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1
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Kamp E, Ascott A, George SMC. Eczema Severity Scoring in Skin of Color: A Review of Current Best Practice and Need for Future Improvement. J Invest Dermatol 2025; 145:735-748. [PMID: 39998455 DOI: 10.1016/j.jid.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 01/29/2025] [Accepted: 02/03/2025] [Indexed: 02/26/2025]
Abstract
Patient- and investigator-reported outcome measures are used in research and clinical practice to assess the severity and impact of atopic dermatitis (AD). Initial validation studies of the most commonly used outcome measures for AD underrepresent patients with skin of color or fail to report race, ethnicity, and skin color altogether. Various adaptations have been proposed. Upgrading the erythema score by 1 when using the Eczema Area and Severity Index in patients with skin of color has been suggested but has not yet been validated. However, the use of a "grey scale" in place of the erythema component has been reported to improve inter-rater reliability. Patients of different ethnicities or with skin of color may be impacted in different ways by AD. The pooling of patient-reported outcome measures is therefore not recommended. The Patient-orientated SCORing for Atopic Dermatitis tool for Black skin is an example of a patient-reported outcome measure specifically adapted and validated for Black skin. Novel methods for assessing AD severity include biomarker assessment using tape strips, photonic testing, and measuring subepidermal low echogenic band thickness. In this article, we review the common and novel AD outcome measures in patients with skin of color to highlight best practices and where further research to develop, adapt, and validate outcome measures will be of benefit to patients with AD with skin of color or from minoritized ethnic groups.
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Affiliation(s)
- Erin Kamp
- Dermatology Department, Brighton General Hospital, University Hospitals Sussex, East Sussex, England
| | - Anna Ascott
- Dermatology Department, Brighton General Hospital, University Hospitals Sussex, East Sussex, England
| | - Susannah M C George
- Dermatology Department, Brighton General Hospital, University Hospitals Sussex, East Sussex, England.
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2
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Kim SH, Kim JH, Choi YM, Seo SM, Jang EY, Lee SJ, Zhang H, Roh Y, Jung YW, Park CO, Jeong DH, Lee KH. Development of a biomarker-based platform for comprehensive skin characterization using minimally invasive skin sampling and quantitative real-time PCR. Skin Res Technol 2024; 30:e13908. [PMID: 39141418 PMCID: PMC11323771 DOI: 10.1111/srt.13908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 07/24/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND Classifying diverse skin types is crucial for promoting skin health. However, efficiently identifying and analyzing relevant biomarkers from a vast array of available genetic data is challenging. Therefore, this study aimed to develop a precise and efficient platform for analyzing specific skin biomarkers using quantitative real-time PCR (qRT-PCR) with the minimal invasive skin sampling method (MISSM). MATERIALS AND METHODS MISSM was used for RNA extraction from skin samples, followed by qRT-PCR analysis to quantify the expression of 20 biomarkers associated with skin characteristics (four biomarkers each for five skin characteristics). Noninvasive measurements from 299 Korean participants were utilized to correlate biomarker expression with skin parameters. Statistical analyses were conducted between biomarker expression levels and noninvasive skin measurements to select the relatively best-performing biomarker for each skin characteristic. RESULTS Collagen type 1 alpha 1 (COL1A1) and moesin (MSN) were identified as skin aging biomarkers. Krüppel-like factor 4 (KLF4) and serine peptidase inhibitor Kazal type 5 (SPINK5) were identified as skin dryness biomarkers, whereas melan-A (MLANA) was selected as a biomarker for understanding pigmentation dynamics. Myelin protein zero like 3 (MPZL3) and high mobility group box 2 (HMGB2) were identified as markers of oily skin and skin sensitivity, respectively. Statistically significant correlations were found between the biomarker expression levels and noninvasive skin characteristic measurements. CONCLUSION This study successfully developed a platform for the precise evaluation of individual skin characteristics using MISSM and qRT-PCR biomarker analysis. By selecting biomarkers that correlate with noninvasive measurements of skin characteristics, we demonstrated the platform's efficacy in assessing diverse skin conditions.
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Affiliation(s)
- Seo Hyeong Kim
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
| | - Ji Hye Kim
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
| | - Yoon Mi Choi
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
| | - Su Min Seo
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
| | - Eun Young Jang
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
| | - Sung Jae Lee
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
| | - Hyun‐Soo Zhang
- Biostatistics Collaboration UnitDepartment of Biomedical Systems InformaticsYonsei University College of MedicineSeoulRepublic of Korea
| | - Yunho Roh
- Biostatistics Collaboration UnitDepartment of Biomedical Systems InformaticsYonsei University College of MedicineSeoulRepublic of Korea
| | - Yeon Woo Jung
- Department of Dermatology & Cutaneous Biology Research InstituteYonsei University College of MedicineSeoulRepublic of Korea
| | - Chang Ook Park
- Department of Dermatology & Cutaneous Biology Research InstituteYonsei University College of MedicineSeoulRepublic of Korea
| | | | - Kwang Hoon Lee
- Cutis Biomedical Research Center Co. Ltd.SeoulRepublic of Korea
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3
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Huang Y, Zhou W, Liu S, Zeng D, Zhou W. Association between polymorphisms and atopic dermatitis susceptibility: A systematic review and meta-analysis. Gene 2024; 913:148397. [PMID: 38513928 DOI: 10.1016/j.gene.2024.148397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
AIM Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that is closely linked to genetic factors. Previous studies have revealed numerous single nucleotide polymorphisms (SNPs) that been related to susceptibility to AD; however, the results are conflicting. Therefore, a meta-analysis was conducted to assess the associations of these polymorphisms and AD risk. MATERIAL AND METHODS PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were retrieved to identify eligible studies, with selected polymorphisms being reported in a minimum of three separate studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. Review Manager 5.3 and STATA 14.0 were used to perform the meta-analysis. RESULTS After screening, 64 studies involving 13 genes (24 SNPs) were selected for inclusion in the meta-analysis. Nine SNPs were positively correlated with AD susceptibility [filaggrin (FLG) R501X, FLG 2282del4, chromosome 11q13.5 rs7927894, interleukin (IL)-17A rs2275913, IL-18 -137 G/C, Toll-like receptor 2 (TLR2) rs5743708, TLR2 A-16934 T, serine protease inhibitor Kazal type-5 (SPINK5) Asn368Ser, interferon-γ (IFN-γ) T874A] and one was negatively associated with AD susceptibility (IL-4 -1098 T/G). The 14 remaining SNPs were not significantly associated with AD susceptibility. CONCLUSIONS Nine SNPs that may be risk factors and one SNP that may be a protective factor for AD were identified, providing a reference for AD prediction, prevention, and therapy.
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Affiliation(s)
- Yunxia Huang
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Wei Zhou
- Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Shunan Liu
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Dan Zeng
- Department of Allergy, Chongqing General Hospital, Chongqing 400014, China
| | - Weikang Zhou
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Allergy, Chongqing General Hospital, Chongqing 400014, China.
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4
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Moltrasio C, Romagnuolo M, Riva D, Colavito D, Ferrucci SM, Marzano AV, Tadini G, Brena M. Netherton Syndrome Caused by Heterozygous Frameshift Mutation Combined with Homozygous c.1258A>G Polymorphism in SPINK5 Gene. Genes (Basel) 2023; 14:genes14051080. [PMID: 37239440 DOI: 10.3390/genes14051080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
Netherton syndrome (NS) is a rare autosomal recessive disorder caused by SPINK5 mutations, resulting in a deficiency in its processed protein LEKTI. It is clinically characterized by the triad of congenital ichthyosis, atopic diathesis, and hair shaft abnormalities. The SPINK5 (NM_006846.4): c.1258A>G polymorphism (rs2303067) shows a significant association with atopy and atopic dermatitis (AD), which share several clinical features with NS. We describe an NS patient, initially misdiagnosed with severe AD, who carried the heterozygous frameshift (null) mutation (NM_006846.4): c.957_960dup combined with homozygous rs2303067 in the SPINK5 gene. Histopathological examination confirmed the diagnosis, whereas an immunohistochemical study showed normal epidermal expression of LEKTI, despite the genetic findings. Our results corroborate the hypothesis that haploinsufficiency of SPINK5, in the presence of a SPINK5 null heterozygous mutation in combination with homozygous SPINK5 rs2303067 polymorphism, can be causative of an NS phenotype, impairing the function of LEKTI despite its normal expression. Due to the clinical overlap between NS and AD, we suggest performing SPINK5 genetic testing to search for the SPINK5 (NM_006846.4): c.1258A>G polymorphism (rs2303067) and ensure a correct diagnosis, mainly in doubtful cases.
