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Laureano AF, Vigato AA, Puzer L, de Araujo DR. Recombinant scFv-Fc Anti-kallikrein 7 Antibody-Loaded Thermosensitive Hydrogels Against Skin Desquamation Disorders. ACS APPLIED BIO MATERIALS 2024; 7:4486-4496. [PMID: 38886921 PMCID: PMC11253099 DOI: 10.1021/acsabm.4c00371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024]
Abstract
Human tissue kallikrein-related peptidase 7 (KLK7) is a serine protease implicated in the physiology of skin desquamation, and its uncontrolled activity can lead to chronic diseases such as psoriasis, atopic dermatitis, and Netherton syndrome. For this reason, kallikrein 7 has been identified as a potential therapeutic target. This work aimed to evaluate Pluronic (PL) hydrogels as topical carriers of four specific scFv-Fc antibodies to inhibit KLK7. The hydrogels comprised PL F127 (30% w/v) alone and a binary F127/P123 (28-2% w/v) system. Each formulation was loaded with 1 μg/mL of each antibody and characterized by physicochemical and pharmaceutical techniques, considering antibody-micelle interactions and hydrogel behavior as smart delivery systems. Results showed that the antibodies were successfully loaded into the PL-based systems, and the sol-gel transition temperature was shifted to high values after the P123 addition. The antibodies released from the gels preserved their rheological properties (G' > G'', 35- to 41-fold) and inhibitory activity against KLK7, even after 24 h. This work presented potential agents targeting KLK7 that may provide strategies for treating skin abnormalities.
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Affiliation(s)
- Ana Flávia
Santarine Laureano
- Department
of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital & Harvard Medical School, CNY149 13th Street, Charlestown, Boston, Massachusetts 02129, United States
- Centro
de Ciências Naturais e Humanas, Universidade
Federal do ABC, Al. da Universidade, s/n-Anchieta, São
Bernardo do Campo, SP 09606-045, Brazil
| | - Aryane Alves Vigato
- Department
of Biomedical Science (BMV), Faculty of Health and Society, Malmö University, Malmö 20506, Sweden
- Biofilms−Research
Center for Biointerfaces, Malmö University, Malmö 20506, Sweden
| | - Luciano Puzer
- Centro
de Ciências Naturais e Humanas, Universidade
Federal do ABC, Al. da Universidade, s/n-Anchieta, São
Bernardo do Campo, SP 09606-045, Brazil
| | - Daniele Ribeiro de Araujo
- Centro
de Ciências Naturais e Humanas, Universidade
Federal do ABC, Av. dos
Estados, 5001, Bloco A, Torre 3, Santo André, SP 09210-580, Brazil
- Departamento
de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Botucatu, 862, Vila Clementino, Sao Paulo, SP 04023-062, Brazil
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Khatib CM, Klein-Petersen AW, Rønnstad ATM, Egeberg A, Christensen MO, Silverberg JI, Thomsen SF, Irvine AD, Thyssen JP. Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis. Exp Dermatol 2024; 33:e15130. [PMID: 38989976 DOI: 10.1111/exd.15130] [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: 12/12/2023] [Revised: 05/23/2024] [Accepted: 06/24/2024] [Indexed: 07/12/2024]
Abstract
Loss-of-function (LoF) mutations in the filaggrin gene (FLG) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude-dependent difference in the prevalence of LoF FLG mutations was systematically evaluated. A systematic review and meta-analysis were performed to estimate the prevalence of LoF FLG mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle-Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9th December 2021. Studies were included if they contained data on the prevalence of LoF FLG mutations in AD patients or from the general population or associations between AD and LoF FLG mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF FLG mutations was 19.1% (95% CI, 17.3-21.0) in AD patients and 5.8% (95% CI, 5.3-6.2) in the general population. There was a significant positive association between AD and LoF FLG mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF FLG mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. FLG LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from FLG LoF mutations remains unknown.
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Affiliation(s)
- Casper Milde Khatib
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Alexander Egeberg
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Simon Francis Thomsen
- Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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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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Schmuth M, Eckmann S, Moosbrugger-Martinz V, Ortner-Tobider D, Blunder S, Trafoier T, Gruber R, Elias PM. Skin Barrier in Atopic Dermatitis. J Invest Dermatol 2024; 144:989-1000.e1. [PMID: 38643989 DOI: 10.1016/j.jid.2024.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 04/23/2024]
Abstract
A compromised permeability barrier is a hallmark of atopic dermatitis (AD). Localized to the outermost skin layer, the stratum corneum (SC) is critically dependent on terminal differentiation of epidermal keratinocytes, which transform into protein-rich corneocytes surrounded by extracellular lamellae of unique epidermal lipids, conferring permeability barrier function. These structures are disrupted in AD. A leaky barrier is prone to environmental insult, which in AD elicits type 2-dominant inflammation, in turn resulting in a vicious cycle further impairing the SC structure. Therapies directed at enforcing SC structure and anti-inflammatory strategies administered by topical and systemic route as well as UV therapy have differential effects on the permeability barrier. The expanding armamentarium of therapeutic modalities for AD treatment warrants optimization of their effects on permeability barrier function.
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Affiliation(s)
- Matthias Schmuth
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria; Institute for Pediatric Dermatology and Rare Diseases, Karl Landsteiner Society, Innsbruck, Austria.
| | - Sonja Eckmann
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | | | | | - Stefan Blunder
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | - Thomas Trafoier
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria
| | - Robert Gruber
- Dermatology, Venerology and Allergy, Medical University Innsbruck, Innsbruck, Austria; Institute for Pediatric Dermatology and Rare Diseases, Karl Landsteiner Society, Innsbruck, Austria
| | - Peter M Elias
- Dermatology, Veteran Affairs Health Care System, San Francisco, California, USA; University of California San Francisco, San Francisco, California, USA
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Chawla HS, Kosta S, Namdeo C, Kataria R, Bhatia K, Sahu R, Joshi P. Genotype Study of Filaggrin Gene Loss-of-Function Mutations in Central India Population with Atopic Dermatitis and Ichthyosis Vulgaris. Indian Dermatol Online J 2023; 14:611-615. [PMID: 37727564 PMCID: PMC10506825 DOI: 10.4103/idoj.idoj_636_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 04/19/2023] [Accepted: 05/22/2023] [Indexed: 09/21/2023] Open
Abstract
Background A genotype study of filaggrin gene loss-of-function mutations in central India can provide valuable insights into the prevalence and association of these mutations with atopic dermatitis (AD) and ichthyosis vulgaris (IV) in the region. The FLG R501X and 2282del4 are both genetic variants in the human gene called filaggrin gene (FLG), which encodes a protein that plays an important role in the formation and maintenance of the skin barrier. In this study, we determined the FLG R501X and 2282del4 variants association with both AD and IV in Central Indian populations. Materials and Methods This case-control study was conducted in the Departments of Dermatology and Molecular and Virology Research and Diagnostic Laboratory at Sri Aurobindo Medical College and Post Graduate Institute, Indore (Madhya Pradesh). The study was approved by the Clinical Research and Ethics Committee. A total of 180 patients aged between 3 months - 60 years who attended the skin outpatient department between March-2021 to June-2022 were recruited in this study. Among them, 60 patients were in AD-group, 60 patients in IV-group, and 60 patients were in the healthy control group. Polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) was used in genotyping for FLG mutations (R501X and 2282del4). Results The most common FLG mutations were R501X (31.6% and 23.3%) and 2282del4 (18.3% and 13.3%) in AD and IV patients with heterozygous (AT) genotype, respectively. The combined mutation (FLG R501X and 2282del4) association was 10% and 5% in the AD and IV groups with heterozygous (AT) genotype, respectively, and in all the patients of control group with wild genotype (AA). There were no significant (P = 0.09) associations found with 2282del14 genotype. Conclusion The R501X mutation in the gene encoding filaggrin is one of the robust genetic associations of AD and IV. The 2282del4 polymorphism was marginally less as compared to R501X.
