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Puppels GJ, Hourihane JO, Nico C, Chaoimh CN, Wong C, Common JE, Caspers PJ, Irvine AD. Highly accurate, noninvasive early identification of infants with a filaggrin loss-of-function mutation by in vivo Raman spectroscopy, followed from birth to 12 months. Ann Allergy Asthma Immunol 2025; 134:457-464. [PMID: 39826898 DOI: 10.1016/j.anai.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Loss-of-function FLG mutation (FLGmut) carriers are at an increased risk of developing atopic dermatitis (AD), characterized by earlier onset and more severe disease. AD is driven by a complex interplay between skin barrier function, TH2 and TH2-dominant immune dysregulation, and dysbiosis. Results from the Short-Term Topical Application for Prevention of Atopic Dermatitis study suggest 2 early initiating AD pathogenetic pathways: an FLGmut-related skin barrier deficiency pathway and an immune function-related inflammatory pathway. The Short-Term Topical Application for Prevention of Atopic Dermatitis study suggested that early preventative intervention with specialized emollients for barrier function augmentation may benefit newborns with FLGmut. This requires early identification of FLGmut carriers, for which noninvasive Raman spectroscopic determination of natural moisturizing factor (NMF) levels in the stratum corneum of the thenar eminence provides a surrogate marker. OBJECTIVE To identify strategies for early identification of infants with FLGmut. METHODS FLG sequencing was performed on 253 infants, and NMF concentrations were measured in the stratum corneum of the palmar eminence (pSC-NMF) using noninvasive Raman spectroscopy at 6 time points after birth. Furthermore, the pSC-NMF concentrations were obtained from both parents of 150 infants. RESULTS Babies are born with little to no NMF. In the first days after birth, NMF levels rapidly increase and 65% of newborns with FLG wild type already reach pSC-NMF concentrations, which excludes them as FLGmut carriers with high specificity. At 2 weeks of age, FLGmut carriers could be distinguished from newborns with FLG wild type with high sensitivity (97%) and specificity (97%). In addition, parent pSC-NMF concentrations offer the possibility to exclude their newborn as FLGmut carriers with high specificity. CONCLUSION Noninvasive Raman spectroscopy enables the accurate early identification of infants with FLGmut.
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Affiliation(s)
- Gerwin J Puppels
- RiverD International B.V. Marconistraat 16, Rotterdam, The Netherlands
| | - Jonathan O'B Hourihane
- Paediatrics and Child Health, Royal College of Surgeons in Ireland, Dublin, Ireland; The Irish Centre for Maternal and Child Health Research (INFANT) Research Centre, University College Cork, Ireland
| | - Claudio Nico
- RiverD International B.V. Marconistraat 16, Rotterdam, The Netherlands
| | - Carol Ni Chaoimh
- The Irish Centre for Maternal and Child Health Research (INFANT) Research Centre, University College Cork, Ireland
| | - Colin Wong
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Immunos, Singapore
| | - John E Common
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Immunos, Singapore; Translational and Clinical Research Institute and National Institute for Health and Care Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Peter J Caspers
- RiverD International B.V. Marconistraat 16, Rotterdam, The Netherlands
| | - Alan D Irvine
- Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
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Nouri Z, Biglari S, Tabatabaiefar MA, Vahidnezhad F, Hozhabrpour A, March ME, Margolis DJ, Gudjonsson JE, Hakonarson H, Vahidnezhad H. Filaggrinopathies-FLG/FLG2: Diagnostic Complexities and Immunotherapy. J Invest Dermatol 2025:S0022-202X(24)03045-8. [PMID: 39927906 DOI: 10.1016/j.jid.2024.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/12/2024] [Accepted: 12/18/2024] [Indexed: 02/11/2025]
Abstract
FLG and FLG2 proteins are expressed in the outer layers of the epidermis, where they are vital in epidermal differentiation and skin barrier formation. Filaggrinopathies involving dysfunctions in these proteins are associated with a spectrum of phenotypic presentations, from monogenic to multifactorial conditions. This review examines biosynthesis and function of FLG and FLG2 proteins and evaluates their molecular pathogenesis in filaggrinopathies. Moreover, genotype-phenotype correlations are assessed, emphasizing genetic diagnosis complexities and diverse immune dysregulation patterns. Finally, it examines ongoing immunotherapeutic approaches by targeting different cytokines as promising treatment options for filaggrinopathies management.
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Affiliation(s)
- Zahra Nouri
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Sajjad Biglari
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Fatemeh Vahidnezhad
- Department of Computer Science and Engineering Technology, University of Maryland Eastern Shore, Princess Anne, Maryland, USA
| | - Amir Hozhabrpour
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious disease, Iran University of Medical Sciences, Tehran, Iran
| | - Michael E March
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - David J Margolis
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | | | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Hassan Vahidnezhad
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
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Song C, Wang K, Li L, Hu L, Bai J, Zhao L, Liu C, Li S. Analysis of candidate variants in a Chinese family with monozygotic twins with keratoconus: a case report. Ophthalmic Genet 2025; 46:31-39. [PMID: 39544142 DOI: 10.1080/13816810.2024.2427295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 04/30/2024] [Accepted: 11/03/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Keratoconus (KC) is an asymmetrical bilateral corneal ectasia, of which the pathogenesis is unknown. Moreover, genetic factors play an important role. We reported ophthalmic findings in a Chinese family with monozygotic twins with KC to describe the clinical features and identify genetic variants. METHODS Comprehensive ophthalmic clinical assessments and examinations, including history, slit-lamp biomicroscopy, best-corrected visual acuity, corneal topography, anterior segment optical coherence tomography, and corneal biomechanics, were carried out on the twins and their parents. Whole-genome sequencing (WGS) was performed to identify variants in this family. SIFT, PolyPhen2, MutationTaster, and CADD were used to predict the effect of amino acid substitutions on the affected protein. RESULTS The twins presented typical KC features. However, their mother did not meet the criteria for a KC diagnosis but exhibited KC subclinical manifestations. After screening, 12 potentially pathogenic variants in 10 genes were identified in both twins and emerged as candidate variants for this family. These genes included 1 previously reported KC-associated variant (ZNF469, c.4384 G>A); 8 variants in 6 KC-associated genes (GRHPR, c.337 G>A, c.862_863del; COL6A1, c.920 G>A; FLG, c.8753C>G; HSPG2, c.9503C>T; KRT82, c.1306 G>A; SCN9A, c.5702_5706del, c.641 G>A); and 3 variants in 3 non-KC-associated genes (PDE6G, c.6C>A; HAL, c.1724C>T; AGBL1, c.2381 G>A). CONCLUSIONS The accumulation of these potentially pathogenic variants in twins may have caused KC in these twins. These results expand the spectrum of KC candidate variants and provide a basis for further studies on KC.