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Affiliation(s)
- Chiara Moltrasio
- Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Maurizio Romagnuolo
- Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Davide Riva
- Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Davide Colavito
- Research & Innovation S.R.L. (R&I Genetics), 35127 Padova, Italy
| | - Silvia Mariel Ferrucci
- Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Angelo Valerio Marzano
- Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Gianluca Tadini
- Pediatric Dermatology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Michela Brena
- Pediatric Dermatology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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5
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Chiricozzi A, Maurelli M, Calabrese L, Peris K, Girolomoni G. Overview of Atopic Dermatitis in Different Ethnic Groups. J Clin Med 2023; 12:2701. [PMID: 37048783 PMCID: PMC10095524 DOI: 10.3390/jcm12072701] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/16/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a high prevalence worldwide, including countries from Asia, Africa, and Latin America, and in different ethnic groups. In recent years, more attention has been placed on the heterogeneity of AD associated with multiple factors, including a patient's ethnic background, resulting in an increasing body of clinical, genetic, epidemiologic, and immune-phenotypic evidence that delineates differences in AD among racial groups. Filaggrin (FLG) mutations, the strongest genetic risk factor for the development of AD, are detected in up to 50% of European and 27% of Asian AD patients, but very rarely in Africans. Th2 hyperactivation is a common attribute of all ethnic groups, though the Asian endotype of AD is also characterized by an increased Th17-mediated signal, whereas African Americans show a strong Th2/Th22 signature and an absence of Th1/Th17 skewing. In addition, the ethnic heterogeneity of AD may hold important therapeutic implications as a patient's genetic predisposition may affect treatment response and, thereby, a tailored strategy that better targets the dominant immunologic pathways in each ethnic subgroup may be envisaged. Nevertheless, white patients with AD represent the largest ethnicity enrolled and tested in clinical trials and the most treated in a real-world setting, limiting investigations about safety and efficacy across different ethnicities. The purpose of this review is to describe the heterogeneity in the pathophysiology of AD across ethnicities and its potential therapeutic implications.
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Affiliation(s)
- Andrea Chiricozzi
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Martina Maurelli
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Laura Calabrese
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ketty Peris
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giampiero Girolomoni
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, 37126 Verona, Italy
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6
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Genetic/Protein Association of Atopic Dermatitis and Tooth Agenesis. Int J Mol Sci 2023; 24:ijms24065754. [PMID: 36982827 PMCID: PMC10055628 DOI: 10.3390/ijms24065754] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/07/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Atopic dermatitis and abnormalities in tooth development (including hypomineralization, hypodontia and microdontia) have been observed to co-occur in some patients. A common pathogenesis pathway that involves genes and protein interactions has been hypothesized. This review aims to first provide a description of the key gene mutations and signaling pathways associated with atopic dermatitis and tooth agenesis (i.e., the absence of teeth due to developmental failure) and identify the possible association between the two diseases. Second, utilizing a list of genes most commonly associated with the two diseases, we conducted a protein–protein network interaction analysis using the STRING database and identified a novel association between the Wnt/β-catenin signaling pathway (major pathway responsible for TA) and desmosomal proteins (component of skin barrier that affect the pathogenesis of AD). Further investigation into the mechanisms that may drive their co-occurrence and underlie the development of the two diseases is warranted.
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7
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Thibault Greugny E, Bensaci J, Fages F, Stamatas GN. Computational modelling predicts impaired barrier function and higher sensitivity to skin inflammation following pH elevation. Exp Dermatol 2023; 32:177-185. [PMID: 36321871 DOI: 10.1111/exd.14698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/04/2022] [Accepted: 10/27/2022] [Indexed: 11/07/2022]
Abstract
Skin surface pH has been identified as a key regulator of the epidermal homeostasis through its action on serine protease activity. These enzymes, like kallikreins (KLK), are responsible for the degradation of corneodesmosomes, the protein structures linking together corneocytes, and are regulated by Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI). KLK activity increases at pH levels higher than physiological. An increase in skin surface pH has been observed in patients suffering from skin diseases characterized by impaired barrier function, like atopic dermatitis. In this work, we introduce an agent-based model of the epidermis to study the impact of a change in skin surface pH on the structural and physiological properties of the epidermis, through the LEKTI-KLK mechanism. We demonstrate that a less acidic pH, compared to the slightly acidic pH observed in healthy skin, is sufficient to significantly affect the water loss at the surface and the amount of irritant permeating through the epidermis. This weakening of the skin barrier function eventually results in a more intense skin inflammation following exposure to an external irritant. This work provides additional evidence that skin surface pH and serine proteases can be therapeutic targets to improve skin barrier integrity.
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Affiliation(s)
- Eléa Thibault Greugny
- Essential Health Translational Science, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France.,Inria Saclay Île-de-France, Lifeware Team, Palaiseau, France
| | - Jalil Bensaci
- Essential Health Translational Science, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France
| | - François Fages
- Inria Saclay Île-de-France, Lifeware Team, Palaiseau, France
| | - Georgios N Stamatas
- Essential Health Translational Science, Johnson & Johnson Santé Beauté France, Issy-les-Moulineaux, France
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8
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Matus CE, Ehrenfeld P, Figueroa CD. The family of kallikrein-related peptidases and kinin peptides as modulators of epidermal homeostasis. Am J Physiol Cell Physiol 2022; 323:C1070-C1087. [PMID: 35993513 DOI: 10.1152/ajpcell.00012.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The epidermis is the outermost skin layer and is part of one of the largest organs in the body; it is supported by the dermis, a network of fibrils, blood vessels, pilosebaceous units, sweat glands, nerves, and cells. The skin as a whole is a protective shield against numerous noxious agents, including microorganisms and chemical and physical factors. These functions rely on the activity of multiple growth factors, peptide hormones, proteases, and specific signaling pathways that are triggered by the activation of distinct types of receptors sited in the cell membranes of the various cell types present in the skin. The human kallikrein family comprises a large group of 15 serine proteases synthesized and secreted by different types of epithelial cells throughout the body, including the skin. At this site, they initiate a proteolytic cascade that generates the active forms of the proteases, some of which regulate skin desquamation, activation of cytokines, and antimicrobial peptides. Kinin peptides are formed by the action of plasma and tissue kallikreins on kininogens, two plasma proteins produced in the liver and other organs. Although kinins are well known for their proinflammatory abilities, in the skin they are also considered important modulators of keratinocyte differentiation. In this review, we summarize the contributions of the kallikreins and kallikrein-related peptidases family and those of kinins and their receptors in skin homeostasis, with special emphasis on their pathophysiological role.
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Affiliation(s)
- Carola E Matus
- Departament of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile.,Center of Molecular Biology and Pharmacogenetics, Universidad de La Frontera, Temuco, Chile.,Center of Biomedical and Morphofunctional Sciences, Universidad de La Frontera, Temuco, Chile
| | - Pamela Ehrenfeld
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.,Center for Interdisciplinary Studies on Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Carlos D Figueroa
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.,Center for Interdisciplinary Studies on Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile
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9
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Hawerkamp HC, Fahy CMR, Fallon PG, Schwartz C. Break on through: The role of innate immunity and barrier defence in atopic dermatitis and psoriasis. SKIN HEALTH AND DISEASE 2022; 2:e99. [PMID: 35677926 PMCID: PMC9168024 DOI: 10.1002/ski2.99] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 01/07/2022] [Accepted: 01/23/2022] [Indexed: 12/20/2022]
Abstract
The human skin can be affected by a multitude of diseases including inflammatory conditions such as atopic dermatitis and psoriasis. Here, we describe how skin barrier integrity and immunity become dysregulated during these two most common inflammatory skin conditions. We summarise recent advances made in the field of the skin innate immune system and its interaction with adaptive immunity. We review gene variants associated with atopic dermatitis and psoriasis that affect innate immune mechanisms and skin barrier integrity. Finally, we discuss how current and future therapies may affect innate immune responses and skin barrier integrity in a generalized or more targeted approach in order to ameliorate disease in patients.
