight status.
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ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis. How ZNF750 accomplishes these dual gene regulatory impacts is unknown. Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif. ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes ∼10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression. In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes.
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The rough coat (rc) spontaneous mutation causes sebaceous gland hypertrophy, hair loss and extracutaneous abnormalities including growth retardation. The rc mice have a missense mutation in the predicted immunoglobulin protein Mpzl3. In this study, we generated Mpzl3 knockout mice to determine its functions in the skin. Homozygous Mpzl3 knockout mice showed unkempt and greasy hair coat and hair loss soon after birth. Histological analysis revealed severe sebaceous gland hypertrophy and increased dermal thickness, but did not detect significant changes in the hair cycle. Mpzl3 null mice frequently developed inflammatory skin lesions; however, the early onset skin abnormalities were not the results of immune defects. The abnormalities in the Mpzl3 knockout mice resemble closely those observed in the rcrc mice, as well as mice heterozygous for both the rc and Mpzl3 knockout alleles, indicating that rc and Mpzl3 are allelic. Using a lacZ reporter gene, we detected Mpzl3 promoter activity in the companion layer and inner root sheath of the hair follicle, sebaceous gland, and epidermis. Loss of MPZL3 function also caused a striking reduction in cutaneous and overall adipose tissue. These data reveal a complex role for Mpzl3 in the control of skin development, hair growth and adipose cell functions.Journal of Investigative Dermatology accepted article preview online, 14 February 2014; doi:10.1038/jid.2014.94.
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Obesity continues to be a global health problem and thus it is imperative that new pathways regulating energy balance be identified. Recently, it was reported that mice carrying a missense mutation in myelin protein zero-like 3 (Mpzl3(rc)) have reduced body weight. In order to determine how Mpzl3 controls energy balance in vivo, we generated mice deficient in myelin protein zero-like 3 (Mpzl3 KO). Interestingly, KO mice were hyperphagic yet had reduced body weight and fat mass. Moreover, KO mice were highly resistant to body weight and fat mass gain after exposure to a high-fat, energy dense diet. These effects on body weight and adiposity were driven in part by a near doubling of whole-body energy expenditure levels in KO mice. KO mice also had reduced blood glucose levels during an i.p, glucose challenge and significant reductions in circulating insulin levels suggesting an increase in insulin sensitivity. In addition, there was an overall increase in oxidative capacity and contractile force in skeletal muscle isolated from KO mice. Hepatic triglyceride levels were reduced by 92% in livers of KO mice in part due to a reduction in de novo lipid synthesis. Interestingly, Mpzl3 mRNA expression in liver was increased in diet-induced obese mice. Moreover, KO mice exhibited an increase in insulin-stimulated Akt signaling in the liver, further demonstrating that Mpzl3 can regulate insulin sensitivity in this tissue. We have determined that Mpzl3 has a novel physiological role in controlling body weight regulation, energy expenditure, glycemic control and hepatic triglyceride synthesis in mice.
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Introduction Complement deficiencies are rare primary immunodeficiency disorders, the diagnosis of which is often underestimated. Only a small number of molecular studies have been carried out for the characterization of the underlying genetic defects in these cases. Purpose Reporting the first family from the Arabian Gulf region with multiple members affected by meningococcemia and abscent serum complement 5 (C5). We tried to correlate clinical, biochemical and molecular genetics features of this family. Methods Determination of the serum level of all complement proteins including the terminal cascade (C5-9), followed by mutation analysis on DNA extracted from fresh blood samples of each alive family member. Results Molecular studies showed a homozygous nonsense mutation in exon 1, with the change of cytosine to thymine at position 55 (55C > T) leading to change of the glutamine amino acid at position 19 to a stop codon (Q19X), and serologically absence of C5 in the serum. A similar but compound heterozygous mutation has been reported in one African–American family. previously. Conclusion Characterization of the underlying mutations in C5 deficient families is important, to understand this uncommon complement deficiency, and try to elucidate structure–function relationships in the C5 gene. This report also highlights the importance of complement screening in cases of sporadic meningococcal Infections, especially in communities with high prevalence of consanguineous marriages, which will ensure timely and adequate clinical interventions.
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Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.