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Affiliation(s)
- Harsimran S. Chawla
- Department of Dermatology, Venerology and Leprosy, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
| | - Susmit Kosta
- Department of Molecular and Virology Research and Diagnostic Laboratory, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
| | - Chaitanya Namdeo
- Department of Dermatology, Venerology and Leprosy, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
| | - Rajesh Kataria
- Department of Dermatology, Venerology and Leprosy, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
| | - Kailash Bhatia
- Department of Dermatology, Venerology and Leprosy, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
| | - Roshni Sahu
- Department of Molecular and Virology Research and Diagnostic Laboratory, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
| | - Pallavi Joshi
- Department of Molecular and Virology Research and Diagnostic Laboratory, Sri Aurobindo Medical College and Post Graduate Institute, Sri Aurobindo University, Indore, Madhya Pradesh, India
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Beheshti R, Stone S, Chandran D, Hicks SD. Multi-Omic Profiles in Infants at Risk for Food Reactions. Genes (Basel) 2022; 13:2024. [PMID: 36360258 PMCID: PMC9690066 DOI: 10.3390/genes13112024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 01/03/2025] Open
Abstract
Food reactions (FR) are multifactorial and impacted by medical, demographic, environmental, and immunologic factors. We hypothesized that multi-omic analyses of host-microbial factors in saliva would enhance our understanding of FR development. This longitudinal cohort study included 164 infants followed from birth through two years. The infants were identified as FR (n = 34) or non-FR (n = 130) using the Infant Feeding Practice II survey and medical record confirmation. Saliva was collected at six months for the multi-omic assessment of cytokines, mRNAs, microRNAs, and the microbiome/virome. The levels of one miRNA (miR-203b-3p, adj. p = 0.043, V = 2913) and one viral phage (Proteus virus PM135, adj. p = 0.027, V = 2955) were lower among infants that developed FRs. The levels of one bacterial phylum (Cyanobacteria, adj. p = 0.048, V = 1515) were higher among infants that developed FR. Logistical regression models revealed that the addition of multi-omic features (miR-203b-3p, Cyanobacteria, and Proteus virus PM135) improved predictiveness for future FRs in infants (p = 0.005, X2 = 12.9), predicting FRs with 72% accuracy (AUC = 0.81, sensitivity = 72%, specificity = 72%). The multi-omic analysis of saliva may enhance the accurate identification of infants at risk of FRs and provide insights into the host/microbiome interactions that predispose certain infants to FRs.
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Affiliation(s)
- Ramin Beheshti
- Penn State Health Milton S Hershey Medical Center, Department of Pediatrics, Hershey, PA 17033, USA
- Department of Pediatrics, Penn State Health Children’s Hospital, 500 University Drive, Hershey, PA 17033, USA
| | - Shane Stone
- Penn State Health Milton S Hershey Medical Center, Department of Pediatrics, Hershey, PA 17033, USA
| | - Desirae Chandran
- Penn State Health Milton S Hershey Medical Center, Department of Pediatrics, Hershey, PA 17033, USA
| | - Steven D. Hicks
- Penn State Health Milton S Hershey Medical Center, Department of Pediatrics, Hershey, PA 17033, USA
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Morizane S, Sunagawa K, Nomura H, Ouchida M. Aberrant serine protease activities in atopic dermatitis. J Dermatol Sci 2022; 107:2-7. [PMID: 35817663 DOI: 10.1016/j.jdermsci.2022.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/19/2022] [Accepted: 06/26/2022] [Indexed: 10/17/2022]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease; the three major factors responsible for AD, i.e., epidermal barrier dysfunction, allergic inflammation, and itching, interact with each other to form a pathological condition. Excessive protease activities are characteristic abnormalities that affect the epidermal barrier in patients with AD. In normal skin, epidermal serine protease activities are controlled by kallikrein-related peptidases (KLKs) and their inhibitors, including lympho-epithelial Kazal-type-related inhibitor (LEKTI). In AD lesions, KLKs are excessively expressed, which results in the enhancement of epidermal serine protease activities and facilitates the invasion by allergens and microorganisms. In addition, some KLKs can activate protease-activated receptor 2 (PAR2) in epidermal keratinocytes and peripheral nerves, resulting in the induction of inflammation and itching. Furthermore, in AD patients with single nucleotide polymorphism (SNP) such as E420K and D386N of SPINK5 which encodes LEKTI, LEKTI function is attenuated, resulting in the activation of KLKs and easy invasion by allergens and microorganisms. Further analysis is needed to elucidate the detailed mechanism underlying the control of serine protease activities, which may lead to the development of new therapeutic and prophylactic agents for AD.
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Affiliation(s)
- Shin Morizane
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.
| | - Ko Sunagawa
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Hayato Nomura
- Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
| | - Mamoru Ouchida
- Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan
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Zani MB, Sant'Ana AM, Tognato RC, Chagas JR, Puzer L. Human Tissue Kallikreins-Related Peptidases Are Targets for the Treatment of Skin Desquamation Diseases. Front Med (Lausanne) 2022; 8:777619. [PMID: 35356049 PMCID: PMC8959125 DOI: 10.3389/fmed.2021.777619] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/22/2021] [Indexed: 11/16/2022] Open
Abstract
Human tissue Kallikrein-related peptidases (hKLKs) are serine proteases distributed in several tissues that are involved in several biological processes. In skin, many are responsible for skin desquamation in the Stratum Corneum (SC) of the epidermis, specially hKLK5, hKLK7, hKLK6, hKLK8, and hKLK14. In SC, hKLKs cleave proteins of corneodesmosomes, an important structure responsible to maintain corneocytes attached. As part of skin desquamation, hKLKs are also involved in skin diseases with abnormal desquamation and inflammation, such as Atopic Dermatitis (AD), psoriasis, and the rare disease Netherton Syndrome (NS). Many studies point to hKLK overexpression or overactive in skin diseases, and they are also part of the natural skin inflammation process, through the PAR2 cleavage pathway. Therefore, the control of hKLK activity may offer successful treatments for skin diseases, improving the quality of life in patients. Diseases like AD, Psoriasis, and NS have an impact on social life, causing pain, itchy and mental disorders. In this review, we address the molecular mechanisms of skin desquamation, emphasizing the roles of human tissue Kallikrein-related peptidases, and the promising therapies targeting the inhibition of hKLKs.