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Affiliation(s)
- H C Hawerkamp
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland
| | - C M R Fahy
- Paediatric Dermatology Children's Health Ireland at Crumlin Dublin Ireland.,Royal United Hospitals NHS Foundation Trust Bath UK
| | - P G Fallon
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland.,National Children's Research Centre Our Lady's Children's Hospital Dublin Ireland.,Clinical Medicine Trinity College Dublin Dublin Ireland
| | - C Schwartz
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland.,Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg Erlangen Germany.,Medical Immunology Campus Erlangen FAU Erlangen-Nürnberg Erlangen Germany
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10
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Cheng J, Wu JJ, Han G. Epidemiology and Characterization of Atopic Dermatitis in East Asian Populations: A Systematic Review. Dermatol Ther (Heidelb) 2021; 11:707-717. [PMID: 33835410 PMCID: PMC8163933 DOI: 10.1007/s13555-021-00516-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction As atopic dermatitis (AD) grows increasingly prevalent in Asian populations worldwide, understanding how environmental, genetic, and cultural factors uniquely influence AD in Asians is essential for informing disease management. Our objectives were to characterize the epidemiology of AD in East Asian populations with sensitivity to the changing demographics of AD in these populations and the effects of urbanization and immigration. Methods A systematic review was performed on epidemiologic studies of AD in East Asian populations over the past 10 years. Results There is a rising prevalence of both pediatric and adult AD in Asian populations worldwide, particularly in Asians living in urban areas. Studies suggest that the children of Asian immigrants may be at higher risk for developing AD, potentially resulting from epigenetic phenomena unique to immigrant populations. A number of genetic polymorphisms implicated in AD are shared by Asian populations around the world and appear to be rare among other ethnic populations. Conclusions As the prevalence of AD continues to increase in Asian populations, it is important to understand its distinct genetic and pathophysiologic profile in these populations, as well as characterize the cultural beliefs and practices surrounding its treatment. Future research should aim to capitalize on our growing understanding of pathophysiologic differences to inform the most promising treatments for AD in Asians. Additionally, the impact of immigration on AD suggests that further investigation of these trends may lead to a greater understanding of the epigenetics of AD.
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Affiliation(s)
- Julia Cheng
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jashin J Wu
- Dermatology Research and Education Foundation, Irvine, CA, USA
| | - George Han
- Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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11
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Park NJ, Bong SK, Lee S, Jung Y, Jegal H, Kim J, Kim SK, Kim YK, Kim SN. Compound K improves skin barrier function by increasing SPINK5 expression. J Ginseng Res 2020; 44:799-807. [PMID: 33192123 PMCID: PMC7655487 DOI: 10.1016/j.jgr.2019.11.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/18/2019] [Accepted: 11/07/2019] [Indexed: 11/26/2022] Open
Abstract
Background The skin acts as a barrier to protect organisms against harmful exogenous agents. Compound K (CK) is an active metabolite of ginsenoside Rb1, Rb2 and Rc, and researchers have focused on its skin protective efficacy. In this study, we hypothesized that increased expression of the serine protease inhibitor Kazal type-5 (SPINK5) may improve skin barrier function. Methods We screened several ginsenosides to increase SPINK5 gene promoter activity using a transactivation assay and found that CK can increase SPINK5 expression. To investigate the protective effect of CK on the skin barrier, RT-PCR and Western blotting were performed to investigate the expression levels of SPINK5, kallikrein 5 (KLK5), KLK7 and PAR2 in UVB-irradiated HaCaT cells. Measurement of transepidermal water loss (TEWL) and histological changes associated with the skin barrier were performed in a UVB-irradiated mouse model and a 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis-like model. Results CK treatment increased the expression of SPINK5 and decreased the expression of its downstream genes, such as KLKs and PAR2. In the UVB-irradiated mouse model and the DNCB-induced atopic dermatitis model, CK restored increased TEWL and decreased hydration and epidermal hyperplasia. In addition, CK normalized the reduced SPINK5 expression caused by UVB or DNCB, thereby restoring the expression of the proteins involved in desquamation to a level similar to normal. Conclusions Our data showed that CK contributes to improving skin-barrier function in UVB-irradiated and DNCB-induced atopic dermatitis-like models through SPINK5. These results suggest that therapeutic attempts with CK might be useful in treating barrier-disrupted diseases.
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Affiliation(s)
- No-June Park
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Sim-Kyu Bong
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Sullim Lee
- Department of Life Science, College of Bio-Nano Technology, Gachon University, Seongnam, Republic of Korea
| | - Yujung Jung
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Hyun Jegal
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Jinchul Kim
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Si-Kwan Kim
- Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yong Kee Kim
- College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Su-Nam Kim
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
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12
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Li Y, Li Y, Li W, Guo X, Zhou S, Zheng H. Genetic polymorphisms in serine protease inhibitor Kazal-type 5 and risk of atopic dermatitis: A meta-analysis. Medicine (Baltimore) 2020; 99:e21256. [PMID: 32664181 PMCID: PMC7360313 DOI: 10.1097/md.0000000000021256] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND This study aimed to investigate the role of serine protease inhibitor Kazal-type 5 (SPINK5) polymorphisms (Asn368Ser, Asp386Asn and Glu420Lys) and the risk of atopic dermatitis (AD). METHODS Studies associated with SPINK5 mutations and AD risk were searched from three databases, including PubMed, Embase, and Cochrane library, with a retrieval deadline of April 22, 2019. An odds ratio (OR) with a 95% confidence interval (95% CI) was chosen as the effect size. Egger's linear regression test was enrolled to assess the level of publication bias. RESULTS Overall, 6 studies met the inclusion criteria for meta-analysis. Significantly statistical differences were calculated between patients with AD and healthy individuals on Asn368Ser polymorphism in the allele model (G vs A: OR = 1.2643, 95% CI = 1.0666-1.4987, P = .0069), co-dominant model (GG vs AA: OR = 1.6609, 95% CI = 1.1736-2.3505, P = .0042; GA vs AA: OR = 1.5448, 95% CI = 1.1263-2.1189, P = .0070), and dominant model (GG+GA vs AA: OR = 1.5700, 95% CI = 1.1656-2.1146, P = .0030). However, no statistically significant difference was found in the recessive model for Asn368Ser and other genetic models for Asp386Asn and Glu420Lys (all P > .05). No significant publication bias was found. CONCLUSION The SPINK5 Asn368Ser polymorphism may be a risk factor for AD.
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13
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Nomura T, Wu J, Kabashima K, Guttman-Yassky E. Endophenotypic Variations of Atopic Dermatitis by Age, Race, and Ethnicity. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2020; 8:1840-1852. [DOI: 10.1016/j.jaip.2020.02.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 02/11/2020] [Accepted: 02/25/2020] [Indexed: 12/21/2022]
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Nomura H, Suganuma M, Takeichi T, Kono M, Isokane Y, Sunagawa K, Kobashi M, Sugihara S, Kajita A, Miyake T, Hirai Y, Yamasaki O, Akiyama M, Morizane S. Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis. Int J Mol Sci 2020; 21:ijms21030913. [PMID: 32019242 PMCID: PMC7038095 DOI: 10.3390/ijms21030913] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/22/2020] [Accepted: 01/28/2020] [Indexed: 11/17/2022] Open
Abstract
The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin- and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC’s serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD.