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Affiliation(s)
- Chunyuan Song
- Aier Eye Hospital, Jinan University, Guangzhou, China
| | - Kehua Wang
- Department of Ophthalmology, Changsha Aier Eye Hospital, Changsha, China
| | - Ling Li
- Department of Ophthalmology, Beijing Aier-Intech Eye Hospital, Beijing, China
- Department of Ophthalmology, Aier Corneal Institute, Beijing, China
| | - Luping Hu
- Department of Ophthalmology, Beijing Aier-Intech Eye Hospital, Beijing, China
| | - Jie Bai
- Department of Ophthalmology, Beijing Aier-Intech Eye Hospital, Beijing, China
- Department of Ophthalmology, Aier Corneal Institute, Beijing, China
| | - Lin Zhao
- Department of Ophthalmology, Beijing Aier-Intech Eye Hospital, Beijing, China
- Department of Ophthalmology, Aier Corneal Institute, Beijing, China
| | - Chang Liu
- Department of Ophthalmology, Beijing Aier-Intech Eye Hospital, Beijing, China
- Department of Ophthalmology, Aier Corneal Institute, Beijing, China
| | - Shaowei Li
- Aier Eye Hospital, Jinan University, Guangzhou, China
- Department of Ophthalmology, Beijing Aier-Intech Eye Hospital, Beijing, China
- Department of Ophthalmology, Aier Corneal Institute, Beijing, China
- Aier Eye Hospital, Tianjin University, Tianjin, China
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Abuabara K, Kidd SA, Ye M, Tully J, Tomaszewski N, Bhutani T, Chen S, Mhatre PG, Ramirez F, Langan SM. The Impact of Stressful Childhood Life Events on Atopic Dermatitis Disease Activity and Severity. J Invest Dermatol 2025:S0022-202X(25)00081-8. [PMID: 39884455 DOI: 10.1016/j.jid.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/13/2024] [Accepted: 01/16/2025] [Indexed: 02/01/2025]
Abstract
Atopic dermatitis (AD) is a prevalent condition associated with stress. However, epidemiological data on the impact of both common and severe childhood stressors are limited. This study aimed to evaluate the impact of stressful life events on AD activity and severity throughout early childhood. We conducted a longitudinal cohort study of 13,972 children aged 1-8.5 years from the Avon Longitudinal Study of Parents and Children. Responses to a standardized stressful life event scale were linked to repeated measures of annual AD period prevalence and severity. After adjusting for potential confounders, we found that for each SD increase in stressful life events, there was a small increased risk of concurrent AD activity (OR = 1.04, 95% confidence interval = 1.01-1.07), which was higher for moderate-to-severe AD (OR = 1.13, 95% confidence interval = 1.03-1.23) and for a cumulative measure of stressful events across childhood (OR = 1.11, 95% confidence interval = 1.07-1.16). The association was driven by common stressful life events which were perceived as more impactful to individual children such as starting a new school or having a new baby sibling, than severe adverse childhood events such as being separated from a parent or abused. These results may help provide anticipatory guidance to families.
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Affiliation(s)
- Katrina Abuabara
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA; School of Public Health, University of California Berkeley, Berkeley, California, USA.
| | - Sharon A Kidd
- Pediatric Blood and Marrow Transplant Division, University of California San Francisco, San Francisco, California, USA
| | - Morgan Ye
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
| | - Janell Tully
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Natalie Tomaszewski
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
| | - Tina Bhutani
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
| | - Shelley Chen
- San Mateo Behavioral Health System Psychiatry Residency Program, San Mateo, California, USA
| | - Pooja G Mhatre
- College of Osteopathic Medicine, Touro University California, Vallejo, California, USA
| | - Faustine Ramirez
- Department of Dermatology, University of California San Francisco, San Francisco, California, USA
| | - Sinéad M Langan
- London School of Hygiene and Tropical Medicine, London, United Kingdom
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Gu X, Wang X, Li B, Wang Y, Zhu W, Su J. Early age of dog exposure is negatively associated with atopic dermatitis: A comprehensive analysis. Pediatr Res 2025:10.1038/s41390-025-03864-x. [PMID: 39837990 DOI: 10.1038/s41390-025-03864-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 06/11/2024] [Accepted: 09/03/2024] [Indexed: 01/23/2025]
Abstract
BACKGROUND Currently, whether exposure to pets is a protective factor for atopic dermatitis (AD) is controversial. OBJECTIVE To investigate the association of pet exposure in early life with the incident AD. METHODS This study was based on PRISMA. The authors independently searched PubMed, Cochrane Library, and EMBASE. We gathered cohort studies reporting on the ratio of pet exposure and incident AD and meta-analyzed them by relative risks (RRs) and 95% confidence interval (CI). Newcastle-Ottawa Scale (NOS) and funnel plot were performed to evaluate the quality of the study and publication bias, respectively. P < 0.05 was considered statistically significant. RESULTS We included 23 studies comprising 3174-25,527 participants with exposure age 0-12. The quality of included studies was generally gorgeous, with NOS 5-8. Dog exposure was negatively associated with the incident AD, with RRs of 0.82 (P = 0.002), but this trend was insignificant in cats (RR = 1.08; P = 0.490) and other pets (RR = 0.94; P = 0.550). Subgroup analysis showed participants exposed to dogs had a further lower AD risk in the North American populations (RR = 0.60; P < 0.001). Publication bias was not supported by the funnel plot. CONCLUSION This study finds exposure to dog pets in early life is negatively associated with newly developed AD, especially in North American populations. IMPACT Currently, whether exposure to pets is a protective factor for atopic dermatitis (AD) is controversial. This study finds exposure to dog pets in early life is negatively associated with newly developed atopic dermatitis, and this trend is more remarkable in North American populations. Associations of exposure to cats and other pets with atopic dermatitis are not found. These results discover a novel insights to prevention AD and related diseases.