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Affiliation(s)
- Marcelo B. Zani
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Sao Bernardo do Campo, Brazil
| | - Aquiles M. Sant'Ana
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Sao Bernardo do Campo, Brazil
| | - Rafael C. Tognato
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Sao Bernardo do Campo, Brazil
| | - Jair R. Chagas
- Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Luciano Puzer
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Sao Bernardo do Campo, Brazil
- *Correspondence: Luciano Puzer
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Yoshida T, Beck LA, De Benedetto A. Skin barrier defects in atopic dermatitis: From old idea to new opportunity. Allergol Int 2022; 71:3-13. [PMID: 34916117 PMCID: PMC8934597 DOI: 10.1016/j.alit.2021.11.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 01/31/2023] Open
Abstract
Atopic dermatitis (AD) is the most common chronic skin inflammatory disease, with a profound impact on patients’ quality of life. AD varies considerably in clinical course, age of onset and degree to which it is accompanied by allergic and non-allergic comorbidities. Skin barrier impairment in both lesional and nonlesional skin is now recognized as a critical and often early feature of AD. This may be explained by a number of abnormalities identified within both the stratum corneum and stratum granulosum layers of the epidermis. The goal of this review is to provide an overview of key barrier defects in AD, starting with a historical perspective. We will also highlight some of the commonly used methods to characterize and quantify skin barrier function. There is ample opportunity for further investigative work which we call out throughout this review. These include: quantifying the relative impact of individual epidermal abnormalities and putting this in a more holistic view with physiological measures of barrier function, as well as determining whether these barrier-specific endotypes predict clinical phenotypes (e.g. age of onset, natural history, comorbidities, response to therapies, etc). Mechanistic studies with new (and in development) AD therapies that specifically target immune pathways, Staphylococcus aureus abundance and/or skin barrier will help us understand the dynamic crosstalk between these compartments and their relative importance in AD.
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10
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Cárdenas GV, Iturriaga C, Hernández CD, Tejos-Bravo M, Pérez-Mateluna G, Cabalin C, Urzúa M, Venegas-Salas LF, Fraga JP, Rebolledo B, Poli MC, Repetto GM, Casanello P, Castro-Rodríguez JA, Borzutzky A. Prevalence of filaggrin loss-of-function variants in Chilean population with and without atopic dermatitis. Int J Dermatol 2021; 61:310-315. [PMID: 34480753 DOI: 10.1111/ijd.15887] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/20/2021] [Accepted: 08/12/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Filaggrin (FLG) loss-of-function variants are major genetic risk factors for atopic dermatitis (AD), but these have not been studied in Latin American populations with and without AD. METHODS FLG variants R501X and 2282del4 were genotyped in 275 Chilean adults with and without AD from the "Early origins of allergy and asthma" (ARIES) cohort and in 227 patients from an AD cohort based in Santiago, Chile. RESULTS Among adults in the ARIES cohort, 3.3% were carriers of R501X and 2.9% of 2282del4 variants, all heterozygotes. In this cohort, 6.2% were FLG variant carriers: 11.1% of subjects reporting AD were carriers of FLG variants vs. 5.2% in those without AD (P = 0.13). In this first cohort, FLG variants were not significantly associated with asthma, allergic rhinitis, or food allergy. In the AD cohort, the prevalence of FLG variants was 7% for R501X, 2.2% for the 2282del4 variant, and 9.3% for the combined genotype. In this cohort, FLG variants were present in 15.5% of severe AD vs. 7.1% of mild-to-moderate AD subjects (P = 0.056). Evaluation of Chilean population from both cohorts combined (n = 502) revealed that FLG variants were not significantly associated with AD (OR = 1.92 [95% CI 0.95-3.9], P = 0.067) but were associated with asthma (OR = 2.16 [95% CI 1.02-4.56], P = 0.039). CONCLUSIONS This is the first study to evaluate FLG loss-of-function variants R501X and 2282del4 in Latin American population, revealing a similar prevalence of these FLG variant carriers to that of European populations. Among Chileans, FLG variants were significantly associated with asthma but not AD.
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Affiliation(s)
- Geovanna V Cárdenas
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Iturriaga
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Caroll D Hernández
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Macarena Tejos-Bravo
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Guillermo Pérez-Mateluna
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Cabalin
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcela Urzúa
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis F Venegas-Salas
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan P Fraga
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Boris Rebolledo
- Institute of Science and Innovation in Medicine, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Maria C Poli
- Institute of Science and Innovation in Medicine, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Gabriela M Repetto
- Institute of Science and Innovation in Medicine, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - Paola Casanello
- Department of Neonatology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Obstetrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - José A Castro-Rodríguez
- Department of Pediatric Pulmonology and Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Arturo Borzutzky
- Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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Laureano AFS, Zani MB, Sant'Ana AM, Tognato RC, Lombello CB, do Nascimento MHM, Helmsing S, Fühner V, Hust M, Puzer L. Generation of recombinant antibodies against human tissue kallikrein 7 to treat skin diseases. Bioorg Med Chem Lett 2020; 30:127626. [PMID: 33096161 DOI: 10.1016/j.bmcl.2020.127626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/09/2020] [Accepted: 10/14/2020] [Indexed: 12/25/2022]
Abstract
Human tissue kallikreins (KLKs) constitute a family of 15 serine proteases that are distributed in various tissues and implicated in several pathological disorders. KLK7 is an unusual serine protease that presents both trypsin-like and chymotrypsin-like specificity and appears to be upregulated in pathologies that are related to skin desquamation processes, such as atopic dermatitis, psoriasis and Netherton syndrome. In recent years, various groups have worked to develop specific inhibitors for this enzyme, as KLK7 represents a potential target for new therapeutic procedures for diseases related to skin desquamation processes. In this work, we selected nine different single-chain variable fragment antibodies (scFv) from a human naïve phage display library and characterized their inhibitory activities against KLK7. The scFv with the lowest IC50 against KLK7 was affinity maturated, which resulted in the generation of four new scFv-specific antibodies for the target protease. These new antibodies were expressed in the scFv-Fc format in HEK293-6E cells, and the characterization of their inhibitory activities against KLK7 showed that three of them presented IC50 values lower than that of the original antibody. The cytotoxicity analysis of these recombinant antibodies demonstrated that they can be safely used in a cellular model. In conclusion, our research showed that in our case, a phage-display methodology in combination with enzymology assays can be a very suitable tool for the development of inhibitors for KLKs, suggesting a new strategy to identify therapeutic protease inhibitors for diseases related to uncontrolled kallikrein activity.
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Affiliation(s)
- Ana Flávia S Laureano
- Universidade Federal do ABC - Centro de Ciências Naturais e Humanas, São Bernardo do Campo, São Paulo, Brazil
| | - Marcelo B Zani
- Universidade Federal do ABC - Centro de Ciências Naturais e Humanas, São Bernardo do Campo, São Paulo, Brazil
| | - Aquiles M Sant'Ana
- Universidade Federal do ABC - Centro de Ciências Naturais e Humanas, São Bernardo do Campo, São Paulo, Brazil
| | - Rafael C Tognato
- Universidade Federal do ABC - Centro de Ciências Naturais e Humanas, São Bernardo do Campo, São Paulo, Brazil
| | - Christiane B Lombello
- Universidade Federal do ABC - Centro de Engenharia, Modelagem e Ciências Sociais aplicadas, São Bernardo do Campo, São Paulo, Brazil
| | - Mônica Helena M do Nascimento
- Universidade Federal do ABC - Centro de Engenharia, Modelagem e Ciências Sociais aplicadas, São Bernardo do Campo, São Paulo, Brazil
| | - Saskia Helmsing
- Technische Universität Braunschweig - Abteilung Biotechnologie, Institut für Biochemie, Biotechnologie und Bioinformatik, Braunschweig, Germany
| | - Viola Fühner
- Technische Universität Braunschweig - Abteilung Biotechnologie, Institut für Biochemie, Biotechnologie und Bioinformatik, Braunschweig, Germany
| | - Michael Hust
- Technische Universität Braunschweig - Abteilung Biotechnologie, Institut für Biochemie, Biotechnologie und Bioinformatik, Braunschweig, Germany
| | - Luciano Puzer
- Universidade Federal do ABC - Centro de Ciências Naturais e Humanas, São Bernardo do Campo, São Paulo, Brazil.