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Affiliation(s)
- Hayato Nomura
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Mutsumi Suganuma
- Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Takuya Takeichi
- Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Michihiro Kono
- Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine, Hondo 1-1-1, Akita-shi, Akita 010-8543, Japan
| | - Yuki Isokane
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Ko Sunagawa
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Mina Kobashi
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Satoru Sugihara
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Ai Kajita
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Tomoko Miyake
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Yoji Hirai
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Osamu Yamasaki
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
| | - Masashi Akiyama
- Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Shin Morizane
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan
- Correspondence: ; Tel.: +81-86-235-7282
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15
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Brunner PM, Guttman-Yassky E. Racial differences in atopic dermatitis. Ann Allergy Asthma Immunol 2019; 122:449-455. [PMID: 30465859 DOI: 10.1016/j.anai.2018.11.015] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/04/2018] [Accepted: 11/12/2018] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To summarize studies investigating ethnical and racial differences in atopic dermatitis (AD) epidemiology, clinical features, and skin and blood phenotypes. DATA SOURCES PubMed literature review (years 2000-2018). STUDY SELECTIONS Articles discussing primarily human disease. RESULTS Higher overall rates of AD were found in Africa and Oceania as opposed to India and Northern and Eastern Europe. In the United States, AD prevalence was found to be higher in African American (19.3%) compared with European American (16.1%) children. Although several studies have consistently found FLG loss-of-function mutations in up to 50% of European and 27% of Asian patients with AD, FLG mutations were 6 times less common in African American than in European American patients, even in patients with severe AD. Thus, FLG mutations seem to play less a pathogenic role in patients of African origin than in individuals of European or Asian ancestry. The immune phenotype of all ethnic groups was characterized by strong TH2 activation, but important differences in immune polarization exist among the different ethnicities. Asian patients with AD had stronger TH17/TH22 activation than African American and European American patients with AD, whereas African American patients had the highest serum IgE levels among all groups, while largely lacking TH1 and TH17 activation. CONCLUSION AD is a heterogeneous disease that has differences among various ethnic and racial groups, which might be important for the development of future, targeted treatments and for personalized medicine approaches.
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Affiliation(s)
- Patrick M Brunner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Emma Guttman-Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
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New Cosmetic Formulation for the Treatment of Mild to Moderate Infantile Atopic Dermatitis. CHILDREN-BASEL 2019; 6:children6020017. [PMID: 30700045 PMCID: PMC6406490 DOI: 10.3390/children6020017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/22/2019] [Accepted: 01/22/2019] [Indexed: 12/21/2022]
Abstract
Atopic dermatitis (AD) is a chronic cutaneous inflammatory disorder, characterized by skin barrier disruption. Dermacare is a new cosmetic formulation, which enhances moisturization, reinforces and repairs the skin barrier, and prevents cutaneous microbiota imbalance. To demonstrate its safety and efficacy, a prospective, open-label, and multicenter study was carried out on patients diagnosed with mild to moderate AD. Transepidermal water loss (TEWL), clinical severity, Desquamation Index, Patient/Investigator Global Assessments, quality of life index, and tolerance were assessed. Adverse events were recorded. Daily application of the new treatment was well tolerated, and adverse events were absent. After 14 days, TEWL showed a 36.7% significant decrease (p = 0.035). At the end of the 28-day treatment, the Desquamation Index showed a reduction in 70% of patients; Eczema Area and Severity Index were reduced by 70.4% (p = 0.002); and skin irritation showed a significant reduction (p = 0.024). Likewise, Patient and Investigator Global Assessments reported a significant improvement in conditions and an overall global worsening when patients restarted their normal treatment. Parent's Index of Quality of Life Index significantly increased by 36.4% (p < 0.05) with Dermacare. In conclusion, a regular use of this new formulation can reduce the risk of relapse and extend the steroid-free treatment periods.
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17
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Kaufman BP, Guttman-Yassky E, Alexis AF. Atopic dermatitis in diverse racial and ethnic groups-Variations in epidemiology, genetics, clinical presentation and treatment. Exp Dermatol 2018; 27:340-357. [DOI: 10.1111/exd.13514] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Bridget P. Kaufman
- Department of Dermatology; Mount Sinai St. Luke's and Mount Sinai West; New York NY USA
| | - Emma Guttman-Yassky
- Department of Dermatology and the Laboratory for Inflammatory Skin Diseases; Icahn School of Medicine at Mount Sinai; New York NY USA
| | - Andrew F. Alexis
- Department of Dermatology; Mount Sinai St. Luke's and Mount Sinai West; New York NY USA
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18
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Yoon NY, Wang HY, Jun M, Jung M, Kim DH, Lee NR, Hong KW, Seo SJ, Choi E, Lee J, Lee H, Choi EH. Simultaneous detection of barrier- and immune-related gene variations in patients with atopic dermatitis by reverse blot hybridization assay. Clin Exp Dermatol 2018; 43:430-436. [PMID: 29380403 DOI: 10.1111/ced.13367] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Hereditary factors are involved in the pathogenesis of atopic dermatitis (AD). However, AD-related gene variations are significantly different across ethnicities. AIM To identify mutations and single-nucleotide polymorphisms (SNPs) in barrier- or immune-related genes from Korean patients with AD and compare the variations with those observed in nonatopic healthy controls (HCs), and to use novel reverse blot hybridization assay (REBA) for AD-related gene variants. METHODS We carried out REBA to simultaneously detect variations in genes related to barrier or immune function, namely, FLG, SPINK5, KLK7, DEFB1, TNFα, KDR, FCER1A, IL4, IL5,IL5RA, IL9, IL10, IL12, IL12R, IL13 and IL18, from Korean patients with AD, and compared the variation to that in nonatopic healthy controls. RESULTS The homozygous mutants of KLK7 and SPINK5-2475, and the heterozygous mutants of FLG 3321delA, SPINK5-1156, DEFB1, KDR, IL5RA, IL9 and IL12RB1 were significantly more frequent in AD. It has been predicted that the larger the number of gene variants, the higher the odds ratio of AD prevalence; however, we did not find any significant correlation between the number of gene variants and AD severity. CONCLUSION Using REBA, we identified more genetic variants that can predict AD occurrence. We also verified that REBA can be used to easily and accurately detect multiple AD-related gene variants simultaneously. In addition, we identified a correlation between KLK7 mutation and AD in Koreans, which is the first such report, to our knowledge.
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Affiliation(s)
- N Y Yoon
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - H Y Wang
- M&D, Inc., Wonju Eco Environmental Technology Center, Wonju, Republic of Korea
| | - M Jun
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - M Jung
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - D H Kim
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - N R Lee
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - K-W Hong
- TheragenEtex Bio Institute, Suwon, Republic of Korea
| | - S J Seo
- Department of Dermatology, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - E Choi
- Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - J Lee
- Department of Biomedical Laboratory Science, Yonsei University College of Health Sciences, Wonju, Republic of Korea
| | - H Lee
- Department of Biomedical Laboratory Science, Yonsei University College of Health Sciences, Wonju, Republic of Korea
| | - E H Choi
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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19
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Ashley SE, Tan HTT, Vuillermin P, Dharmage SC, Tang MLK, Koplin J, Gurrin LC, Lowe A, Lodge C, Ponsonby AL, Molloy J, Martin P, Matheson MC, Saffery R, Allen KJ, Ellis JA, Martino D. The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants. Allergy 2017; 72:1356-1364. [PMID: 28213955 DOI: 10.1111/all.13143] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. OBJECTIVE To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. METHOD We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. RESULTS SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. CONCLUSIONS We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.