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Affiliation(s)
- Xiaoyu Gu
- Department of Dermatology Hunan Engineering Research Center of Skin Health and Disease Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, 410008, China.
- Furong Laboratory, Changsha, Hunan, 410008, China.
| | - Xinquan Wang
- Department of Dermatology Hunan Engineering Research Center of Skin Health and Disease Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, 410008, China
- Furong Laboratory, Changsha, Hunan, 410008, China
| | - Binfa Li
- Department of Dermatology Hunan Engineering Research Center of Skin Health and Disease Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ying Wang
- Department of Dermatology Hunan Engineering Research Center of Skin Health and Disease Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, 410008, China
- Furong Laboratory, Changsha, Hunan, 410008, China
| | - Wu Zhu
- Department of Dermatology Hunan Engineering Research Center of Skin Health and Disease Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, 410008, China.
- Furong Laboratory, Changsha, Hunan, 410008, China.
| | - Juan Su
- Department of Dermatology Hunan Engineering Research Center of Skin Health and Disease Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, 410008, China.
- Furong Laboratory, Changsha, Hunan, 410008, China.
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Weng PC, Zhang JF, Kuo CF, Huang YH. Atopic dermatitis and the outcomes of pregnancy and offspring: A nationwide population-based study in Taiwan. J Dtsch Dermatol Ges 2025; 23:54-63. [PMID: 39679774 DOI: 10.1111/ddg.15555] [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: 03/31/2024] [Accepted: 08/04/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND AND OBJECTIVES Studies have identified increased risks of pregnancy complications in expectant mothers with atopic dermatitis (AD). However, the associations between maternal AD and adverse pregnancy or offspring outcomes in Asians remain unexplored. Our aim was to investigate the relationship between maternal AD and adverse pregnancy and offspring outcomes in Taiwan. PATIENTS AND METHODS This retrospective cohort study collected data from Taiwan's National Health Insurance Research Database and the Taiwan Maternal and Child Health Database between 2003 and 2019. We recruited 15,495 AD mothers and 77,475 non-AD mothers, as well as 19,173 children born to AD mothers and 95,865 children born to non-AD mothers, using propensity score matching. Pregnancy and offspring outcomes were compared in the maternal and offspring cohorts, respectively. RESULTS AD mothers had higher risks of threatened abortion, preeclampsia/eclampsia, premature rupture of membranes, threatened preterm labor, fetal growth restriction, antepartum hemorrhage, postpartum hemorrhage, anemia, surgical complications, infections, pulmonary events, and renal events, with adjusted hazard ratios of 1.09-1.71. Children born to AD mothers had increased risks of AD, allergic rhinitis, asthma, alopecia areata, and attention deficit hyperactivity disorder, with adjusted hazard ratios of 1.05-2.29. CONCLUSIONS There is a significant association between maternal AD and adverse pregnancy and offspring outcomes in Taiwan.
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Affiliation(s)
- Pei-Chun Weng
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Jun-Fu Zhang
- Center for Artificial Intelligence in Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Computer Science, National Chengchi University, Taipei, Taiwan
| | - Chang-Fu Kuo
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Yu-Huei Huang
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Tang X, Li M. The role of the skin in the atopic march. Int Immunol 2024; 36:567-577. [PMID: 39271155 DOI: 10.1093/intimm/dxae053] [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: 06/04/2024] [Accepted: 09/12/2024] [Indexed: 09/15/2024] Open
Abstract
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called "atopy") and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred to as the "atopic march" (AM). Clinical, genetic, and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
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Affiliation(s)
- Xin Tang
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, Université de Strasbourg, Illkirch 67404, France
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 40000, People's Republic of China
| | - Mei Li
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, Université de Strasbourg, Illkirch 67404, France
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Blaess M, Csuk R, Schätzl T, Deigner HP. Elongation of Very Long-Chain Fatty Acids (ELOVL) in Atopic Dermatitis and the Cutaneous Adverse Effect AGEP of Drugs. Int J Mol Sci 2024; 25:9344. [PMID: 39273293 PMCID: PMC11395647 DOI: 10.3390/ijms25179344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/15/2024] Open
Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease, in particular among infants, and is characterized, among other things, by a modification in fatty acid and ceramide composition of the skin's stratum corneum. Palmitic acid and stearic acid, along with C16-ceramide and 2-hydroxy C16-ceramide, occur strikingly in AD. They coincide with a simultaneous decrease in very long-chain ceramides and ultra-long-chain ceramides, which form the outermost lipid barrier. Ceramides originate from cellular sphingolipid/ceramide metabolism, comprising a well-orchestrated network of enzymes involving various ELOVLs and CerSs in the de novo ceramide synthesis and neutral and acid CERase in degradation. Contrasting changes in long-chain ceramides and very long-chain ceramides in AD can be more clearly explained by the compartmentalization of ceramide synthesis. According to our hypothesis, the origin of increased C16-ceramide and 2-hydroxy C16-ceramide is located in the lysosome. Conversely, the decreased ultra-long-chain and very long-chain ceramides are the result of impaired ELOVL fatty acid elongation. The suggested model's key elements include the lysosomal aCERase, which has pH-dependent long-chain C16-ceramide synthase activity (revaCERase); the NADPH-activated step-in enzyme ELOVL6 for fatty acid elongation; and the coincidence of impaired ELOVL fatty acid elongation and an elevated lysosomal pH, which is considered to be the trigger for the altered ceramide biosynthesis in the lysosome. To maintain the ELOVL6 fatty acid elongation and the supply of NADPH and ATP to the cell, the polyunsaturated PPARG activator linoleic acid is considered to be one of the most suitable compounds. In the event that the increase in lysosomal pH is triggered by lysosomotropic compounds, compounds that disrupt the transmembrane proton gradient or force the breakdown of lysosomal proton pumps, non-HLA-classified AGEP may result.