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Disrupted skin barrier due to altered keratinocyte differentiation is common in pathologic conditions such as atopic dermatitis, ichthyosis and psoriasis. However, the molecular cascades governing keratinocyte terminal differentiation are poorly understood. We have previously demonstrated that a dominant mutation in ZNF750 leads to a clinical phenotype reminiscent of psoriasis and seborrheic dermatitis. Here we show that ZNF750 is a nuclear protein bearing a functional C-terminal nuclear localization signal. ZNF750 was specifically expressed in the epidermal suprabasal layers and its expression was augmented during differentiation, both in human skin and in-vitro, peaking in the granular layer. Silencing of ZNF750 in Ca2+-induced HaCaT keratinocytes led to morphologically apparent arrest in the progression of late differentiation, as well as diminished apoptosis and sustained proliferation. ZNF750 knockdown cells presented with markedly reduced expression of epidermal late differentiation markers, including gene subsets of epidermal differentiation complex and skin barrier formation such as FLG, LOR, SPINK5, ALOX12B and DSG1, known to be mutated in various human skin diseases. Furthermore, overexpression of ZNF750 in undifferentiated cells induced terminal differentiation genes. Thus, ZNF750 is a regulator of keratinocyte terminal differentiation and with its downstream targets can serve in future elucidation of therapeutics for common diseases of skin barrier.
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Dandruff is characterized by a flaky, pruritic scalp and affects up to half the world's population post-puberty. The aetiology of dandruff is multifactorial, influenced by Malassezia, sebum production and individual susceptibility. The commensal yeast Malassezia is a strong contributory factor to dandruff formation, but the presence of Malassezia on healthy scalps indicates that Malassezia alone is not a sufficient cause. A healthy stratum corneum (SC) forms a protective barrier to prevent water loss and maintain hydration of the scalp. It also protects against external insults such as microorganisms, including Malassezia, and toxic materials. Severe or chronic barrier damage can impair proper hydration, leading to atypical epidermal proliferation, keratinocyte differentiation and SC maturation, which may underlie some dandruff symptoms. The depleted and disorganized structural lipids of the dandruff SC are consistent with the weakened barrier indicated by elevated transepidermal water loss. Further evidence of a weakened barrier in dandruff includes subclinical inflammation and higher susceptibility to topical irritants. We are proposing that disruption of the SC of the scalp may facilitate dandruff generation, in part by affecting susceptibility to metabolites from Malassezia. Treatment of dandruff with cosmetic products to directly improve SC integrity while providing effective antifungal activity may thus be beneficial. © 2012 Unilever PLC. ICS © 2012 Society of Cosmetic Scientists and the Société Française de Cosmétologie.
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We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.
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The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacterial and viral infections and autoimmune manifestations. MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated. These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency. Our results characterize a new mechanism in primary T-cell immunodeficiencies and highlight a role of the MST1/FOXO1 pathway in controlling the death of human naive T cells.
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Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene encoding filaggrin in a subset of patients with AD. We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Compared with normal skin, filaggrin expression was significantly reduced (P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 +/- 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 +/- 0.03). Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
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The Mst1 and Mst2 protein kinases are the mammalian homologs of hippo, a major inhibitor of cell proliferation in Drosophila. Mst1 is most abundant in lymphoid tissues. Mice lacking Mst1 exhibit markedly reduced levels of the Mst1 regulatory protein Nore1B/RAPL in lymphoid cells, whereas Mst2 abundance is unaltered. Mst1-null mice exhibit normal T cell development but low numbers of mature naïve T cells with relatively normal numbers of effector/memory T cells. In vitro, the Mst1-deficient naïve T cells exhibit markedly greater proliferation in response to stimulation of the T cell receptor whereas the proliferative responses of the Mst1-null effector/memory T cell cohort is similar to wild type. Thus, elimination of Mst1 removes a barrier to the activation and proliferative response of naïve T cells. The levels of Mst1 and Nore1B/RAPL in wild-type effector/memory T cells are approximately 10% those seen in wild-type naïve T cells, which may contribute to the enhanced proliferative responses of the former. Freshly isolated Mst1-null T cells exhibit high rates of ongoing apoptosis, a likely basis for their low numbers in vivo; they also exhibit defective clustering of LFA-1, as previously observed for Nore1B/RAPL-deficient T cells. Among known Mst1 substrates, only the phosphorylation of the cell cycle inhibitory proteins MOBKL1A/B is lost entirely in TCR-stimulated, Mst1-deficient T cells. Mst1/2-catalyzed MOBKL1A/B phosphorylation slows proliferation and is therefore a likely contributor to the anti-proliferative action of Mst1 in naïve T cells. The Nore1B/RAPL-Mst1 complex is a negative regulator of naïve T cell proliferation.