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20
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Dežman K, Korošec P, Rupnik H, Rijavec M. SPINK5
is associated with early-onset and CHI3L1
with late-onset atopic dermatitis. Int J Immunogenet 2017; 44:212-218. [DOI: 10.1111/iji.12327] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 03/20/2017] [Accepted: 05/31/2017] [Indexed: 01/08/2023]
Affiliation(s)
- K. Dežman
- University Clinic of Respiratory and Allergic Diseases Golnik; Golnik Slovenia
| | - P. Korošec
- University Clinic of Respiratory and Allergic Diseases Golnik; Golnik Slovenia
| | - H. Rupnik
- Department of Dermatovenereology; University Medical Centre Ljubljana; Ljubljana Slovenia
- Dermatology Centre Arsderma; Ljubljana Slovenia
| | - M. Rijavec
- University Clinic of Respiratory and Allergic Diseases Golnik; Golnik Slovenia
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21
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Bauer SM. Atopic Eczema: Genetic Associations and Potential Links to Developmental Exposures. Int J Toxicol 2017; 36:187-198. [DOI: 10.1177/1091581817701075] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Atopic eczema (AE), or atopic dermatitis (AD), is a common inflammatory skin disease with a disrupted epidermal barrier and an allergic immune response. AD/AE is prominently characterized by a symptomatic itch and transient skin lesions. Infants compose a significant percentage affected. Two models have been proposed to explain AD/AE skin pathology: the gut microbiome-focused inside-outside model and the outside-inside model concentrating on the disrupted skin barrier/skin microbiome. Gene disruptions contributing to epidermal structure, as well as those in immune system genes, are implicated. Over 30 genes have been linked to AD/AE with Flg and Tmem79/Matt alterations being common. Other linked disruptions are in the interleukin-1 family of cytokines/receptors and the TH2 gene family of cytokines. Inheritable epigenetic modifications of the genes or associated proteins may also be involved. Skin barrier disruption and the allergic immune response have been the main foci in mechanistic studies of AD/AE, but the role of the environment is becoming more apparent. Thus, an examination of in utero exposures could be very helpful in understanding the heterogeneity of AD/AE. Although research is limited, there is evidence that developmental exposure to environmental tobacco smoke or phthalates may impact disease. Management for AD/AE includes topical corticosteroids and calcineurin inhibitors, which safely facilitate improvements in select individuals. Disease heterogeneity warrants continued research not only into elucidating disease mechanism(s), via identification of contributing genetic alterations, but also research to understand how/when these genetic alterations occur. This may lead to the cure that those affected by AD/AE eagerly await.
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Affiliation(s)
- Stephen M. Bauer
- Assistant Professor of Biology, Department of Biology, Belmont Abbey College, Belmont, NC, USA
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22
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Liang Y, Chang C, Lu Q. The Genetics and Epigenetics of Atopic Dermatitis-Filaggrin and Other Polymorphisms. Clin Rev Allergy Immunol 2017; 51:315-328. [PMID: 26385242 DOI: 10.1007/s12016-015-8508-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by a combination of genetic and environmental factors. Genetic evidences depict a complex network comprising by epidermal barrier dysfunctions and dysregulation of innate and adaptive immunity in the pathogenesis of AD. Mutations in the human filaggrin gene (FLG) are the most significant and well-replicated genetic mutation associated with AD, and other mutations associated with epidermal barriers such as SPINK5, FLG-2, SPRR3, and CLDN1 have all been linked to AD. Gene variants may also contribute to the abnormal innate and adaptive responses found in AD, including mutations in PRRs and AMPs, TSLP and TSLPR, IL-1 family cytokines and receptors genes, vitamin D pathway genes, FCER1A, and Th2 and other cytokines genes. GWAS and Immunochip analysis have identified a total of 19 susceptibility loci for AD. Candidate genes at these susceptibility loci identified by GWAS and Immunochip analysis also suggest roles for epidermal barrier functions, innate and adaptive immunity, interleukin-1 family signaling, regulatory T cells, the vitamin D pathway, and the nerve growth factor pathway in the pathogenesis of AD. Increasing evidences show the modern lifestyle (i.e., the hygiene hypothesis, Western diet) and other environmental factors such as pollution and environmental tobacco smoke (ETS) lead to the increasing prevalence of AD with the development of industrialization. Epigenetic alterations in response to these environmental factors, including DNA methylation and microRNA related to immune system and skin barriers, have been found to contribute to the pathogenesis of AD. Genetic variants and epigenetic alteration might be the key tools for the molecular taxonomy of AD and provide the background for the personalized management.
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Affiliation(s)
- Yunsheng Liang
- Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Changsha, Hunan, 410011, China
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, 95616, USA
| | - Qianjin Lu
- Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Changsha, Hunan, 410011, China.
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23
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24
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Bin L, Leung DYM. Genetic and epigenetic studies of atopic dermatitis. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2016; 12:52. [PMID: 27777593 PMCID: PMC5069938 DOI: 10.1186/s13223-016-0158-5] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 10/04/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory disease caused by the complex interaction of genetic, immune and environmental factors. There have many recent discoveries involving the genetic and epigenetic studies of AD. METHODS A retrospective PubMed search was carried out from June 2009 to June 2016 using the terms "atopic dermatitis", "association", "eczema", "gene", "polymorphism", "mutation", "variant", "genome wide association study", "microarray" "gene profiling", "RNA sequencing", "epigenetics" and "microRNA". A total of 132 publications in English were identified. RESULTS To elucidate the genetic factors for AD pathogenesis, candidate gene association studies, genome-wide association studies (GWAS) and transcriptomic profiling assays have been performed in this period. Epigenetic mechanisms for AD development, including genomic DNA modification and microRNA posttranscriptional regulation, have been explored. To date, candidate gene association studies indicate that filaggrin (FLG) null gene mutations are the most significant known risk factor for AD, and genes in the type 2 T helper lymphocyte (Th2) signaling pathways are the second replicated genetic risk factor for AD. GWAS studies identified 34 risk loci for AD, these loci also suggest that genes in immune responses and epidermal skin barrier functions are associated with AD. Additionally, gene profiling assays demonstrated AD is associated with decreased gene expression of epidermal differentiation complex genes and elevated Th2 and Th17 genes. Hypomethylation of TSLP and FCER1G in AD were reported; and miR-155, which target the immune suppressor CTLA-4, was found to be significantly over-expressed in infiltrating T cells in AD skin lesions. CONCLUSIONS The results suggest that two major biologic pathways are responsible for AD etiology: skin epithelial function and innate/adaptive immune responses. The dysfunctional epidermal barrier and immune responses reciprocally affect each other, and thereby drive development of AD.
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Affiliation(s)
- Lianghua Bin
- The Department of Dermatology, the First Affiliated Hospital, Jinan University, Guangzhou, China
- Biomedical Translational Research Institute, Jinan University, Guangzhou, China
- Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Room K926i, Denver, CO 80206 USA
| | - Donald Y. M. Leung
- Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Room K926i, Denver, CO 80206 USA
- Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Clinical Specialty in Allergy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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25
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Jarrett R, Ogg G. Lipid-specific T cells and the skin. Br J Dermatol 2016; 175 Suppl 2:19-25. [DOI: 10.1111/bjd.14908] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2016] [Indexed: 12/23/2022]
Affiliation(s)
- R. Jarrett
- MRC Human Immunology Unit; Weatherall Institute of Molecular Medicine; NIHR Biomedical Research Centre; Radcliffe Department of Medicine; University of Oxford; Oxford OX3 9DS U.K
| | - G. Ogg
- MRC Human Immunology Unit; Weatherall Institute of Molecular Medicine; NIHR Biomedical Research Centre; Radcliffe Department of Medicine; University of Oxford; Oxford OX3 9DS U.K
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Mast cells are dispensable in a genetic mouse model of chronic dermatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1575-87. [PMID: 25843682 DOI: 10.1016/j.ajpath.2015.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/26/2015] [Accepted: 02/12/2015] [Indexed: 01/12/2023]
Abstract
Chronic inflammatory skin diseases, such as atopic dermatitis, affect a large percentage of the population, but the role of different immune cells in the pathogenesis of these disorders is largely unknown. Recently, we found that mice lacking fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 (K5-R1/R2 mice) in the epidermis have a severe impairment in the epidermal barrier, which leads to the development of a chronic inflammatory skin disease that shares many features with human atopic dermatitis. Using Fgfr1-/Fgfr2-deficient mice, we analyzed the consequences of the loss of mast cells. Mast cells accumulated and degranulated in the skin of young Fgfr1-/Fgfr2-deficient mice, most likely as a consequence of increased expression of the mast cell chemokine Ccl2. The increase in mast cells occurred before the development of histological abnormalities, indicating a functional role of these cells in the inflammatory skin phenotype. To test this hypothesis, we mated the Fgfr1-/Fgfr2-deficient mice with mast cell-deficient CreMaster mice. Surprisingly, loss of mast cells did not or only mildly affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, accumulation and activation of different immune cells, or expression of different proinflammatory cytokines in the skin. These results reveal that mast cells are dispensable for the development of chronic inflammation in response to a defect in the epidermal barrier.