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Affiliation(s)
- Markus Blaess
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany
| | - René Csuk
- Organic Chemistry, Martin-Luther University Halle-Wittenberg, Kurt-Mothes, Str. 2, D-06120 Halle (Saale), Germany
| | - Teresa Schätzl
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany
| | - Hans-Peter Deigner
- Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Str. 17, D-78054 Villingen-Schwenningen, Germany
- Fraunhofer Institute IZI, Leipzig, EXIM Department, Schillingallee 68, D-18057 Rostock, Germany
- Faculty of Science, Tuebingen University, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany
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Elgenidy A, Gad EF, Shabaan I, Abdelrhem H, Wassef PG, Elmozugi T, Abdelfattah M, Mousa H, Nasr M, Salah-Eldin M, Altaweel A, Hussein A, Bazzazeh M, Elganainy MA, Ali AM, Ezzat M, Elhoufey A, Alatram AA, Hammour A, Saad K. Examining the association between autism spectrum disorder and atopic eczema: meta-analysis of current evidence. Pediatr Res 2024:10.1038/s41390-024-03456-1. [PMID: 39128926 DOI: 10.1038/s41390-024-03456-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 07/03/2024] [Accepted: 07/18/2024] [Indexed: 08/13/2024]
Abstract
OBJECTIVES This study aims to investigate the association between autism spectrum disorder (ASD) and atopic eczema (AE), shedding light on potential associations and underlying mechanisms. METHODS A comprehensive review of literature was conducted to identify relevant studies published up to August 2023. Various electronic databases, including PubMed, Embase, Scopus, Web of Science, and Cochrane, were searched using specific keywords related to ASD and AE. RESULTS The meta-analysis covered a total of 30 studies. The first analysis included 23 studies with a combined total of 147430 eczema patients in the ASD group and 8895446 eczema patients in non-ASD group. We calculated the risk ratio of eczema in ASD and non-ASD groups, which revealed a significantly higher risk of eczema in patients with ASD (RR 1.34; 95% CI 1.03, 1.76). The second analysis included seven studies with a combined total of 3570449 ASD patients in the AE group and 3253973 in the non-Eczema group. The risk ratio of ASD in the Eczema and Non-Eczema groups showed an insignificantly increased risk of ASD in patients with eczema (RR 1.67; 95% CI 0.91, 3.06). CONCLUSION This study underscores the possible link between ASD and atopic eczema, shedding light on their potential association. IMPACT Our study conducted a meta-analysis on the association between autism spectrum disorder (ASD) and atopic eczema (AE), shedding light on potential associations and underlying mechanisms. The review we conducted covered a total of 30 studies. This study underscores the possible link between ASD and atopic eczema, shedding light on their potential association.
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Affiliation(s)
| | - Eman F Gad
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt
| | - Islam Shabaan
- Department of Psychiatry, Faculty of Medicine, Al Azhar University, Assiut, Egypt
| | | | | | - Taher Elmozugi
- Faculty of Medicine, Benghazi University, Benghazi, Libya
| | | | - Hisham Mousa
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Nasr
- Faculty of Medicine, Al-Azhar University, New Damietta, Egypt
| | | | - Ahmed Altaweel
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | | | | | - Ahmed M Ali
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt
| | - Mohamed Ezzat
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Amira Elhoufey
- Department of Community Health Nursing, Alddrab University College, Jazan University, Jazan, 45142, Saudi Arabia
- Department of Community Health Nursing, Faculty of Nursing, Assiut University, Assiut, Egypt
| | - Abdulrahman A Alatram
- Department of Psychiatry, College of Medicine, Majmaah University, Al Majmaah, Saudi Arabia
| | - Ahmed Hammour
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Khaled Saad
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt.
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Calabrese L, D’Onghia M, Lazzeri L, Rubegni G, Cinotti E. Blocking the IL-4/IL-13 Axis versus the JAK/STAT Pathway in Atopic Dermatitis: How Can We Choose? J Pers Med 2024; 14:775. [PMID: 39064029 PMCID: PMC11278138 DOI: 10.3390/jpm14070775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
Atopic dermatitis (AD) is an immune-mediated skin disorder with a chronic-relapsing course and a multifactorial pathogenesis. In contrast to the traditional concept of AD as solely a type 2 immune-activated disease, new findings highlight the disease as highly heterogeneous, as it can be classified into variable phenotypes based on clinical/epidemiological or molecular parameters. For many years, the only therapeutic option for moderate-severe AD was traditional immunosuppressive drugs. Recently, the area of systemic therapy of AD has significantly flourished, and many new substances are now marketed, licensed, or in the last step of clinical development. Biological agents and small molecules have enriched the therapeutic armamentarium of moderate-to-severe AD, such as dupilumab, tralokinumab, lebrikizumab (monoclonal antibodies targeting the IL-4/13 pathway), abrocitinib, upadacitinib, and baricitinib (JAK inhibitors). Indeed, the AD treatment paradigm is now split into two main approaches: targeting the IL-4/13 axis or the JAK/STAT pathway. Both approaches are valid and have strong evidence of preclinical and clinical efficacy. Therefore, the choice between the two can often be difficult and represents a major challenge for dermatologists. Indeed, several important factors must be taken into account, such as the heterogeneity of AD and its classification in phenotypes, patients' comorbidities, age, and personal preferences. The aim of our review is to provide an overview of the clinical and molecular heterogeneities of AD and to explore the factors and parameters that, in clinical practice, may help inform clinical decision-making.