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To ascertain the molecular mechanism that causes murine C5 deficiency, genomic and cDNA libraries were constructed from mouse liver DNA and mRNA employing the congenic strains B10.D2/nSnJ and B10.D2/oSnJ that are sufficient and deficient for C5, respectively. Genomic fragments were isolated which correspond to PvuII and HindIII restriction fragment length polymorphisms associated with C5 deficiency. Sequence analyses demonstrated that each of these polymorphisms resulted from single base pair substitutions and that neither substitution would probably cause or contribute to the C5 deficiency. Sequence analyses of C5 sufficient and deficient cDNAs revealed a 2 base-pair deletion in the deficient cDNAs. The "TA" deletion was located near the 5' end of the cDNA. This deletion shifts the reading frame of the C5 mRNA so that the termination codon UGA is present 4 base pairs downstream from the deletion. Genomic DNA was amplified and sequenced corresponding to the area surrounding the 2-base pair deletion. Six C5-deficient strains, A/HeJ, AKR/J, DBA/2J, NZB/B1NJ, SWR/J, and B10.D2/oSnJ, and four C5-sufficient strains, Balb/CJ, C57Bl/6J, DBA/1J, and B10.D2/nSnJ, were analyzed. The sequencing data revealed that the 2 base pairs were deleted from the C5 gene of each deficient mouse tested but not from the C5 gene of any sufficient mouse. These data demonstrate that: 1) there is an identical 2-base pair deletion in an exon of the C5 gene in several different C5-deficient mouse strains; 2) the mRNA transcribed from the C5D gene retains this deletion; and 3) this mutation should result in C5 protein deficiency.
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The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.
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Mutations in the mouse Brachyury (T) gene are characterized by a dominant reduction of tail length and recessive lethality. Two quantitative trait loci, Brachyury-modifier 1 and 2 (Brm1 and Brm2) are defined by alleles that enhance the short-tail Brachyury phenotype. Here we report on a genetic analysis of a visible dominant mutation Abnormal feet and tail (Aft) located in the vicinity of Brm1. Affected animals display kinky tails and syndactyly in the hindlimbs, both likely resulting from a defect in apoptosis. We observed an unusual genetic incompatibility between Aft and certain genetic backgrounds. We show that Aft and T are likely to interact genetically, since some double heterozygotes are tailless. In addition to the tail and hindlimb phenotypes, Aft-bearing mutants display characteristic late-onset skin lesions. We therefore tested for allelism between Aft and a closely linked recessive mutation rough coat (rc) and found that these two mutations are likely nonallelic. Our results provide a valuable resource for the study of mammalian skin development and contribute to the genetic analysis of Brachyury function.
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Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free, small-world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4, and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation.
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Cutaneous eruptions are commonly seen in acquired immunodeficiency syndrome (AIDS). Seborrheic dermatitis in this patient population is usually more severe and difficult to diagnose and treat. The butterfly distribution of the rash and the interpretation of the biopsy may suggest a diagnosis of discoid lupus erythematosus, unless the pathologist is aware of the underlying immunodeficiency. We present two cases of patients with documented acquired immunodeficiency syndrome whose initial biopsies were interpreted as discoid lupus but whose cutaneous seborrheic dermatitis actually paralleled human immunodeficiency virus disease activity.
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Background Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by hemolysis, platelet consumption, and renal injury. Eculizumab, a mAb that blocks complement activity, has been successfully used in aHUS. Objectives To optimize eculizumab therapy in aHUS patients by monitoring complement functional tests and markers of disease activity. Patients/Methods We studied 18 patients with aHUS (10 males; eight females; age range, 2-40years) treated with eculizumab to induce and/or maintain disease remission. Patients were followed up for a cumulative observation period of 160months, during which blood samples were obtained at various time intervals to measure complement activity (Wieslab for the classical, alternative and mannose-binding lectin complement pathways) and the parameters of disease activity (haptoglobin and lactate dehydrogenase serum levels, and platelet count). The intravenous eculizumab doses of 12-33mgkg(-1) were initially administered every week, with the interval between doses being gradually extended to 2weeks, 3weeks and 4weeks on the basis of strict laboratory and clinical control. ResultsComplement activity was normal before eculizumab treatment, regardless of the state of the disease (activity or remission). It was completely suppressed 1week, 2weeks and 3weeks after the last eculizumab infusion (mean valuesstandard deviation: 1%+/- 1% to 3%+/- 5% for both the classical and alternative pathways; P=0.0001 vs. baseline), and partially suppressed after 4weeks (22%+/- 26% and 16%+/- 27%; P=0.0001 vs. baseline). The increase in the time interval between eculizumab infusions did not change disease activity markers. Conclusions Monitoring complement tests can allow a safe reduction in the frequency of eculizumab administration in aHUS while keeping the disease in remission.
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Patients with inborn errors of interleukin-17F (IL-17F) or IL-17RA display chronic mucocutaneous candidiasis (CMC). We report a biallelic missense mutation (T536I) in the adaptor molecule ACT1 in two siblings with CMC. The mutation, located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors, with no effect on homodimerization. The patients' fibroblasts failed to respond to IL-17A and IL-17F, and their T cells to IL-17E. By contrast, healthy individuals homozygous for the common variant D10N, located in the ACT1 tumor necrosis factor receptor-associated factor-interacting domain and previously associated with psoriasis, had impaired, but not abolished, responses to IL-17 cytokines. SEFIR-independent interactions of ACT1 with other proteins, such as CD40, heat shock protein 70 (HSP70) and HSP90, were not affected by the T536I mutation. Overall, human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. Moreover, other ACT1-dependent IL-17 cytokines seem to be largely redundant in host defense.