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Matsui T, Amagai M. Dissecting the formation, structure and barrier function of the stratum corneum. Int Immunol 2015; 27:269-80. [PMID: 25813515 DOI: 10.1093/intimm/dxv013] [Citation(s) in RCA: 232] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 03/19/2015] [Indexed: 02/06/2023] Open
Abstract
The skin is the largest organ of the mammalian body. The outermost layer of mammalian skin, the stratum corneum (SC) of the epidermis, consists of piles of dead corneocytes that are the end-products of terminal differentiation of epidermal keratinocytes. The SC performs a crucial barrier function of epidermis. Langerhans cells, when activated, extend their dendrites through tight junctions just beneath the SC to capture external antigens. Recently, knowledge of the biology of corneocytes ('corneobiology') has progressed rapidly and many key factors that modulate its barrier function have been identified and characterized. In this review article on the SC, we summarize its evolution, formation, structure and function. Cornification is an important step of SC formation at the conversion of living epithelial cells to dead corneocytes, and consists of three major steps: formation of the intracellular keratin network, cornified envelopes and intercellular lipids. After cornification, the SC undergoes chemical reactions to form the mature SC with different functional layers. Finally, the SC is shed off at the surface ('desquamation'), mediated by a cascade of several proteases. This review will be helpful to understand our expanding knowledge of the biology of the SC, where immunity meets external antigens.
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Affiliation(s)
- Takeshi Matsui
- Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
| | - Masayuki Amagai
- Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Pucheu-Haston CM, Bizikova P, Marsella R, Santoro D, Nuttall T, Eisenschenk MNC. Review: Lymphocytes, cytokines, chemokines and the T-helper 1-T-helper 2 balance in canine atopic dermatitis. Vet Dermatol 2015; 26:124-e32. [DOI: 10.1111/vde.12205] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2015] [Indexed: 02/03/2023]
Affiliation(s)
- Cherie M. Pucheu-Haston
- Department of Veterinary Clinical Sciences; School of Veterinary Medicine; Louisiana State University; 1909 Skip Bertman Drive Baton Rouge LA 70803 USA
| | - Petra Bizikova
- Department of Clinical Sciences; College of Veterinary Medicine; North Carolina State University; 1060 William Moore Drive Raleigh NC 27607 USA
| | - Rosanna Marsella
- Department of Small Animal Clinical Sciences; College of Veterinary Medicine; University of Florida; 2015 SW 16th Avenue Gainesville FL 32610 USA
| | - Domenico Santoro
- Department of Small Animal Clinical Sciences; College of Veterinary Medicine; University of Florida; 2015 SW 16th Avenue Gainesville FL 32610 USA
| | - Tim Nuttall
- Royal (Dick) School of Veterinary Studies; Easter Bush Veterinary Centre; University of Edinburgh; Roslin EH25 9RG UK
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Unravelling the complex genetic background of atopic dermatitis: from genetic association results towards novel therapeutic strategies. Arch Dermatol Res 2015; 307:659-70. [PMID: 25693656 DOI: 10.1007/s00403-015-1550-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 01/14/2015] [Accepted: 01/31/2015] [Indexed: 02/06/2023]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease arising from complex interaction between genetic and environmental factors. As the starting point of the so-called "atopic march", e.g. the progression towards allergic asthma in some but not all affected children, AD has come into focus for potential disease-modifying strategies. To elucidate the genetic factors influencing AD development, linkage, association as well as genome-wide association studies have been performed over the last two decades. The results suggest that besides variation in immune-mediated pathways, an intact skin barrier function plays a key role in AD development. Mutations in the gene encoding filaggrin, a major structural protein in the epidermis, have been consistently associated with AD, especially the early-onset persistent form of disease, and are regarded as the most significant known risk factor for AD development to date. Additionally, variation in some other genes involved in skin integrity and barrier function have shown association with AD. However, the known genetic risk factors can only explain a small part of the heritability at the moment. Whole-exome or whole-genome sequencing studies have not been reported yet, but will probably soon evaluate the influence of rare variations for AD development. Additionally, large multi-centre studies comprehensively incorporating gene-gene and gene-environment interactions as well as epigenetic mechanisms might further elucidate the genetic factors underlying AD pathogenesis and, thus, open the way for a more individualized treatment in the future.
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Gillespie RMC, Brown SJ. From the outside-in: Epidermal targeting as a paradigm for atopic disease therapy. World J Dermatol 2015; 4:16-32. [DOI: 10.5314/wjd.v4.i1.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Revised: 11/29/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.
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Kiritsi D, Valari M, Fortugno P, Hausser I, Lykopoulou L, Zambruno G, Fischer J, Bruckner-Tuderman L, Jakob T, Has C. Whole-exome sequencing in patients with ichthyosis reveals modifiers associated with increased IgE levels and allergic sensitizations. J Allergy Clin Immunol 2015; 135:280-3. [DOI: 10.1016/j.jaci.2014.09.042] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 07/16/2014] [Accepted: 09/22/2014] [Indexed: 02/06/2023]
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Environmental effects on immune responses in patients with atopy and asthma. J Allergy Clin Immunol 2014; 134:1001-8. [PMID: 25439226 DOI: 10.1016/j.jaci.2014.07.064] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 07/25/2014] [Accepted: 07/30/2014] [Indexed: 12/13/2022]
Abstract
Despite attempts and some successes to improve air quality over the decades, current US national trends suggest that exposure to outdoor and indoor air pollution remains a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Emerging science also suggests that environmental exposures during the prenatal period and early childhood years increase the risk of asthma. Multiple mechanisms mediate this risk because a wide range of deleterious air pollutants contribute to the pathogenesis of asthma across a variety of complex asthma phenotypes. In this review we will consider the role of altered innate and adaptive immune responses, gene-environment interactions, epigenetic regulation, and possibly gene-environment-epigene interactions. Gaining a greater understanding of the mechanisms that underlie the effect of exposure to air pollution on asthma, allergies, and other airway diseases can identify targets for therapy. Such interventions will include pollutant source reduction among those most exposed and most vulnerable and novel pharmaceutical strategies to reduce asthma morbidity.
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Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific genetic and immunological mechanisms. The rapid development of new techniques in molecular biology had ushered in new discoveries on the role of cytokines, chemokines, and immune cells in the pathogenesis of AD. New polymorphisms of AD are continually being reported in different populations. The physical and immunological barrier of normal intact skin is an important part of the innate immune system that protects the host against microbials and allergens that are associated with AD. Defects in the filaggrin gene FLG may play a role in facilitating exposure to allergens and microbial pathogens, which may induce Th2 polarization. Meanwhile, Th22 cells also play roles in skin barrier impairment through IL-22, and AD is often considered to be a Th2/Th22-dominant allergic disease. Mast cells and eosinophils are also involved in the inflammation via Th2 cytokines. Release of pruritogenic substances by mast cells induces scratching that further disrupts the skin barrier. Th1 and Th17 cells are mainly involved in chronic phase of AD. Keratinocytes also produce proinflammatory cytokines such as thymic stromal lymphopoietin (TSLP), which can further affect Th cells balance. The immunological characteristics of AD may differ for various endotypes and phenotypes. Due to the heterogeneity of the disease, and the redundancies of these mechanisms, our knowledge of the pathophysiology of the disease is still incomplete, which is reflected by the absence of a cure for the disease.