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Affiliation(s)
- Laura Calabrese
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100 Siena, Italy
- Institute of Dermatology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Martina D’Onghia
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100 Siena, Italy
| | - Laura Lazzeri
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100 Siena, Italy
| | - Giovanni Rubegni
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100 Siena, Italy
| | - Elisa Cinotti
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100 Siena, Italy
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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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12
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McCarthy RL, Tawfik SS, Theocharopoulos I, Atkar R, McDonald B, Dhoat S, Hughes A, Thomas BR, O’Toole EA. Vitamin D deficiency and atopic dermatitis severity in a Bangladeshi population living in East London: A cross-sectional study. SKIN HEALTH AND DISEASE 2024; 4:e358. [PMID: 38846698 PMCID: PMC11150754 DOI: 10.1002/ski2.358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/30/2024] [Accepted: 03/01/2024] [Indexed: 06/09/2024]
Abstract
Background Atopic eczema is a common, chronic, inflammatory skin condition with considerable heterogeneity. South Asian people living in the UK frequently have low serum vitamin D3 (25(OH)D3), and those with atopic disease can present with severe eczema. The association between vitamin D deficiency and eczema severity, and the role of vitamin D supplementation in atopic eczema is inconsistent, and under-researched in people with Asian ancestry. Objectives This cross-sectional study investigates the association between serum 25(OH)D3 and eczema severity in a cohort of South Asian children and young adults living in London. Methods Eligible participants were Bangladeshi children and young adults aged 0-30 years with eczema, living in London and participating in the Tower Hamlets Eczema Assessment study. Data was collected via parent/patient self-reporting, clinical history and examination, and hospital databases. 25(OH)D3 levels were documented retrospectively, if available, from hospital databases. Eczema severity was classified by Eczema Area and Severity Index (EASI) score less than or greater than 10 (clear-mild vs. moderate-severe). Multivariate logistic regression was used to adjust for confounding factors. Results 681 participants were included in analyses. 25(OH)D3 results were available for 49.6% (338/681), 84.3% of which had deficient or insufficient lowest 25(OH)D3. Lowest 25(OH)D3 was inversely correlated with EASI score (Spearman's rank R 2 = -0.24, p < 0.001). 26.1% (178/681) had EASI >10 and a lower median lowest and nearest 25(OH)D3. After adjustment for confounding EASI > 10 was significantly associated with a lowest 25(OH)D3 < 25 (OR 3.21, 95%CI 1.35, 8.60), use of mild-moderate potency topical steroid on the face and neck (OR 3.11, 95%CI 1.86, 5.31), calcineurin inhibitor on the face and neck (OR 2.79, 95% CI 1.26, 6.10) and potent - very potent topical steroid on the face and neck (OR2.23, 95%CI 1.02, 4.77) and body (OR 2.11, 95%CI 1.18, 3.87). Discussion Vitamin D plays a role in modulation of proteins required for skin barrier function and regulation of the innate immune system, suggesting 25(OH)D3 deficiency contributes to skin inflammation. This study demonstrates a relationship between 25(OH)D3 deficiency and worse eczema severity in a cohort of South Asian children and young adults.
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Affiliation(s)
- Rebecca L. McCarthy
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
- Blizard InstituteThe Faculty of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Soha S. Tawfik
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
- Blizard InstituteThe Faculty of Medicine and DentistryQueen Mary University of LondonLondonUK
- Department of DermatologyVenereology and AndrologyFaculty of MedicineAlexandria UniversityAlexandriaEgypt
| | - Ioannis Theocharopoulos
- Blizard InstituteThe Faculty of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Ravinder Atkar
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
| | - Bryan McDonald
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
| | - Sasha Dhoat
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
| | - Aaron Hughes
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
- Blizard InstituteThe Faculty of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Bjorn R. Thomas
- Blizard InstituteThe Faculty of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Edel A. O’Toole
- Dermatology DepartmentThe Royal London HospitalBarts Health NHS TrustLondonUK
- Blizard InstituteThe Faculty of Medicine and DentistryQueen Mary University of LondonLondonUK
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13
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Ciprandi G, Licari A, Tosca MA, Miraglia Del Giudice M, Belloni Fortina A, Marseglia GL. An updated reappraisal of dupilumab in children and adolescents with moderate-severe atopic dermatitis. Pediatr Allergy Immunol 2024; 35:e14181. [PMID: 38934228 DOI: 10.1111/pai.14181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life.
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Affiliation(s)
| | - Amelia Licari
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | | | - Michele Miraglia Del Giudice
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Belloni Fortina
- Pediatric Dermatology Unit, Department of Women's and Child's Health (SDB), University of Padua, Padua, Italy
| | - Gian Luigi Marseglia
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
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14
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Lapp T, Mann C, Jakob T, Reinhard T, Maier PC. Atopic Keratoconjunctivitis: Pathophysiology, Clinic, and Potential New Therapeutic Concepts. Klin Monbl Augenheilkd 2024; 241:607-618. [PMID: 38604222 DOI: 10.1055/a-2244-2885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2024]
Abstract
Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease with a bipolar age distribution in childhood, adolescence and middle adulthood. Up to 50% of AD patients show ocular involvement, which can be potentially sight threatening. Clinically, the majority of cases present with atopic blepharo(kerato)conjunctivitis or atopic keratoconjunctivitis (AKC); other clinical variants from this group of inflammatory ocular surface diseases are keratoconjunctivitis vernalis in childhood and adolescence and allergic conjunctivitis. In addition to the aforementioned blepharitis, keratitis and conjunctivitis, AD is also associated with eyelid involvement with subsequent eyelid malposition, limbal insufficiency with the development of pseudopterygia, (chronic) cicatrizing conjunctivitis with symblephara formation and fornix shortening, as well as ocular surface malignancies such as conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma. In addition, an association with AD or AKC has been described for keratoconus. Whereas the therapy of AD in dermatology has made revolutionary advances in recent years through the use of biologicals, the primary use of these biologicals in ophthalmological complications is still very hesitant. Treatment here is often provided using topical steroids and calcineurin inhibitors. The following article summarises recent developments in basic and clinical dermatological research and discusses them in the context of current concepts for ophthalmological therapy.