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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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Di Paolo CT, Diamandis EP, Prassas I. The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets. Crit Rev Clin Lab Sci 2020; 58:1-16. [PMID: 32568598 DOI: 10.1080/10408363.2020.1775171] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The skin is a vital organ of the human body, serving numerous protective and functional roles that are essential for survival. Residing in the epidermis are various epidermal proteases responsible for the establishment and regulation of barrier function. The human tissue kallikrein-related peptidase family conserves homeostasis of the skin barrier through their roles in desquamation, antimicrobial defense, innate immune response, and barrier maintenance. The activity of kallikreins is tightly regulated and dysregulation of kallikrein activity is seen to contribute to the formation of several inflammatory skin disorders. This review highlights the roles of kallikreins in skin homeostasis and pathologies. Due to their part in these skin disorders, inhibitors of the skin kallikreins have become attractive therapeutics. Over the past few years, both natural and synthetic inhibitors of several kallikreins have been identified and are undergoing further development as treatments to restore compromised barrier function. This review summarizes the kallikrein inhibitors under development for this purpose. These inhibitors remain promising therapeutics in cases of severe skin inflammation not well managed by current therapies.
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Affiliation(s)
- Caitlin T Di Paolo
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
| | - Eleftherios P Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, Canada
| | - Ioannis Prassas
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
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14
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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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15
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Egawa G, Kabashima K. Barrier dysfunction in the skin allergy. Allergol Int 2018; 67:3-11. [PMID: 29153780 DOI: 10.1016/j.alit.2017.10.002] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 09/30/2017] [Accepted: 10/04/2017] [Indexed: 12/14/2022] Open
Abstract
The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier dysfunction is one of the most predisposing factors for the development of skin allergic diseases such as atopic dermatitis. In this article, we summarize how the physical barrier of the skin is organized and review its link to the pathomechanism of skin allergic diseases. We describe the formation of the SC barrier in terms of the following five categories: 1) filaggrin metabolism; 2) cornified envelope; 3) intercellular lipids; 4) corneodesmosome; and 5) corneocyte desquamation. New approaches to restoring the skin barrier function are also discussed.
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16
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Jun M, Wang HY, Lee S, Choi E, Lee H, Choi EH. Differences in Genetic Variations Between Treatable and Recalcitrant Atopic Dermatitis in Korean. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2018; 10:244-252. [PMID: 29676071 PMCID: PMC5911443 DOI: 10.4168/aair.2018.10.3.244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 02/14/2018] [Accepted: 02/18/2018] [Indexed: 12/15/2022]
Abstract
Purpose Variations in barrier- or immune response-related genes are closely related to the development of atopic dermatitis (AD). This study was designed to identify genetic variations and clinical features to predict ‘recalcitrant AD.’ Methods AD patients were classified as treatable and recalcitrant. Treatable AD patients showed satisfactory clinical improvement with basic and topical treatments. Recalcitrant AD patients used systemic immune-suppressants for over 4 weeks as they had not shown clinical improvement with basic and topical treatments. The frequency of gene variations in barrier- (FLG 3321delA, FLG K4022X, KLK7, SPINK 1156, SPINK 1188, SPINK 2475) and immune response- (DEFB1, KDR, IL-5RA, IL-9, and IL-12RB1a, b) related genes were compared between each AD group and the controls. Results Of all, 249 treatable AD and 32 recalcitrant AD were identified. Heterozygous mutations (Hetero) in KLK7 was more frequent in recalcitrant AD patients than treatable AD, without statistical significance. Hetero in DEFB1 was more frequent in treatable AD patients. However, no other significant genetic differences between treatable and recalcitrant AD was observed. Instead, higher initial Eczema Area Severity Index (EASI) score, serum immunoglobulin E (IgE) level, allergen specific IgE for house dust mites, and family history of atopic diseases were associated with recalcitrant AD with statistical significance. Conclusions According to our study, no genetic variation to predict recalcitrant AD was identified, suggesting that clinical manifestation, rather than genetic variations of AD patients is more likely to be an important factor in predicting the prognosis of AD. Further large-scale studies on the correlation between genetic variation and recalcitrant AD are needed.
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Affiliation(s)
- Myungsoo Jun
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hye Young Wang
- Optipharm, Inc., Wonju Eco Environmental Technology Center, Wonju, Korea
| | - Solam Lee
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Eunhee Choi
- Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hyeyoung Lee
- Department of Biomedical Laboratory Science, Yonsei University College of Health Sciences, Wonju, Korea
| | - Eung Ho Choi
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea.
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17
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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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18
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De Vuyst E, Salmon M, Evrard C, Lambert de Rouvroit C, Poumay Y. Atopic Dermatitis Studies through In Vitro Models. Front Med (Lausanne) 2017; 4:119. [PMID: 28791291 PMCID: PMC5523664 DOI: 10.3389/fmed.2017.00119] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 07/11/2017] [Indexed: 11/13/2022] Open
Abstract
Atopic dermatitis (AD) is a complex inflammatory skin condition that is not fully understood. Epidermal barrier defects and Th2 immune response dysregulations are thought to play crucial roles in the pathogenesis of the disease. A vicious circle takes place between these alterations, and it can further be complicated by additional genetic and environmental factors. Studies investigating in more depth the etiology of the disease are thus needed in order to develop functional treatments. In recent years, there have been significant advances regarding in vitro models reproducing important features of AD. However, since a lot of models have been developed, finding the appropriate experimental setting can be difficult. Therefore, herein, we review the different types of in vitro models mimicking features of AD. The simplest models are two-dimensional culture systems composed of immune cells or keratinocytes, whereas three-dimensional skin or epidermal equivalents reconstitute more complex stratified tissues exhibiting barrier properties. In those models, hallmarks of AD are obtained, either by challenging tissues with interleukin cocktails overexpressed in AD epidermis or by silencing expression of pivotal genes encoding epidermal barrier proteins. Tissue equivalents cocultured with lymphocytes or containing AD patient cells are also described. Furthermore, each model is placed in its study context with a brief summary of the main results obtained. In conclusion, the described in vitro models are useful tools to better understand AD pathogenesis, but also to screen new compounds in the field of AD, which probably will open the way to new preventive or therapeutic strategies.