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Affiliation(s)
- Zhanglei Mu
- Department of Dermatology, Peking University People's Hospital, No11, Xizhimen South Street, Beijing, 100044, China
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Gene expression in the skin of dogs sensitized to the house dust mite Dermatophagoides farinae. G3-GENES GENOMES GENETICS 2014; 4:1787-95. [PMID: 25098772 PMCID: PMC4199687 DOI: 10.1534/g3.114.013003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Atopic dermatitis is a multifactorial allergic skin disease in humans and dogs. Genetic predisposition, immunologic hyperreactivity, a defective skin barrier, and environmental factors play a role in its pathogenesis. The aim of this study was to analyze gene expression in the skin of dogs sensitized to house dust mite antigens. Skin biopsy samples were collected from six sensitized and six nonsensitized Beagle dogs before and 6 hr and 24 hr after challenge using skin patches with allergen or saline as a negative control. Transcriptome analysis was performed by the use of DNA microarrays and expression of selected genes was validated by quantitative real-time RT-PCR. Expression data were compared between groups (unpaired design). After 24 hr, 597 differentially expressed genes were detected, 361 with higher and 226 with lower mRNA concentrations in allergen-treated skin of sensitized dogs compared with their saline-treated skin and compared with the control specimens. Functional annotation clustering and pathway- and co-citation analysis showed that the genes with increased expression were involved in inflammation, wound healing, and immune response. In contrast, genes with decreased expression in sensitized dogs were associated with differentiation and barrier function of the skin. Because the sensitized dogs did not show differences in the untreated skin compared with controls, inflammation after allergen patch test probably led to a decrease in the expression of genes important for barrier formation. Our results further confirm the similar pathophysiology of human and canine atopic dermatitis and revealed genes previously not known to be involved in canine atopic dermatitis.
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Fölster-Holst R, Dähnhardt-Pfeiffer S, Dähnhardt D, Proksch E. The role of skin barrier function in atopic dermatitis: an update. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/edm.12.17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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36
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Hovnanian A. Netherton syndrome: new advances in the clinic, disease mechanism and treatment. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/edm.11.85] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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37
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Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res 2013; 351:289-300. [DOI: 10.1007/s00441-013-1558-1] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 12/17/2012] [Indexed: 01/31/2023]
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38
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Silverberg JI, Silverberg NB. Atopic Dermatitis: Update on Pathogenesis and Comorbidities. CURRENT DERMATOLOGY REPORTS 2012. [DOI: 10.1007/s13671-012-0021-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Management of patients with atopic dermatitis: the role of emollient therapy. Dermatol Res Pract 2012; 2012:836931. [PMID: 23008699 PMCID: PMC3449106 DOI: 10.1155/2012/836931] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Accepted: 06/19/2012] [Indexed: 12/20/2022] Open
Abstract
Atopic dermatitis is a common inflammatory skin disorder that afflicts a growing number of young children. Genetic, immune, and environmental factors interact in a complex fashion to contribute to disease expression. The compromised stratum corneum found in atopic dermatitis leads to skin barrier dysfunction, which results in aggravation of symptoms by aeroallergens, microbes, and other insults. Infants—whose immune system and epidermal barrier are still developing—display a higher frequency of atopic dermatitis. Management of patients with atopic dermatitis includes maintaining optimal skin care, avoiding allergic triggers, and routinely using emollients to maintain a hydrated stratum corneum and to improve barrier function. Flares of atopic dermatitis are often managed with courses of topical corticosteroids or calcineurin inhibitors. This paper discusses the role of emollients in the management of atopic dermatitis, with particular emphasis on infants and young children.
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Abstract
Despite the acknowledged contributions of a defective epidermal permeability barrier, dryness of the skin, and the propensity to develop secondary infections to the etiology and pathophysiology of atopic dermatitis (AD), these epidermal changes have, until recently, been assumed to reflect downstream consequences that are secondary phenomena of the primary immunologic abnormality--the historical "inside-outside" view that AD is basically an intrinsic inflammatory disease. In this review, we focused on the role of the epidermal barrier function in the pathophysiology of AD. Specifically, we presented data in support of a barrier-initiated pathogenesis of AD, ie, the "outside-inside" concept. First, we reviewed the evidence on the existence of inherited barrier abnormalities in AD. Reported studies on the possible association of mutations in the filaggrin gene (FLG) and data on human tissue kallikreins (KLKs) and AD have been addressed. We then dealt with the question of the causal link between impaired epidermal barrier and inflammation. Finally, the association between innate immune defense system and the increased avidity of Staphylococcus aureus for atopic skin was examined. Despite very convincing evidence to support the barrier-initiated pathogenesis of AD, the view that AD reflects the downstream consequences of a primary immunologic abnormality cannot be dismissed out of hand. Almost every line of evidence in support of the role of the epidermal barrier as the "driver" of the disease activity can be challenged and at least partially contradicted by opposing evidence. Until more data are available and until all the dust settles around this issue, we should take advantage of what we already know and use our knowledge for practical purposes. Deployment of specific strategies to restore the barrier function in AD means the use of moisturizers as first-line therapy.
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Affiliation(s)
- Ronni Wolf
- Dermatology Unit, Kaplan Medical Center, Rehovot 76100, Israel.
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41
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Fortugno P, Furio L, Teson M, Berretti M, El Hachem M, Zambruno G, Hovnanian A, D'Alessio M. The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. Hum Mol Genet 2012; 21:4187-200. [DOI: 10.1093/hmg/dds243] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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Fruth K, Goebel G, Koutsimpelas D, Gosepath J, Schmidtmann I, Mann WJ, Brieger J. Low SPINK5 expression in chronic rhinosinusitis. Laryngoscope 2012; 122:1198-204. [PMID: 22570283 DOI: 10.1002/lary.23300] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 02/16/2012] [Accepted: 02/22/2012] [Indexed: 01/22/2023]
Abstract
OBJECTIVES/HYPOTHESIS Chronic rhinosinusitis (CRS) is a multifactorial disease that probably arises as a result of genetic diversity and environmental factors. SPINK5 is a serine protease inhibitor, which is supposed to be an important regulator of epithelial barrier maintenance. The role of SPINK5 polymorphisms and expression in CRS, especially in individuals with aspirin intolerance, is unclear. STUDY DESIGN SPINK5 single-nucleotide polymorphisms (SNPs) and SPINK5 expression levels were correlated with CRS without (CRSsNP) and with nasal polyps (CRSwNP), aspirin intolerance, asthma, and allergies. METHODS One hundred four nasal tissue samples, 15 from patients with CRSsNP, 59 from patients with CRSwNP, and 30 from healthy controls of the inferior turbinate, were analyzed for their SPINK5 status. Genotypes of four SPINK5 single nucleotide polymorphism (SNPs; G1258A, G2475T, A2915G, and A1103G), as well as SPINK5 mRNA expression levels, were determined by polymerase chain reaction. RESULTS No correlation between any SPINK5 SNP and CRSsNP, CRSwNP, or allergies and asthma was observed. The heterozygous SNPs G1258A and A1103G were observed more frequently in aspirin-intolerant patients; the homozygous (A/A) genotype of SNP 1258 and the homozygous (G/G) genotype SNP 1103 were less frequent. There was no correlation between the analyzed SNPs and the level of SPINK5 expression. It was noted that in individuals with CRSwNP, aspirin intolerance, and allergies, SPINK5 expression was lowered. CONCLUSIONS G1258A and A1103G polymorphisms are distinctive for the aspirin intolerance syndrome. Lowered SPINK5 expression might be a contributing factor leading to CRS, and appears to be characteristic for patients suffering from aspirin intolerance and from allergies.
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Affiliation(s)
- Kai Fruth
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
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Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest 2012; 122:440-7. [PMID: 22293182 DOI: 10.1172/jci57416] [Citation(s) in RCA: 252] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Classic atopic dermatitis is complicated by asthma, allergic rhinitis, and food allergies, cumulatively referred to as atopic diseases. Recent discoveries of mutations in the filaggrin gene as predisposing factors for atopic diseases have refocused investigators' attention on epidermal barrier dysfunction as a causative mechanism. The skin's barrier function has three elements: the stratum corneum (air-liquid barrier), tight junctions (liquid-liquid barrier), and the Langerhans cell network (immunological barrier). Clarification of the molecular events underpinning epidermal barrier function and dysfunction should lead to a better understanding of the pathophysiological mechanisms of atopic diseases.