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Psoriatic arthritis (PsA) increases the disease burden associated with psoriasis by further diminishing quality of life, increasing health care costs and cardiovascular risk, and potentially causing progressive joint damage. The presence of PsA influences psoriasis treatment by increasing overall disease complexity and, within the framework of current guidelines and recommendations, requiring the use of conventional disease-modifying anti-rheumatic drugs or tumor necrosis factor-α inhibitors in order to prevent progressive joint damage. Despite its important impact, PsA is still under-diagnosed in dermatology practice. Dermatologists are well positioned to recognize and treat PsA, given that it characteristically presents, on average, 10 years subsequent to the appearance of skin symptoms. Regular screening of psoriasis patients for early evident joint symptoms should be incorporated into daily dermatologic practice. Although drugs effective in PsA are available, not all patients may respond to treatment, and others may lose their initial response over time. New investigational therapies, such as inhibitors of interleukin-17A, interleukin-12/23, Janus kinase 3, or phosphodiesterase-4, may address unmet needs in psoriatic disease, with further research needed to determine the role of these agents in reducing joint damage and other comorbidities.
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A 3 month old male child was brought to the hospital with complaints of skin rashes, developmental delay, seizures, seborrheic dermatitis, alopecia and mild, acidosis. The child was subjected to a simple metabolic screening protocol. The result of the screening and the clinical symptoms provided an index pointing towards biotinidase deficiency., a rare autosomal recessive, inherited metabolic disorder. The enzyme was then assayed by using n-biotinylp-aminobenzoate as substrate and the diagnosis confirmed. A follow-up of the case indicated the efficacy, of biotin supplementation in biotinidase deficiency.
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Despite an increasing knowledge of dandruff and seborrheic dermatitis (D/SD), the pathophysiological understanding is still incomplete but suggests a role of Malassezia yeasts in triggering inflammatory and hyper-proliferative epidermal responses. The objective of this report is to review published literature from in vivo studies of D/SD populations to provide a more complete description of overall scalp health. New biomolecular capabilities establish a depth of pathophysiological understanding not previously achievable with traditional means of investigation. Biomarkers representing inflammation, hyper-proliferation and barrier function are all perturbed by the D/SD condition and robustly respond to therapeutic resolution. These biomarkers can be sampled noninvasively, enabling their use in routine clinical evaluations as either surrogate endpoints or complementary ones to classical signs/symptoms to broaden the etiological learning.
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Atopic dermatitis (AD) can be categorized into the extrinsic and intrinsic types. Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens, whereas intrinsic or non-allergic AD exhibits normal total IgE values and the absence of specific IgE. While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20% with female predominance. The clinical features of intrinsic AD include relative late onset, milder severity, and Dennie-Morgan folds, but no ichthyosis vulgris or palmar hyperlinearity. The skin barrier is perturbed in the extrinsic, but not intrinsic type. Filaggrin gene mutations are not a feature of intrinsic AD. The intrinsic type is immunologically characterized by the lower expression of interleukin (IL) -4, IL-5, and IL-13, and the higher expression of interferon-gamma. It is suggested that intrinsic AD patients are not sensitized with protein allergens, which induce Th2 responses, but with other antigens, and metals might be one of the candidates of such antigens.
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Seborrheic dermatitis is an inflammatory dermatosis with a prevalence of 1-3% in the general population. It is recognized more commonly in those infected by human immunodeficiency virus (HIV). No studies have looked at Seborrheic dermatitis in the context of immunosuppression secondary to organ transplantation. Therefore, we investigated the prevalence of Seborrheic dermatitis in a renal transplant population and characteristics of those affected. A prospective study of 308 renal transplant recipients (RTRs) was carried out. All participants were examined for Seborrheic dermatitis. Descriptive statistics were employed and associations with Seborrheic dermatitis were examined using Fisher's exact test to calculate P-exact values, and Student's t-test was used to compare mean ages and time since transplantation. Statistical analysis was carried out using SPSS version 14.0 for Windows. Seborrheic dermatitis was identified in 29/308 (9.5%) patients and was more common in males (P-exact = 0.004) and in those who had been transplanted for longer (P = 0.02). The disease was mild-moderate severity in the majority but an unusual flexural appearance was recorded in 7/29 patients. Seborrheic dermatitis was less likely in those taking prednisolone (P-exact = 0.006) or tacrolimus (P-exact = 0.008). Seborrheic dermatitis was significantly associated with cutaneous malignancy, in particular squamous cell carcinoma (P-exact < 0.0001). Seborrheic dermatitis is more common than other inflammatory dermatoses in immunosuppressed RTRs, but is not as frequent as in those immunosuppressed secondary to HIV. Degree and duration of exposure to immunosuppression and increased colonization with Malassezia yeast genus are likely be important in the aetiology of Seborrheic dermatitis in RTRs. Further studies are required to clarify this.