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Affiliation(s)
- Evelyne De Vuyst
- Cell and Tissue Laboratory, URPhyM-NARILIS, University of Namur, Namur, Belgium
| | | | - Céline Evrard
- Cell and Tissue Laboratory, URPhyM-NARILIS, University of Namur, Namur, Belgium
| | | | - Yves Poumay
- Cell and Tissue Laboratory, URPhyM-NARILIS, University of Namur, Namur, Belgium
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19
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The Skin as a Route of Allergen Exposure: Part I. Immune Components and Mechanisms. Curr Allergy Asthma Rep 2017; 17:6. [PMID: 28185161 DOI: 10.1007/s11882-017-0674-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE OF REVIEW To highlight recent contributions in the literature that enhance our understanding of the cutaneous immune response to allergen. RECENT FINDINGS Defects in skin barrier function in infancy set the stage for the development of atopic dermatitis (AD) and allergy. Both genetic and environmental factors can contribute to damage of the stratum corneum (SC), with activation of specific protease enzymes under high pH conditions playing a key role. Immune cells and mediators in the dermis and epidermis impair SC repair mechanisms and support allergy development. In barrier-disrupted skin, type 2 innate lymphoid cells (ILC2s), mast cells (MCs), and basophils have been shown to promote AD and pathogenic Th2 responses in murine models. Skin barrier disruption favors induction of systemic Th2-associated inflammatory pathways. A better understanding of the ontogeny and regulation of these complex networks in infant skin is needed to guide future strategies for allergy treatment and prevention.
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20
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Eosinophilic esophagitis and colonic mucosal eosinophilia in Netherton syndrome. J Allergy Clin Immunol 2017; 139:2003-2005.e1. [DOI: 10.1016/j.jaci.2016.10.045] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 10/05/2016] [Accepted: 10/17/2016] [Indexed: 01/07/2023]
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Park KD, Pak SC, Park KK. The Pathogenetic Effect of Natural and Bacterial Toxins on Atopic Dermatitis. Toxins (Basel) 2016; 9:toxins9010003. [PMID: 28025545 PMCID: PMC5299398 DOI: 10.3390/toxins9010003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 12/15/2016] [Accepted: 12/19/2016] [Indexed: 12/18/2022] Open
Abstract
Atopic dermatitis (AD) is a common allergic skin disease that is associated with chronic, recurrent eczematous and pruritic lesions at the flexural folds caused by interacting factors related to environmental and immune system changes. AD results in dry skin, and immunoglobulin E-mediated allergic reactions to foods and environmental allergens. While steroids and anti-histamines temporarily relieve the symptoms of AD, the possibility of side effects from pharmacological interventions remains. Despite intensive research, the underlying mechanisms for AD have not been clarified. A study of Staphylococcus aureus (S. aureus) established the role of its toxins in the pathogenesis of AD. Approximately 90% of patients with AD experience S. aureus colonization and up to 50%–60% of the colonizing S. aureus is toxin-producing. Any damage to the protective skin barrier allows for the entry of invading allergens and pathogens that further drive the pathogenesis of AD. Some natural toxins (or their components) that have therapeutic effects on AD have been studied. In addition, recent studies on inflammasomes as one component of the innate immune system have been carried out. Additionally, studies on the close relationship between the activation of inflammasomes and toxins in AD have been reported. This review highlights the literature that discusses the pathogenesis of AD, the role of toxins in AD, and the positive and negative effects of toxins on AD. Lastly, suggestions are made regarding the role of inflammasomes in AD.
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Affiliation(s)
- Kyung-Duck Park
- Department of Dermatology, College of Medicine, Catholic University of Daegu, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Korea.
| | - Sok Cheon Pak
- School of Biomedical Sciences, Charles Sturt University, Panorama Avenue, Bathurst NSW 2795, Australia.
| | - Kwan-Kyu Park
- Department of Pathology, College of Medicine, Catholic University of Daegu, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Korea.
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22
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Brown SJ. Molecular mechanisms in atopic eczema: insights gained from genetic studies. J Pathol 2016; 241:140-145. [DOI: 10.1002/path.4810] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 09/12/2016] [Accepted: 09/14/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Sara J Brown
- School of Medicine, Ninewells Hospital & Medical School; University of Dundee; Dundee UK
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23
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Ahuja SK, Manoharan MS, Harper NL, Jimenez F, Hobson BD, Martinez H, Ingale P, Liu YG, Carrillo A, Lou Z, Kellog DL, Ahuja SS, Rather CG, Esch RE, Ramirez DA, Clark RA, Nadeau K, Andrews CP, Jacobs RL, He W. Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge. J Allergy Clin Immunol 2016; 139:844-854. [PMID: 27658763 DOI: 10.1016/j.jaci.2016.08.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.
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Affiliation(s)
- Sunil K Ahuja
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex; Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, Tex; Department of Biochemistry, University of Texas Health Science Center, San Antonio, Tex.
| | - Muthu Saravanan Manoharan
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Nathan L Harper
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex; Foundation for Advancing Veterans' Health Research, San Antonio, Tex
| | - Fabio Jimenez
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex; Foundation for Advancing Veterans' Health Research, San Antonio, Tex
| | - Benjamin D Hobson
- Department of Pediatrics, School of Medicine, Stanford University, Stanford, Calif; Sean N. Parker Center for Allergy Research, School of Medicine, Stanford University, Stanford, Calif
| | - Hernan Martinez
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex; Foundation for Advancing Veterans' Health Research, San Antonio, Tex
| | - Puraskar Ingale
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Ya-Guang Liu
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Andrew Carrillo
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Zheng Lou
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Dean L Kellog
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Seema S Ahuja
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | | | - Robert E Esch
- School of Natural Sciences, Lenoir-Rhyne University, Hickory, NC
| | | | - Robert A Clark
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
| | - Kari Nadeau
- Department of Pediatrics, School of Medicine, Stanford University, Stanford, Calif; Sean N. Parker Center for Allergy Research, School of Medicine, Stanford University, Stanford, Calif; Division of Allergy, Immunology, and Rheumatology, Lucile Packard Children's Hospital at Stanford Hospital, Stanford, Calif
| | | | | | - Weijing He
- Veterans Administration Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Tex; Department of Medicine, University of Texas Health Science Center, San Antonio, Tex
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Lee NR, Yoon NY, Jung M, Kim JY, Seo SJ, Wang HY, Lee H, Sohn YB, Choi EH. Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization. J Korean Med Sci 2016; 31:1307-18. [PMID: 27478344 PMCID: PMC4951563 DOI: 10.3346/jkms.2016.31.8.1307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 04/21/2016] [Indexed: 01/05/2023] Open
Abstract
X-linked ichthyosis (XLI) is a recessively inherited ichthyosis. Skin barrier function of XLI patients reported in Western countries presented minimally abnormal or normal. Here, we evaluated the skin barrier properties and a skin barrier-related gene mutation in 16 Korean XLI patients who were diagnosed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. Skin barrier properties were measured, cytokine expression levels in the stratum corneum (SC) were evaluated with the tape stripped specimen from skin surface, and a genetic test was done on blood. XLI patients showed significantly lower SC hydration, but normal basal trans-epidermal water loss and skin surface pH as compared to a healthy control group. Histopathology of ichthyosis epidermis showed no acanthosis, and levels of the pro-inflammatory cytokines in the corneal layer did not differ between control and lesional/non-lesional skin of XLI patients. Among the mutations in filaggrin (FLG), kallikrein 7 (KLK7), and SPINK5 genes, the prevalence of KLK7 gene mutations was significantly higher in XLI patients (50%) than in controls (0%), whereas FLG and SPINK5 prevalence was comparable. Korean XLI patients exhibited unimpaired skin barrier function and frequent association with the KLK7 gene polymorphism, which may differentiate them from Western XLI patients.