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Affiliation(s)
- Thabo Lapp
- Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Deutschland
- Augenzentrum am St. Franziskus Hospital, Münster, Deutschland
| | - Caroline Mann
- Haut- und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Deutschland
| | - Thilo Jakob
- Klinik für Dermatologie und Allergologie, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - Thomas Reinhard
- Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Deutschland
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15
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Graff P, Woerz D, Wilzopolski J, Voss A, Sarrazin J, Blimkie TM, Weiner J, Kershaw O, Panwar P, Hackett T, Lau S, Brömme D, Beule D, Lee YA, Hancock REW, Gruber AD, Bäumer W, Hedtrich S. Extracellular Matrix Remodeling in Atopic Dermatitis Harnesses the Onset of an Asthmatic Phenotype and Is a Potential Contributor to the Atopic March. J Invest Dermatol 2024; 144:1010-1021.e23. [PMID: 37838332 DOI: 10.1016/j.jid.2023.09.278] [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: 08/17/2022] [Revised: 08/30/2023] [Accepted: 09/02/2023] [Indexed: 10/16/2023]
Abstract
The development of atopic dermatitis in infancy, and subsequent allergies, such as asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, however the course of disease indicates an inter-epithelial crosstalk, through the onset of inflammation in the skin and progression to other mucosal epithelia. In this study, we investigated if and how skin-lung epithelial crosstalk contributes to the development of the atopic march. First, we emulated inter-epithelial crosstalk through indirect coculture of bioengineered atopic-like skin disease models and three-dimensional bronchial epithelial models triggering an asthma-like phenotype in the latter. A subsequent secretome analysis identified thrombospondin-1, CD44, complement factor C3, fibronectin, and syndecan-4 as potentially relevant skin-derived mediators. Because these mediators are extracellular matrix-related proteins, we then studied the involvement of the extracellular matrix, unveiling distinct proteomic, transcriptomic, and ultrastructural differences in atopic samples. The latter indicated extracellular matrix remodeling triggering the release of the above-mentioned mediators. In vivo mouse data showed that exposure to these mediators dysregulated activated circadian clock genes which are increasingly discussed in the context of atopic diseases and asthma development. Our data point toward the existence of a skin-lung axis that could contribute to the atopic march driven by skin extracellular matrix remodeling.
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Affiliation(s)
- Patrick Graff
- Institute for Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany
| | - Dana Woerz
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany
| | - Jenny Wilzopolski
- Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Germany
| | - Anne Voss
- Institute of Veterinary Pathology, Freie Universität Berlin, Germany
| | - Jana Sarrazin
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany
| | - Travis M Blimkie
- Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, British Columbia, Canada
| | - January Weiner
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany
| | - Olivia Kershaw
- Institute of Veterinary Pathology, Freie Universität Berlin, Germany
| | - Preety Panwar
- Department of Oral Biological & Medical Sciences, Faculty of Dentistry, University of British Columbia; Centre for Blood Research, University of British Columbia, British Columbia, Canada
| | - Tillie Hackett
- Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia; Centre for Heart Lung Innovation, St Paul's Hospital, British Columbia, Canada
| | - Susanne Lau
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin, Berlin, Germany
| | - Dieter Brömme
- Department of Oral Biological & Medical Sciences, Faculty of Dentistry, University of British Columbia; Centre for Blood Research, University of British Columbia, British Columbia, Canada
| | - Dieter Beule
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany
| | - Young-Ae Lee
- Max Delbrück Center for Molecular Medicine, Berlin, Germany, Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany
| | - Robert E W Hancock
- Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, University of British Columbia, British Columbia, Canada
| | - Achim D Gruber
- Institute of Veterinary Pathology, Freie Universität Berlin, Germany
| | - Wolfgang Bäumer
- Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Germany
| | - Sarah Hedtrich
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Germany; Max Delbrück Center for Molecular Medicine, Berlin, Germany, Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.
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16
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Yamamura Y, Nakashima C, Otsuka A. Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human. Front Med (Lausanne) 2024; 11:1342176. [PMID: 38590314 PMCID: PMC10999685 DOI: 10.3389/fmed.2024.1342176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/26/2024] [Indexed: 04/10/2024] Open
Abstract
The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.
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Affiliation(s)
| | - Chisa Nakashima
- Department of Dermatology, Faculty of Medicine, Kindai University Hospital, Osaka, Japan
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Rusiñol L, Puig L. Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis. Int J Mol Sci 2024; 25:1042. [PMID: 38256115 PMCID: PMC10815999 DOI: 10.3390/ijms25021042] [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: 12/16/2023] [Revised: 01/07/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in industrialized societies, influenced by both environmental changes and a genetic predisposition. However, the exact immune factors driving these chronic, progressive diseases are not fully understood. By using multi-omics techniques in cutaneous IMIDs, it is expected to advance the understanding of skin biology, uncover the underlying mechanisms of skin conditions, and potentially devise precise and personalized approaches to diagnosis and treatment. We provide a narrative review of the current knowledge in genomics, epigenomics, and proteomics of atopic dermatitis and psoriasis. A literature search was performed for articles published until 30 November 2023. Although there is still much to uncover, recent evidence has already provided valuable insights, such as proteomic profiles that permit differentiating psoriasis from mycosis fungoides and β-defensin 2 correlation to PASI and its drop due to secukinumab first injection, among others.
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Affiliation(s)
- Lluís Rusiñol
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
- Institut de Recerca Sant Pau (IR SANT PAU), 08041 Barcelona, Spain
- Unitat Docent Hospital Universitari Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain
| | - Lluís Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
- Institut de Recerca Sant Pau (IR SANT PAU), 08041 Barcelona, Spain
- Unitat Docent Hospital Universitari Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain
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18
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Li B, Fuxench ZC. Atopic Dermatitis: Disease Background and Risk Factors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1447:11-19. [PMID: 38724780 DOI: 10.1007/978-3-031-54513-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.