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We have recently reported a mutation within the conserved immunoglobulin V-type domain of the predicted adhesion protein Mpzl3 (MIM 611707) in rough coat (rc) mice with severe skin abnormalities and progressive cyclic hair loss. In this study, we tested the hypothesis that the human orthologue MPZL3 on chromosome 11q23.3 is a candidate for similar symptoms in humans. The predicted conserved MPZL3 protein has two transmembrane motifs flanking an extracellular Ig-like domain. The R100Q rc mutation is within the Ig-domain recognition loop that has roles in T-cell receptors and cell adhesion. Results of the rc mouse study, 3D structure predictions, homology with Myelin Protein Zero and EVA1, comprehensive database analyses of polymorphisms and mutations within the human MPZL3 gene and its cell, tissue expression and immunostaining pattern indicate that homozygous or compound heterozygous mutations of MPZL3 might be involved in immune-mediated human hereditary disorders with hair loss.
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A three month old baby presented with refractory seizures, dermatosis and persistent metabolic acidosis. Biotinidase deficiency was diagnosed on enzyme assay. Patient responded dramatically to biotin supplementation.
A syndrome consisting of a hypocalcified-hypoplastic enamel, onycholysis with subungual hyperkeratosis, seborrheic dermatitis of the scalp, and hypofunction of the sweat glands with rough dry skin is inherited as an autosomal dominant trait in a kindred of Caucasian ancestry.
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The defect in Leiner's disease, which presents in early infancy with extensive dermatitis, diarrhoea, and failure to thrive, has been attributed to a defect of the fifth component of complement (C5). We report 2 brothers with extensive dermatitis and dysgammaglobulinaemia. Both died. The older showed symptoms of Leiner's disease: C5 tests were not performed. The younger had extensive dermatitis and was found to have the C5 defect. He developed normally, but died suddenly with pertussis. We postulate that the C5 defect is not the sole cause of Leiner's disease as has been suggested, but that hypogammaglobulinaemia or other lymphoid deficiency is also required for its expression.
Seborrhoeic dermatitis is a common skin disease mainly affecting the scalp and face. The etiology of seborrhoeic dermatitis is unknown but a connection with the lipophilic yeast Pityrosporum ovale has been found in a number of treatment studies. P. ovale belongs to the normal cutaneous flora but is also an opportunistic pathogen. The purpose of these studies was to examine how the density of P. ovale changes with age, to determine the number of P. ovale in seborrhoeic dermatitis compared to controls, to study the immunological functions in patients with seborrhoeic dermatitis, to evaluate different methods of detecting antibodies against P. ovale and to describe how the patients experience their disease. The number of P. ovale on clinically normal skin decreases with increasing age. In patients with seborrhoeic dermatitis, the number of P. ovale in lesional skin was not increased compared to healthy skin in the patients or in healthy controls. A reduction of the skin surface lipids was seen in elderly healthy individuals. The lipid content on the skin in patients with seborrhoeic dermatitis was higher than in controls (p = 0.0001). Serum IgG antibodies against P. ovale measured with indirect immunofluorescence decreased parallel to increasing age in healthy individuals and no difference was found between patients with seborrhoeic dermatitis and healthy controls. ELISA with a P. ovale protein extract was the only method that demonstrated a difference in immune response between patients and controls when this method was compared with four other assays (p = 0.03). Immunological screening was done in 30 patients with seborrhoeic dermatitis. No major abnormalities in the humoral and local immune system were found but T-cell and NK-cell aberrations were found in several patients with seborrhoeic dermatitis. One-third of the patients had low lymphocyte stimulations with Concanavalin-A and phytohaemagglutinin and almost half of the patients had high frequencies of circulating natural killer-cells. In a questionnaire answered by 431 patients with seborrhoeic dermatitis, we found indications that hereditary, the season, mental stress and the work environment influence the disease. The investigations suggest that the number of P. ovale in seborrhoeic dermatitis is of minor importance. How each individual reacts to P. ovale and the amount of skin surface lipids are probably of greater importance in the development of seborrhoeic dermatitis.