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Affiliation(s)
- Noo Ri Lee
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Na Young Yoon
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Minyoung Jung
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Ji-Yun Kim
- Institute of Atopic Dermatitis, Department of Dermatology, Chung-Ang University Hospital, Seoul, Korea
| | - Seong Jun Seo
- Institute of Atopic Dermatitis, Department of Dermatology, Chung-Ang University Hospital, Seoul, Korea
| | - Hye-young Wang
- M&D, Inc. Wonju Eco Environmental Technology Center, Wonju, Korea
| | - Hyeyoung Lee
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju, Korea
| | - Young Bae Sohn
- Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea
| | - Eung Ho Choi
- Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
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Cubero JL, Isidoro-García M, Segura N, Benito Pescador D, Sanz C, Lorente F, Dávila I, Colás C. Filaggrin gene mutations and new SNPs in asthmatic patients: a cross-sectional study in a Spanish population. Allergy Asthma Clin Immunol 2016; 12:31. [PMID: 27462351 PMCID: PMC4960762 DOI: 10.1186/s13223-016-0137-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 07/05/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Several null-mutations in the FLG gene that produce a decrease or absence of filaggrin in the skin and predispose to atopic dermatitis and ichthyosis vulgaris have been described. The relationship with asthma is less clear and may be due to the influence of atopy in patients with associated asthma. METHODS Four hundred individuals were included, 300 patients diagnosed with asthma divided into two groups according to their phenotype (allergic and non-allergic asthma) and 100 strictly characterized controls. The coding region and flanking regions of the FLG gene were amplified by PCR. We proceeded to the characterization of potential gene variants in that region by RFLP and sequencing and analysed their association with lung function parameters, asthma control and severity, and quality of life. RESULTS We identified two null-mutations (R501X and 2282del4), seven SNPs previously described in databases and three SNPs that had not been previously described. One of the SNP identified in this study (1741A > T) was more frequently detected in patients with non-allergic asthma, worse FVC, FEV1 and PEF values and a higher treatment step. In addition, lowered spirometric values were observed in the non-allergic group carrying any of the nonsynonymous SNPs. CONCLUSIONS In the association study of genetic variants of the FLG gene in our population the 1741A > T polymorphism seems to be associated with non-allergic asthma.
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Affiliation(s)
- José Luis Cubero
- Allergy Department, University Hospital Lozano Blesa of Zaragoza, Avda. San Juan Bosco 15. 50.009, Zaragoza, Spain ; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
| | - María Isidoro-García
- Department of Clinical Biochemistry, University Hospital of Salamanca, Salamanca, Spain ; Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain ; Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Nieves Segura
- Allergy Department, University Hospital Lozano Blesa of Zaragoza, Avda. San Juan Bosco 15. 50.009, Zaragoza, Spain ; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
| | | | - Catalina Sanz
- Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain ; Microbiology and Genetics Department, University of Salamanca, Salamanca, Spain
| | - Félix Lorente
- Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain ; Paediatrics Department, University Hospital of Salamanca, Salamanca, Spain ; Biomedical and Diagnostic Sciences Department, University of Salamanca, Salamanca, Spain
| | - Ignacio Dávila
- Instituto Biosanitario de Salamanca (IBSAL), Salamanca, Spain ; Allergy Department, University Hospital of Salamanca, Salamanca, Spain ; Biomedical and Diagnostic Sciences Department, University of Salamanca, Salamanca, Spain
| | - Carlos Colás
- Allergy Department, University Hospital Lozano Blesa of Zaragoza, Avda. San Juan Bosco 15. 50.009, Zaragoza, Spain ; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
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Egawa G, Kabashima K. Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march. J Allergy Clin Immunol 2016; 138:350-358.e1. [PMID: 27497277 DOI: 10.1016/j.jaci.2016.06.002] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 06/08/2016] [Accepted: 06/13/2016] [Indexed: 10/21/2022]
Abstract
Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic "atopic (allergic) march." In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function.
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Affiliation(s)
- Gyohei Egawa
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Singapore Immunology Network (SIgN) and Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore; PRESTO, Japan Science and Technology Agency, Saitama, Japan.
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Dukhanin AS. PH OF THE TOPICAL DRUG VEHICLE: SELECTING AN OPTIMUM VALUE AND ROLE OF THE BUFFER SYSTEM. VESTNIK DERMATOLOGII I VENEROLOGII 2016. [DOI: 10.25208/0042-4609-2016-92-2-110-114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The following three groups of factors must be taken into consideration for selecting an optimum pH value of a topical drug: pharmaceutical, pharmacological and compatibility factors. To ensure a stable pH value, the drug vehicle comprises different buffer systems: single component and two-component ones. The optimum conditions for selecting and maintaining the vehicle pH were examined by the example of glucocorticosteroid-based topical drugs.
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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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Abstract
BACKGROUND Little is known about the predictors of eczema severity in the US population. OBJECTIVES We sought to determine the distribution and associations of childhood eczema severity in the United States. METHODS We analyzed the data from the 2007 National Survey of Children's Health, a prospective questionnaire-based study of a nationally representative sample of 91,642 children (range, 0-17 years). RESULTS The prevalence of childhood eczema was 12.97% (95% confidence interval [95% CI], 12.42-13.53); 67.0% (95% CI, 64.8-69.2) had mild disease, 26.0% (95% CI, 23.9-28.1) had moderate disease, and 7.0% (95% CI, 5.8-8.3) had severe disease. There was significant statewide variation of the distribution of eczema severity (Rao-Scott χ, P = 0.004), with highest rates of severe disease in Mid-Atlantic and Midwestern states. In univariate models, eczema severity was increased with older age, African American and Hispanic race/ethnicity, lower household income, oldest child in the family, home with a single mother, lower paternal/maternal education level, maternal general health, maternal/paternal emotional health, dilapidated housing, and garbage on the streets. In multivariate survey logistic regression models using stepwise and backward selection, moderate-to-severe eczema was associated with older age, lower household income, and fair or poor maternal health but inversely associated with birthplace outside the United States. CONCLUSIONS These data indicate that environmental and/or lifestyle factors play an important role in eczema severity.
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Red face revisited: Endogenous dermatitis in the form of atopic dermatitis and seborrheic dermatitis. Clin Dermatol 2014; 32:109-15. [PMID: 24314384 DOI: 10.1016/j.clindermatol.2013.05.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Atopic dermatitis and seborrheic dermatitis are multifactorial dermatitides that are known collectively as endogenous dermatitis. Both conditions can affect the face, but they have clinical, epidemiological, and physiopathological peculiarities that distinguish them from each other. These two diseases are very common all around the world. Atopic dermatitis is associated with xerosis and increased susceptibility to irritants and proteins; patients with this condition have a tendency to develop asthma, allergic rhinitis, and systemic manifestations that are mediated by immunoglobulin E. Seborrheic dermatitis is a moderate chronic dermatitis that is restricted to regions with a high production of sebum and areas that have cutaneous folds. There are many studies about pathophysiology related to the immunology and genetics of atopic dermatitis, but little is known about the genetic and immunological markers of seborrheic dermatitis.
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Clinical Management of Atopic Dermatitis: Practical Highlights and Updates from the Atopic Dermatitis Practice Parameter 2012. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2014; 2:361-9; quiz 370. [DOI: 10.1016/j.jaip.2014.02.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 02/25/2014] [Accepted: 02/26/2014] [Indexed: 11/20/2022]
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Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder, and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of antimicrobial peptides and proteases, are also discussed.