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Affiliation(s)
- Akiharu Kubo
- Department of Dermatology, Keio University School of Medicine, Shinanomachi 35, Shinjuku, Tokyo 160-8582, Japan
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Lan CCE, Tu HP, Wu CS, Ko YC, Yu HS, Lu YW, Li WC, Chen YC, Chen GS. Distinct SPINK5 and IL-31 polymorphisms are associated with atopic eczema and non-atopic hand dermatitis in Taiwanese nursing population. Exp Dermatol 2011; 20:975-9. [PMID: 22017185 DOI: 10.1111/j.1600-0625.2011.01374.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The term 'hand dermatitis' describes inflammatory skin condition localized to the hands. Nurses working at hospital settings are prone to develop hand dermatitis. The current study aimed to evaluate whether certain genetic polymorphisms were associated with the development of atopic eczema or non-atopic hand dermatitis in Taiwanese population. Nurses of Kaohsiung Medical University Hospital were recruited. Atopic eczema, non-atopic hand dermatitis and normal control groups were identified. The serine protease inhibitor Kazal type 5 (SPINK5), filaggrin and interleukin-31 (IL-31) gene variants were compared between the diseased and control groups. Our results showed that rs2303070 T allele of SPINK5 (assuming recessive model; OR=3.58, 95% CI 1.63-7.84; P=0.0014) and rs7977932 G allele of IL-31 (assuming recessive model; OR=18.25, 95% CI =3.27-101.94; P=0.0009) were associated with increased risks of developing atopic eczema, while rs6892205 G allele of SPINK5 (assuming dominant model; OR=3.79, 95% CI 1.55-9.28; P=0.0036) was associated with the development of non-atopic hand dermatitis. In summary, our results showed that distinct SPINK5 and IL-31 gene variants were associated with the development of atopic eczema and non-atopic hand dermatitis. The barrier function, particularly those regulated by SPINK5, may play an important role in the development of both atopic eczema and non-atopic hand dermatitis.
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Affiliation(s)
- Cheng-Che E Lan
- Department of Dermatology, Kaohsiung Medical University Hospital, , Kaohsiung, Taiwan
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Bin L, Kim BE, Hall CF, Leach SM, Leung DYM. Inhibition of transcription factor specificity protein 1 alters the gene expression profile of keratinocytes leading to upregulation of kallikrein-related peptidases and thymic stromal lymphopoietin. J Invest Dermatol 2011; 131:2213-22. [PMID: 21753780 PMCID: PMC3193562 DOI: 10.1038/jid.2011.202] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsy samples obtained from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in skin biological processes by using a small-interfering RNA (siRNA) technique to knock down Sp1 gene expression in normal human keratinocytes (NHKs) and investigated the genome-wide gene expression profiling of Sp1-silenced NHKs. The gene arrays revealed that 53 genes had greater than 3-fold changes in the expression in Sp1-silenced NHKs as compared with scrambled siRNA-silenced cells. Strikingly, six kallikrein (KLK)-related peptidase genes, namely KLK5, KLK6, KLK7, KLK8, KLK10, and KLK12, were upregulated in NHKs following Sp1 silencing. Functionally, protease activity was significantly enhanced in Sp1-silenced keratinocytes as compared with scrambled siRNA-silenced keratinocytes. Moreover, thymic stromal lymphopoietin (TSLP), an epithelial-derived T(H)2-promoting cytokine, was induced in Sp1-silenced keratinocytes because of elevated KLK activity. These results indicate that Sp1 expression deficiency leads to abnormally increased KLK protease activity in keratinocytes and may contribute to T(H)2 immune responses in the skin by inducing TSLP.
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Affiliation(s)
- Lianghua Bin
- Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA
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Freidin MB, Bragina EY, Fedorova OS, Deev IA, Kulikov ES, Ogorodova LM, Puzyrev VP. Genome-wide association study of allergic diseases in Russians of West Siberia. Mol Biol 2011. [DOI: 10.1134/s0026893311020075] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Zhao LP, Di Z, Zhang L, Wang L, Ma L, Lv Y, Hong Y, Wei H, Chen HD, Gao XH. Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. J Eur Acad Dermatol Venereol 2011; 26:572-7. [PMID: 21585560 DOI: 10.1111/j.1468-3083.2011.04120.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Defect in the SPINK5 gene is known to be implicated in Netherton syndrome (NS), and has been suggested to be a locus predisposing to atopy in general. Coding polymorphisms in SPINK5 exons 13, 14 and 26 have been reported to be associated with atopic dermatitis (AD), asthma and high level of IgE. OBJECTIVES To examine whether the SPINK5 gene polymorphisms are associated with AD in Northeast China, and to assess how variants influence selected phenotypic traits. METHODS A case-control study was conducted on four non-synonymous polymorphisms in the coding region of SPINK5 in AD and controls. The SPINK5 gene polymorphisms were analyzed using the PCR and RFLP methods. RESULTS For the four non-synonymous SNPs, A1103G(Asn368Ser), G1156A(Asp386Asn), G1258A(Glu420Lys), G2475T(Glu825Asp) in SPINK5, the allelic frequencies in the AD cohort were 0.55 for 1103G, 0.57 for 1156A, 0.54for 1258A, 0.62 for 2475T, consistent with those already published in the original British and Japanese cohorts. The T allele of SNP 2475G > T was found to be significantly associated with AD. There were significant differences in genotype frequencies for G1258A(Glu420Lys) and G2475T(Glu825Asp) but not for A1103G(Asn368Ser) and G1156A(Asp386Asn). Genotypes GA(420Glu/Lys), TT (2475Asp/Asp) and GT(2475Glu/Asp) were significantly more frequent in AD. However, the SPINK5 gene polymorphisms was found not to be associated with AD in regard to either serum IgE levels, concurrent allergic asthma or early onset of AD. CONCLUSIONS Our study confirms the association between SPINK5 and AD.
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Affiliation(s)
- L P Zhao
- Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, China
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Namkung JH, Lee JE, Kim E, Byun JY, Kim S, Shin ES, Cho EY, Yang JM. Hint for association of single nucleotide polymorphisms and haplotype in SPINK5 gene with atopic dermatitis in Koreans. Exp Dermatol 2011; 19:1048-53. [PMID: 21087323 DOI: 10.1111/j.1600-0625.2010.01142.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Clinical studies, including twin studies, support the concept that the risk of atopic dermatitis (AD) may be mediated through skin-specific genes, rather than simply through systemic immune or atopy risk genes. The SPINK5 gene is expressed on epithelial surfaces and may provide protection against other allergenic serine proteases. Mutations in the SPINK5 gene result in Netherton syndrome, a disorder characterised by AD, ichthyosis, and elevated serum IgE levels. We genotyped 21 single nucleotide polymorphisms (SNPs) from the SPINK5 gene for 1090 case-control samples (631 patients with AD and 459 normal controls) and analysed the SNPs and haplotypes in this gene and also searched for gene-gene interactions between SPINK5 and the DEFB1 gene that we previously reported. Six SNPs [rs17718511 (P = 0.026), rs17860502 (P = 0.024), KN0001820 (P = 0.045), rs60978485 (P = 0.007), rs17718737 (P = 0.02), and rs1422985 (P = 0.038)] and the haplotype TAA (rs60978485, rs6892205, rs2303064; P = 0.023) in the SPINK5 gene showed significant different allelic or genotypic distributions between the AD group and the control group. We also found that four SNPs [rs17718511 (P = 0.033), rs17860502 (P = 0.031), rs60978485 (P = 0.005), rs17718737 (P = 0.023)] and the haplotype TAA (P = 0.02) in the SPINK5 gene showed associations with the susceptibility of the allergic type of AD (ADe). In addition to this finding, we speculate that the SNPs from DEFB1 and SPINK5 affect the individual susceptibility to development of ADe in an additive manner. This study provides evidence for a significant interaction between allergens and the SPINK5 gene that may contribute to ADe susceptibility.
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Affiliation(s)
- Jung-Hyun Namkung
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Marsella R, Olivry T, Carlotti DN. Current evidence of skin barrier dysfunction in human and canine atopic dermatitis. Vet Dermatol 2011; 22:239-48. [DOI: 10.1111/j.1365-3164.2011.00967.x] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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