Article
The safety and efficacy of five prototype, live anthrax vaccines were studied in Hartley guinea pigs and CBA/J and A/J mice. Two of the strains, Bacillus anthracis FD111 and FD112, are Aro- mutants derived by Tn916 mutagenesis of B. anthracis UM23-1. Bacillus subtilis PA1 and PA2 contain a recombinant plasmid, pPA101 or pPA102, respectively, that carries the gene from B. anthracis encoding synthesis of protective antigen (PA). The final strain, B. subtilis PA7, was isolated in this study from B. subtilis DB104 transformed with pPA101. All five strains were less virulent in guinea pigs and A/J and CBA/J mice than the toxinogenic, nonencapsulated B. anthracis veterinary vaccine Sterne strain. A/J and CBA/J inbred mice represent strains that are innately susceptible and resistant, respectively, to the Sterne strain. These differences in susceptibility are due to differences in ability to produce complement component 5. In guinea pigs, immunization with PA1 or PA2 vegetative cells or PA7 spores protected greater than or equal to 95% from an intramuscular spore challenge with the virulent, "vaccine-resistant" B. anthracis Ames strain. Strain PA2 vegetative cells and strain PA7 spores were as effective as the Sterne strain in Sterne-resistant CBA/J mice, protecting 70% of the mice from Ames strain spore challenge. Immunization with FD111 or FD112 vegetative cells fully protected guinea pigs from challenge. Immunization with FD111 cells protected up to 100% of CBA/J mice and up to 70% of A/J mice.
Article
Many cutaneous disorders are associated with acquired immunodeficiency syndrome. We prospectively evaluated eighteen patients with acquired immunodeficiency syndrome and twelve patients with the immunodeficiency syndrome-related complex for dermatologic disorders. A high prevalence of seborrheic dermatitis was found in patients with acquired immunodeficiency syndrome--83%, in comparison with 1% to 3% of historic control subjects. Patients with the related complex also had an increased incidence of 42%. Seborrheic dermatitis in this population was often more explosive, inflammatory, and severe than is usually seen in otherwise healthy patients. Severity of seborrheic dermatitis correlated with a poor overall prognosis in our patients. Additionally, seborrheic dermatitis may be one of the most common cutaneous manifestations of acquired immunodeficiency syndrome.
Article
A new mutation, affecting skin and hair, occurred in an expansion colony of Him:OF1 mice. Test crosses showed that a single autosomal recessive gene was responsible for this trait. Homozygotes have sparse greasy fur and lower viability and fertility than normal littermates. Histological observations showed hypertrophy of sebaceous glands, hyperkeratosis, parakeratosis, acanthosis and signs of inflammation. The disease was named 'inherited seborrheic dermatitis' and the gene name seb is proposed.
Article
The T-cell repertoire found in the periphery is thought to be shaped by two developmental events in the thymus that involve the antigen receptors of T lymphocytes. First, interactions between T cells and major histocompatibility complex (MHC) molecules select a T-cell repertoire skewed towards recognition of antigens in the context of self-MHC molecules. In addition, T cells that react strongly to self-MHC molecules are eliminated by a process called self-tolerance. We have recently described transgenic mice expressing the alpha beta T-cell receptor from the cytotoxic T lymphocyte 2C (ref. 11). The clone 2C was derived from a BALB.B (H-2b) anti-BALB/c (H-2d) mixed lymphocyte culture and is specific for the Ld class I MHC antigen. In transgenic H-2b mice, a large fraction of T cells in the periphery expressed the 2C T-cell receptor. These T cells were predominantly CD4-CD8+ and were able to specifically lyse target cells bearing Ld. We now report that in the periphery of transgenic mice expressing Ld, functional T cells bearing the 2C T-cell receptor were deleted. This elimination of autoreactive T cells appears to take place at or before the CD4+CD8+ stage in thymocyte development. In addition, we report that in H-2s mice, a non-autoreactive target haplotype, large numbers of CD8+ T cells bearing the 2C T-cell receptor were not found, providing strong evidence for the positive selection of the 2C T-cell receptor specificity by H-2b molecules.
Article
The second family with a deficiency of phagocytosis enhancement (opsonization) related to a dysfunction of the fifth component of serum complement is reported. The clinical entity is similar to that of the first family, as well as that described by Leiner, in 1908. The four cardinal features are: (1) generalized seborrheic dermatitis; (2) intractable, severe diarrhea; (3) recurrent local and systemic infections, usually of gram-negative etiology; and (4) marked wasting and dystrophy. The diagnostic laboratory finding is the demonstration of deficient opsomc activity in the patient's serum. This demonstration requires a laboratory assay which measures uptake of a particle which requires C5 for total opsonization. Baker's yeast satisfies these requirements, whereas phagocytic assays utilizing such particles as erythrocytes, pneumococci, or latex particles are inadequate screening procedures for C5 deficiency. A functional assay is necessary, since immuno-chemical measurement of C5 has been normal in all deficient family members. Life-saving therapy has been administered to two patients with the disorder through the use of fresh plasma. Fresh plasma contains opsonically active C5, which is absent in 5-day-old stored bank blood. Based upon genetic and laboratory criteria, separate mechanisms of C5 dysfunction may be involved in the present family and that previously reported.