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Affiliation(s)
- Rachana Agrawal
- Department of Medicine, University of Virginia Health System, Allergy Division, PO Box 801355, Charlottesville, VA, 22908-1355, USA,
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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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Elias PM. Barrier-repair therapy for atopic dermatitis: corrective lipid biochemical therapy. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17469872.3.4.441] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Elias PM. Lipid abnormalities and lipid-based repair strategies in atopic dermatitis. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1841:323-30. [PMID: 24128970 DOI: 10.1016/j.bbalip.2013.10.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/27/2013] [Accepted: 10/01/2013] [Indexed: 01/30/2023]
Abstract
Prior studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes atopic dermatitis (AD). We review here increasing evidence that the inflammation in AD results primarily from inherited abnormalities in epidermal structural and enzymatic proteins that impact permeability barrier function. We also will show that the barrier defect can be attributed to a paracellular abnormality due to a variety of abnormalities in lipid composition, transport and extracellular organization. Accordingly, we also review the therapeutic implications of this emerging pathogenic paradigm, including several current and potentially novel, lipid-based approaches to corrective therapy. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
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Affiliation(s)
- Peter M Elias
- Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA.
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36
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Ballardini N, Kull I, Söderhäll C, Lilja G, Wickman M, Wahlgren CF. Eczema severity in preadolescent children and its relation to sex, filaggrin mutations, asthma, rhinitis, aggravating factors and topical treatment: a report from the BAMSE birth cohort. Br J Dermatol 2013; 168:588-94. [PMID: 23445315 DOI: 10.1111/bjd.12196] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Filaggrin (FLG) mutations are major genetic determinants for eczema, but their role in eczema severity needs further investigation. Children with eczema are at higher risk of having asthma and rhinitis but it is not known if this risk is associated with the severity of eczema. OBJECTIVES To investigate eczema severity in relation to sex, FLG mutations, asthma, rhinitis and topical treatment among preadolescent children in a population-based cohort. METHODS Parental questionnaires were used to obtain data on symptoms of eczema, asthma, and rhinitis among 3301 preadolescent children. Eczema severity was evaluated based on sleep disturbance, extent of disease and total time with eczema the previous year. Genotyping was performed in 1854 individuals for three common FLG mutations (R501X, R2447X and 2282del4). Results Eczema was more prevalent among girls (14·5%) than boys (9·4%). FLG mutations were detected in 13·1% of children with mild eczema and 12·5% with moderate-to-severe eczema. Of children with moderate-to-severe eczema, 45·1% had rhinitis and 22·0% had asthma compared with 32·7% and 13·8% of children with mild eczema, respectively. Children with moderate-to-severe eczema used moisturizers and topical glucocorticoids more frequently than children with mild eczema. Boys used moisturizers less frequently than girls. CONCLUSIONS More preadolescent girls than boys had eczema. FLG mutations did not influence eczema severity in our population-based cohort. Prevalence of rhinitis and asthma was associated with eczema severity, with the highest prevalence among boys with moderate-to-severe eczema.
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Affiliation(s)
- N Ballardini
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden.
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Asai Y, Greenwood C, Hull PR, Alizadehfar R, Ben-Shoshan M, Brown SJ, Campbell L, Michel DL, Bussières J, Rousseau F, Fujiwara TM, Morgan K, Irvine AD, McLean WI, Clarke A. Filaggrin gene mutation associations with peanut allergy persist despite variations in peanut allergy diagnostic criteria or asthma status. J Allergy Clin Immunol 2013; 132:239-42. [PMID: 23684069 PMCID: PMC3919206 DOI: 10.1016/j.jaci.2013.03.043] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 02/19/2013] [Accepted: 03/28/2013] [Indexed: 12/19/2022]
Affiliation(s)
- Yuka Asai
- Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada
- Division of Clinical Epidemiology, Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Celia Greenwood
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
- Department of Oncology and the Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Peter R. Hull
- Division of Dermatology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Reza Alizadehfar
- Division of Allergy and Clinical Immunology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Moshe Ben-Shoshan
- Division of Allergy and Clinical Immunology, Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | | | | | - Deborah L. Michel
- Division of Dermatology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | | | | | - T. Mary Fujiwara
- Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada
| | - Kenneth Morgan
- Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada
- Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | | | | | - Ann Clarke
- Division of Clinical Epidemiology, Department of Medicine, McGill University, Montreal, Quebec, Canada
- Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
- Division of Allergy/Clinical Immunology, Department of Medicine, McGill University, Montreal, Quebec, Canada
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Schneider L, Tilles S, Lio P, Boguniewicz M, Beck L, LeBovidge J, Novak N, Bernstein D, Blessing-Moore J, Khan D, Lang D, Nicklas R, Oppenheimer J, Portnoy J, Randolph C, Schuller D, Spector S, Tilles S, Wallace D. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013; 131:295-9.e1-27. [PMID: 23374261 DOI: 10.1016/j.jaci.2012.12.672] [Citation(s) in RCA: 283] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 12/18/2012] [Indexed: 10/27/2022]
Abstract
This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Atopic dermatitis: a practice parameter update 2012." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. Published practice parameters of the Joint Task Force on Practice Parameters for Allergy & Immunology are available online at http://www.jcaai.org.
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The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 2013; 131:280-91. [PMID: 23374260 DOI: 10.1016/j.jaci.2012.12.668] [Citation(s) in RCA: 269] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 12/12/2012] [Accepted: 12/12/2012] [Indexed: 12/15/2022]
Abstract
Filaggrin is a major structural protein in the stratum corneum of the epidermis. Mutations in the filaggrin gene are the most significant known genetic risk factor for the development of atopic dermatitis. Mutations in the human filaggrin gene (FLG) also confer risk for the associated allergic diseases of food allergy, asthma, and allergic rhinitis. These discoveries have highlighted the importance of skin barrier function in the pathogenesis of atopic diseases and have motivated a surge in research characterizing the filaggrin-deficient skin barrier and its consequences. In this review we discuss the mechanisms through which mutations in this protein contribute to the pathogenesis of atopic dermatitis and associated atopic conditions. We focus on recent human and murine discoveries characterizing the filaggrin-deficient epidermis with respect to biophysical, immunologic, and microbiome abnormalities.
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40
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Landeck L, Visser M, Skudlik C, Brans R, Kezic S, John SM. Clinical course of occupational irritant contact dermatitis of the hands in relation to filaggrin genotype status and atopy. Br J Dermatol 2013; 167:1302-9. [PMID: 22962861 DOI: 10.1111/bjd.12035] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Filaggrin loss-of-function mutations and atopy may alter the clinical course of irritant contact dermatitis (ICD). OBJECTIVE To investigate the clinical course of patients with occupational ICD according to loss-of-function mutations in the filaggrin gene (FLG) and atopy. METHODS In a prospective cohort study, the clinical course, use of topical corticosteroids, sick leave, recovery rate and job continuation were investigated in 459 inpatients treated for occupational ICD of the hands. Patients were genotyped for four FLG mutations, examined for atopy and followed for up to 3 years after discharge. RESULTS Our study included 327 (71·2%) atopic individuals and 132 nonatopic individuals. Overall, 68 patients showed a mutation in the FLG alleles R501X, R2447X, S3247X and 2282del4 (60 atopic and eight nonatopic). Nonatopic patients with ICD responded well to therapeutic approaches, while atopy status made subjects more resistant to therapy, resulting in lower rates of recovery and job continuation and higher use of topical corticosteroids. Carriage of FLG loss-of-function mutations in combination with atopy worsened the course. The risk of abandoning one's profession in this group was significantly increased when compared with 'pure' ICD (odds ratio 3·1) after 3 years. CONCLUSIONS Patients with atopy are a special risk population for ICD. In the presence of atopy, FLG mutations seem to be a modifier of the severity of the clinical course in ICD. Early-stage identification of this subgroup may result in additional emphasis to these patients regarding the importance of adherence to specific therapeutic interventions.