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Affiliation(s)
- Becky Li
- Department of Dermatology, Howard University School of Medicine, Washington, DC, USA
| | - Zelma Chiesa Fuxench
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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19
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Lai A, Owens K, Patel S, Nicholas M. The Impact of Air Pollution on Atopic Dermatitis. Curr Allergy Asthma Rep 2023; 23:435-442. [PMID: 37233850 PMCID: PMC10214316 DOI: 10.1007/s11882-023-01095-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2023] [Indexed: 05/27/2023]
Abstract
PURPOSE OF REVIEW Atopic dermatitis (AD) remains a dermatological disease that imposes a significant burden on society. Air pollution has previously been linked to both the onset and severity of atopic dermatitis. As air pollution remains a critical environmental factor impacting human health, this review seeks to provide an overview of the relationship between different air pollutants and AD. RECENT FINDINGS AD can develop from multiple causes that can be broadly grouped into epidermal barrier dysfunction and immune dysregulation. Air pollution imposes significant health risks and includes a wide variety of pollutant types. AD has been linked to outdoor air pollutants such as particulate matter (PM), volatile organic compounds (VOC), gaseous compounds, and heavy metals. Exposure to indoor pollutants such as tobacco smoke and fungal molds has also been associated with an increased incidence of AD. While different pollutants impact distinct molecular pathways in the cell, they mostly converge on ROS product, DNA damage, and dysregulated T-cell activity and cytokine production. The presented review suggests a strengthening tie between air pollution and AD. It points to opportunities for further studies to clarify, as well as potential therapeutic opportunities that leverage the mechanistic relationships between air pollution and AD.
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Affiliation(s)
- Austin Lai
- Duke University School of Medicine, Durham, NC, 27710, USA
| | - Kelly Owens
- Duke University School of Medicine, Durham, NC, 27710, USA
| | - Surya Patel
- Department of Dermatology, Duke University, Durham, NC, 27710, USA
| | - Matilda Nicholas
- Department of Dermatology, Duke University, Durham, NC, 27710, USA.
- , Durham, USA.
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20
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Pontikas A, Antonatos C, Evangelou E, Vasilopoulos Y. Candidate Gene Association Studies in Atopic Dermatitis in Participants of European and Asian Ancestry: A Systematic Review and Meta-Analysis. Genes (Basel) 2023; 14:1456. [PMID: 37510360 PMCID: PMC10379179 DOI: 10.3390/genes14071456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/12/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
Atopic dermatitis (AD) has been extensively investigated for genetic associations utilizing both candidate gene approaches and genome-wide scans. Here, we comprehensively evaluated the available literature to determine the association of candidate genes in AD to gain additional insight into the etiopathogenesis of the disease. We systematically screened all studies that explored the association between polymorphisms and AD risks in cases of European and Asian ancestry and synthesized the available evidence through a random-effects meta-analysis. We identified 99 studies that met our inclusion/exclusion criteria that examined 17 candidate loci in Europeans and 14 candidate genes in Asians. We confirmed the significant associations between FLG variants in both European and Asian populations and AD risk, while synthesis of the available data revealed novel loci mapped to IL18 and TGFB1 genes in Europeans and IL12RB1 and MIF in Asians that have not yet been identified by genome-wide association studies. Our findings provide comprehensive evidence for AD risk loci in cases of both European and Asian ancestries, validating previous associations as well as revealing novel loci that could imply previously unexplored biological pathways.
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Affiliation(s)
- Alexandros Pontikas
- Laboratory of Genetics, Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Charalabos Antonatos
- Laboratory of Genetics, Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Evangelos Evangelou
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, 45110 Ioannina, Greece
- Biomedical Research Institute, Foundation for Research and Technology-Hellas, 45110 Ioannina, Greece
- Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK
| | - Yiannis Vasilopoulos
- Laboratory of Genetics, Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
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Abstract
Atopic dermatitis (AD) is a pruritic inflammatory skin disease that disproportionately affects skin of color patients. African American, Asian, and Hispanic patients carry disproportionate disease burdens, with increased prevalence, disease severity, and health care utilization. AD has a unique clinical presentation in skin of color patients, often with greater extensor involvement, dyspigmentation, and papular and lichenified presentations. Erythema is also more difficult to appreciate and can result in an underappreciation of disease severity in skin of color patients. In this review, we highlight the important manifestations of AD across all skin types, including nuances in treatment.
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Affiliation(s)
- Waleed Adawi
- Department of Dermatology, Johns Hopkins University School of Medicine
| | - Hannah Cornman
- Department of Dermatology, Johns Hopkins University School of Medicine
| | - Anusha Kambala
- Department of Dermatology, Johns Hopkins University School of Medicine
| | - Shanae Henry
- Department of Dermatology, Johns Hopkins University School of Medicine
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine.
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Grafanaki K, Antonatos C, Maniatis A, Petropoulou A, Vryzaki E, Vasilopoulos Y, Georgiou S, Gregoriou S. Intrinsic Effects of Exposome in Atopic Dermatitis: Genomics, Epigenomics and Regulatory Layers. J Clin Med 2023; 12:4000. [PMID: 37373692 DOI: 10.3390/jcm12124000] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/03/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Atopic dermatitis (AD) or atopic eczema is an increasingly manifested inflammatory skin disorder of complex etiology which is modulated by both extrinsic and intrinsic factors. The exposome includes a person's lifetime exposures and their effects. We recently reviewed the extrinsic exposome's environmental risk factors that contribute to AD. The periods of pregnancy, infancy, and teenage years are recognized as crucial stages in the formation of AD, where the exposome leads to enduring impacts on the immune system. However, research is now focusing on the interactions between intrinsic pathways that are modulated by the extrinsic exposome, including genetic variation, epigenetic modifications, and signals, such as diet, stress, and microbiome interactions. As a result, immune dysregulation, barrier dysfunction, hormonal fluctuations, and skin microbiome dysbiosis are important factors contributing to AD development, and their in-depth understanding is crucial not only for AD treatment but also for similar inflammatory disorders.