Article
A patient, previously described, was found to have increased susceptibility to bacterial infections related to a deficiency of serum enhancement of in vitro phagocytosis. The same deficiency affected the patient's mother and 15 other relatives. The deficiency was shown to involve a dysfunction of the fifth component of complement (C5) by the fact that the phagocytosis-enhancing activity of the mother's serum was restored to normal by the addition of highly purified C5. Also, serum from mice with a genetic deficiency of C5 indicated poor enhancement of phagocytosis, and the addition of highly purified C5 to the Co-deficient mouse serum restored phagocytosis-enhancing activity. Finally, the addition of C5-deficient mouse serum to the mother's serum failed to improve the phagocytosis-enhancing effect of the maternal serum, whereas the addition of small amounts of normal mouse serum did. In view of the patient's clinical susceptibility to primarily gram-negative bacteria, the in vitro dysfunction of ...
Article
Hereditary C5 deficiency has been reported in several families of different ethnic backgrounds and from different geographic regions, but the molecular genetic defect causing C5 deficiency has not been delineated in any of them. To examine the molecular basis of C5 deficiency in the African-American population, the exons and intron/exon boundaries of the C5 structural genes from three C5-deficient (C5D) African-American families were sequenced, revealing two nonsense mutations. The nonsense mutations are located in exon 1 (C84AG to TAG) in two of the C5D families (Rhode Island and North Carolina) and in exon 36 (C4521GA to TGA) in the third C5D family (New York). The exon 1 and 36 mutations are contained in codons that encode the first amino acid of the C5 beta-chain (Gln1 to Stop) and residue 1458 in the alpha-chain (Arg1458 to Stop), respectively. Allele-specific PCR and sequence analyses demonstrated that the exon 1 mutation is present in only one of the C5 null genes in both the Rhode Island and North Carolina families, and the exon 36 mutation is contained in only one C5 null gene in the New York family. Neither of the nonsense mutations was found in the European or Caucasian-American C5D individuals examined. Collectively, these data indicate that: 1) C5 deficiency is caused by several different molecular genetic defects, 2) C5 deficiency in the African-American population can be explained in part by two distinct nonsense mutations in exons 1 and 36, and 3) compound heterozygosity exists in all of the reported African-American C5D families.
Article
121 mice homozygous for the gene seb (inherited seborrhoeic dermatitis) and their 142 unaffected heterozygous littermates were kept for their natural lifespan. Heterozygotes showed 84.1% total tumour incidence in males and 95.9% in females. The most common neoplasms were lymphomas, osteomas, lung tumours and neoplasms of the female genital tract. Homozygotes showed a tumour incidence of 36.1% in males and 45.0% in females. The reduction in incidence included all types of neoplasms except epithelial tumours of the skin: skin tumours were detected in 11 homozygous but only in one heterozygous animal. Life expectancy was not affected significantly by genotype. Homozygous mice showed rough and greasy fur and became alopecic with age. Energy intake was increased but growth and depository fat was reduced compared with heterozygous mice. Higher heat loss may incompletely be compensated by higher metabolic rate and thus 'dietary restriction' results in decreased tumour rates. As females show small gonads and a higher increase in food consumption hormonal factors may also be involved.
Article
Pelage skin of C3H/HeJ mice homozygous at an autosomal recessive mutant locus, rough fur (ruf) which is located on chromosome 9, was histologically analyzed. Sebaceous glands synthesizing lipids were larger in the mutant mice than in controls in an examination by Sudan IV staining. Electron microscopic analysis of the sebaceous gland showed that lipid droplets were denser in mutant mice than in control mice, and that they were irregular in shape in ruf mice while those of controls were round. Our results suggested that rough fur (ruf) mice might be an animal model for hyperlipogenesis of the pelage skin.
Article
Transmission electron microscopy of scalp tape strips indicates that dandruff scalp possesses abnormal stratum corneum (SC) ultrastructure that is normalized by treatment with small-particle zinc pyrithione (ZPT). Similar abnormalities occur throughout the scalp of those with dandruff, even where no flaking is present. SC abnormalities are consistent with hyperproliferation, including parakeratosis, lipid droplets within corneocytes, few desmosomes, corneocyte membrane interdigitation, and excessive disorganized intercellular lipid. Reversal of SC abnormalities would require treatment of the cause(s) of dandruff, not merely flake removal. A protocol was developed to quantify scalp structural abnormalities by scoring cells from scalp tape strips for yeast number, amount of intercellular lipid, normal intercellular lipid structures, prevalence of intracellular lipid droplets, parakeratotic corneocytes, and corneocyte interdigitation. This protocol was used to compare dandruff and normal SC to dandruff SC treated with either commercial ZPT-containing shampoo or a placebo. Treatment with commercial ZPT shampoo significantly returned SC ultrastructure to normal, suggesting control of the cause of dandruff.