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Affiliation(s)
- L Landeck
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany.
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Yoshikawa Y, Sasahara Y, Takeuchi K, Tsujimoto Y, Hashida-Okado T, Kitano Y, Hashimoto-Tamaoki T. Transcriptional Analysis of Hair Follicle-Derived Keratinocytes from Donors with Atopic Dermatitis Reveals Enhanced Induction of IL32 Gene by IFN-γ. Int J Mol Sci 2013; 14:3215-27. [PMID: 23385231 PMCID: PMC3588040 DOI: 10.3390/ijms14023215] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/23/2013] [Accepted: 01/29/2013] [Indexed: 02/07/2023] Open
Abstract
We cultured human hair follicle-derived keratinocytes (FDKs) from plucked hairs. To gain insight into gene expression signatures that can distinguish atopic dermatitis from non-atopic controls without skin biopsies, we undertook a comparative study of gene expression in FDKs from adult donors with atopic dermatitis and non-atopic donors. FDK primary cultures (atopic dermatitis, n = 11; non-atopic controls, n = 7) before and after interferon gamma (IFN-γ) treatment were used for microarray analysis and quantitative RT-PCR. Comparison of FDKs from atopic and non-atopic donors indicated that the former showed activated pathways with innate immunity and decreased pathways of cell growth, as indicated by increased NLRP2 expression and decreased DKK1 expression, respectively. Treatment with IFN-γ induced the enhanced expression of IL32, IL1B, IL8, and CXCL1 in the cells from atopic donors compared to that in cells from non-atopic donors at 24 h after treatment. IL1B expression in FDKs after IFN-γ treatment correlated with IL32 expression. We hypothesized that overexpression of IL32 in hair follicle keratinocytes of patients with atopic dermatitis would lead to the excessive production of pro-IL1β and that the activation of IL1β from pro-IL1β by inflammasome complex, in which NLRP2 protein might be involved, would be augmented. This is the first report to show enhanced induction of cytokine/chemokine genes by IFN-γ in atopic dermatitis using cultured FDKs.
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Affiliation(s)
- Yoshie Yoshikawa
- Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; E-Mails: (Y.Y.); (Y.S.); (K.T.); (T.H.-T.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-798-45-6587; Fax: +81-798-40-7639
| | - Yusuke Sasahara
- Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; E-Mails: (Y.Y.); (Y.S.); (K.T.); (T.H.-T.)
| | - Katsuyuki Takeuchi
- Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; E-Mails: (Y.Y.); (Y.S.); (K.T.); (T.H.-T.)
| | - Yoshimasa Tsujimoto
- Takara Bio Inc., Seta 3-4-1, Otsu, Shiga 520-2193, Japan; E-Mails: (Y.T.); (T.H.-O.)
| | - Takashi Hashida-Okado
- Takara Bio Inc., Seta 3-4-1, Otsu, Shiga 520-2193, Japan; E-Mails: (Y.T.); (T.H.-O.)
| | - Yukio Kitano
- Hyogo College of Medicine, Hyogo 663-8501, Japan; E-Mail:
| | - Tomoko Hashimoto-Tamaoki
- Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; E-Mails: (Y.Y.); (Y.S.); (K.T.); (T.H.-T.)
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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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Interactions between FLG mutations and allergens in atopic dermatitis. Arch Dermatol Res 2012; 304:787-93. [PMID: 22903496 DOI: 10.1007/s00403-012-1282-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 07/24/2012] [Accepted: 08/02/2012] [Indexed: 10/28/2022]
Abstract
Filaggrin gene (FLG) mutations and sensitization in patients with atopic dermatitis (AD) have been well documented. However, whether an interaction exists between these mutations and specific sensitization in AD patients is still unknown. The aim of the study was to explore the interaction between FLG mutations and specific sensitization in AD patients. A total of 249 AD outpatients were recruited in the current study. Skin prick tests were conducted to assess the patient's sensitization to specific allergens. FLG mutations were analyzed through comprehensive sequencing. Logistic regression analyses were conducted to determine the interactions between FLG mutations and sensitization present. The mean age of the patients was 3.5 years, and the mean age of onset of AD was 9.6 months. The mean SCORAD of the patients was 25.8. Fourteen types of mutations were identified in the FLG of 64 patients. A total of 24 (9.6 %) and 29 (11.6 %) cases were mutated with 3321delA and K4671X, respectively. Sensitization to at least one type of allergen was detected in 118 patients (47.4 %). Logistic regression analyses showed that FLG mutations presented an interaction with sensitization to peanut and did not interact with the other detected allergens among AD patients. Sensitization to peanut allergens would have an interaction with the mutation of K4671X and the combined mutations in FLG in patients with atopic dermatitis. However, sensitization to the other common allergens might not interact with FLG mutations in the development of atopic dermatitis.
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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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Marsella R. Are transepidermal water loss and clinical signs correlated in canine atopic dermatitis? A compilation of studies. Vet Dermatol 2012; 23:238-e49. [DOI: 10.1111/j.1365-3164.2012.01055.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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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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Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol 2012; 41:282-95. [PMID: 21174234 DOI: 10.1007/s12016-010-8231-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Excessive Th2 cell signaling and IgE production play key roles in the pathogenesis of atopic dermatitis (AD). Yet, recent information suggests that the inflammation in AD instead is initiated by inherited insults to the barrier, including a strong association between mutations in FILAGGRIN and SPINK5 in Netherton syndrome, the latter of which provides an important clue that AD is provoked by excess serine protease activity. But acquired stressors to the barrier may also be required to initiate inflammation in AD, and in addition, microbial colonization by Staphylococcus aureus both amplifies inflammation, but also further stresses the barrier in AD. Therapeutic implications of these insights are as follows: While current therapy has been largely directed toward ameliorating Th2-mediated inflammation and/or pruritus, these therapies are fraught with short-term and potential long-term risks. In contrast, "barrier repair" therapy, with a ceramide-dominant triple-lipid mixture of stratum corneum lipids, is more logical, of proven efficacy, and it provides a far-improved safety profile.
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48
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Actualités sur la physiopathologie de la dermatite atopique. BULLETIN DE L'ACADÉMIE NATIONALE DE MÉDECINE 2012. [DOI: 10.1016/s0001-4079(19)31798-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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49
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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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Abstract
For at least half a century, noninvasive techniques have been available to quantify skin barrier function, and these have shown that a number of human skin conditions and disorders are associated with defects in skin permeability. In the past decade, several genes responsible for skin barrier defects observed in both monogenetic and complex polygenic disorders have been elucidated and functionally characterized. This has led to an explosion of work in the past 6 years that has identified pathways connecting epidermal barrier disruption and antigen uptake, as well as the quality and/or magnitude of the antigen-specific adaptive immune response. This review will introduce the notion that diseases arise from the dynamic crosstalk that occurs between skin barrier and the immune system using atopic dermatitis or eczema as the disease prototype. Nevertheless, the concepts put forth are highly relevant to a number of antigen-driven disorders for which skin barrier is at least transiently compromised, such as psoriasis, allergic contact dermatitis, and blistering disorders.
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