Article
Seborrheic dermatitis is present in 1% to 3% of immunocompetent adults, and is more prevalent in men than in women. Seborrheic dermatitis may be seen in conjunction with other skin diseases, such as rosacea, blepharitis or ocular rosacea, and acne vulgaris. Malassezia yeasts have been associated with seborrheic dermatitis. Abnormal or inflammatory immune system reactions to these yeasts may be related to development of seborrheic dermatitis. Treatment modalities for seborrheic dermatitis include keratolytic agents, corticosteroids, and more recently, antifungal agents. Antifungal agents do not carry a risk of skin atrophy or telangiectasia with prolonged use, and it is more prudent to consider antifungals than corticosteroid preparations. The wide range of antifungal formulations available (creams, shampoos, or oral) provides safe, effective, and flexible treatment options for seborrheic dermatitis.
Article
1. A test has been devised to measure hemolytic complement activity of mouse serum. The chief requirement for detecting mouse hemolytic complement is the use of extremely large amounts of sensitizing antibody. The hemolytic factor measured in mouse serum is indeed complement. This is indicated by the thermolability, sensitivity to EDTA, and failure to lyse unsensitized cells of the hemolytic factor. 2. Among several strains of inbred mice tested, two were found to be lacking hemolytic complement. One of these strains, B10·D2 is supposedly co-isogenic, except for the histocompatibility locus H-2, with the strain C57BL/10SnHz which contains complement. The data suggest that the two strains must differ by at least one additional gene, and this one is a determinent of complement activity.
Article
The inflammatory functions of complement component 5 (C5) are mediated by its receptor, C5R1, which is expressed on bronchial, epithelial, vascular endothelial and smooth muscle cells. A susceptibility locus for murine allergen-induced airway hyper-responsiveness was identified in a region syntenic to human chromosome 19q13, where linkage to asthma has been demonstrated and where the gene encoding C5R1 is localized. The aim of this study was to screen for novel polymorphisms in the C5R1 gene and to determine whether any identified polymorphisms are associated with asthma and/or atopy and whether they are functional. Single-nucleotide polymorphism (SNP) detection in the gene encoding C5R1 was performed by direct sequencing. Genotyping was performed in three populations characterized for asthma and/or atopy: (1) 823 German children from The Multicenter Allergy Study; (2) 146 individuals from Tangier Island, Virginia, a Caucasian isolate; and (3) asthma case-parent trios selected from 134 families (N=783) in Barbados. Functional studies were performed to evaluate differences between the wild-type and the variant alleles. We identified a novel SNP in the promoter region of C5R1 at position -245 (T/C). Frequency of the -245C allele was similar in the German (31.5%) and Tangier Island (36.3%) populations, but higher in the Afro-Caribbean population (53.0%; P=0.0039 to <0.0001). We observed no significant associations between the -245 polymorphism and asthma or atopy phenotypes. Upon examination of the functional consequences of the -245T/C polymorphism, we did not observe any change in promoter activity. This new marker may provide a valuable tool to assess the risk for C5a-associated disorders, but it does not appear to be associated with asthma and/or atopy.
Article
The rough coat (rc) is a spontaneous recessive mutation in mice. To identify the mutated gene, we have characterized the rc phenotype and initiated linkage mapping. The rc mice show growth retardation, cyclic and progressive hair loss, hyperplastic epidermis, abnormal hair follicles, cardiac muscle degeneration, and reduced amount of collagen and elastin in the skin and heart. The rc locus was mapped at 32.0 cM on chromosome 9, close to the loxl gene. Lysyl oxidase-like (LOXL) protein is a novel copper-containing amine oxidase that is required for the cross-linking of elastin and collagen in vitro. LOXL is expressed at high levels in the skin and heart, where the rc mice show strong phenotype. The expression pattern and the genetic proximity to rc suggested loxl as a potential candidate gene. In rc mice, the loxl mRNA was reduced in the skin and the LOXL protein in the heart, dermis, atrophic hair follicles, and sebaceous glands. No mutations, however, were identified within the coding region of loxl, and offspring from rc/rc and loxl null mice crossing were phenotypically normal. Based on these results, loxl appears non-allelic to rc. Heart- and skin-specific downregulation of LOXL in rc mice, however, may contribute to the extracellular matrix alterations and the rc phenotype.