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Affiliation(s)
- Katerina Grafanaki
- Department of Dermatology-Venereology, School of Medicine, University of Patras, 26504 Patras, Greece
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Charalabos Antonatos
- Laboratory of Genetics, Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Alexandros Maniatis
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Antonia Petropoulou
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Eleftheria Vryzaki
- Department of Dermatology-Venereology, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Yiannis Vasilopoulos
- Laboratory of Genetics, Section of Genetics, Cell Biology and Development, Department of Biology, University of Patras, 26504 Patras, Greece
| | - Sophia Georgiou
- Department of Dermatology-Venereology, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Stamatis Gregoriou
- Department of Dermatology-Venereology, Faculty of Medicine, Andreas Sygros Hospital, National and Kapodistrian University of Athens, 16121 Athens, Greece
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Paul AA, Szulc NA, Kobiela A, Brown SJ, Pokrzywa W, Gutowska-Owsiak D. In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers. Front Mol Biosci 2023; 10:1105678. [PMID: 37200867 PMCID: PMC10185843 DOI: 10.3389/fmolb.2023.1105678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/19/2023] [Indexed: 05/20/2023] Open
Abstract
Background: Loss of function mutation in FLG is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by FLG. Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin. Objective: To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover. Methods: The effect of inhibition of proteasome and deubiquitinases on the level and modifications of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed in silico using the DEGRONOPEDIA and Clustal Omega tool. Results: Inhibition of proteasome and deubiquitinases stabilizes profilaggrin and its high molecular weight of presumably ubiquitinated derivatives. In silico analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. FLG mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes. Conclusion: The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. FLG mutations alter those key elements, affecting the degradation routes and the mutated products' stability.
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Affiliation(s)
- Argho Aninda Paul
- Experimental and Translational Immunology Group, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, University of Gdansk, Gdansk, Poland
| | - Natalia A. Szulc
- Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
| | - Adrian Kobiela
- Experimental and Translational Immunology Group, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, University of Gdansk, Gdansk, Poland
| | - Sara J. Brown
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Wojciech Pokrzywa
- Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
| | - Danuta Gutowska-Owsiak
- Experimental and Translational Immunology Group, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, University of Gdansk, Gdansk, Poland
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Chiricozzi A, Maurelli M, Calabrese L, Peris K, Girolomoni G. Overview of Atopic Dermatitis in Different Ethnic Groups. J Clin Med 2023; 12:2701. [PMID: 37048783 PMCID: PMC10095524 DOI: 10.3390/jcm12072701] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/16/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a high prevalence worldwide, including countries from Asia, Africa, and Latin America, and in different ethnic groups. In recent years, more attention has been placed on the heterogeneity of AD associated with multiple factors, including a patient's ethnic background, resulting in an increasing body of clinical, genetic, epidemiologic, and immune-phenotypic evidence that delineates differences in AD among racial groups. Filaggrin (FLG) mutations, the strongest genetic risk factor for the development of AD, are detected in up to 50% of European and 27% of Asian AD patients, but very rarely in Africans. Th2 hyperactivation is a common attribute of all ethnic groups, though the Asian endotype of AD is also characterized by an increased Th17-mediated signal, whereas African Americans show a strong Th2/Th22 signature and an absence of Th1/Th17 skewing. In addition, the ethnic heterogeneity of AD may hold important therapeutic implications as a patient's genetic predisposition may affect treatment response and, thereby, a tailored strategy that better targets the dominant immunologic pathways in each ethnic subgroup may be envisaged. Nevertheless, white patients with AD represent the largest ethnicity enrolled and tested in clinical trials and the most treated in a real-world setting, limiting investigations about safety and efficacy across different ethnicities. The purpose of this review is to describe the heterogeneity in the pathophysiology of AD across ethnicities and its potential therapeutic implications.
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Affiliation(s)
- Andrea Chiricozzi
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Martina Maurelli
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Laura Calabrese
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ketty Peris
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giampiero Girolomoni
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, 37126 Verona, Italy
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Atluri K, Manne S, Nalamothu V, Mantel A, Sharma PK, Babu RJ. Advances in Current Drugs and Formulations for the Management of Atopic Dermatitis. Crit Rev Ther Drug Carrier Syst 2023; 40:1-87. [PMID: 37585309 DOI: 10.1615/critrevtherdrugcarriersyst.2023042979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with a complex pathophysiology. Treatment of AD remains challenging owing to the presence of a wide spectrum of clinical phenotypes and limited response to existing therapies. However, recent genetic, immunological, and pathophysiological insights into the disease mechanism resulted in the invention of novel therapeutic drug candidates. This review provides a comprehensive overview of current therapies and assesses various novel drug delivery strategies currently under clinical investigation. Further, this review majorly emphasizes on various topical treatments including emollient therapies, barrier repair agents, topical corticosteroids (TCS), phosphodiesterase 4 (PDE4) inhibitors, calcineurin inhibitors, and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway inhibitors. It also discusses biological and systemic therapies, upcoming treatments based on ongoing clinical trials. Additionally, this review scrutinized the use of pharmaceutical inactive ingredients in the approved topical dosage forms for AD treatment.
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Affiliation(s)
| | | | | | | | | | - R Jayachandra Babu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
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26
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Ziyab AH, Holloway JW, Ali YM, Zhang H, Karmaus W. Eczema among adolescents in Kuwait: Prevalence, severity, sleep disturbance, antihistamine use, and risk factors. World Allergy Organ J 2022; 16:100731. [PMID: 36601260 PMCID: PMC9791032 DOI: 10.1016/j.waojou.2022.100731] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/15/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Background Eczema (atopic dermatitis) is a common inflammatory skin disease that is more prevalent in children and adolescents than adults. In Kuwait, there is a lack of empirical knowledge on eczema epidemiology among adolescents. Therefore, this study aimed to estimate the prevalence of eczema symptoms and severity, assess the frequency of eczema-related nocturnal sleep disturbance and its relation to antihistamine use, and determine factors that are associated with eczema prevalence and eczema-related nocturnal sleep disturbance. Methods A school-based cross-sectional study enrolled adolescents (n = 3864) aged 11-14 years across Kuwait. Information on eczema symptoms and clinical history, use of antihistamines, parental history of eczema, mode of delivery, and childhood life-style factors and exposures were reported by parents. Current eczema was defined as chronic or chronically relapsing itchy dermatitis with characteristic morphology and distribution in the past 12 months. Among subjects reporting current itchy rash, frequency of nocturnal sleep disturbance due to itchy rash in the past 12 months was reported as: never, <1 night per week, and ≥1 nights per week. Associations were assessed by applying a modified Poisson regression to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). Results The prevalence estimate of current (past 12 months) itchy rash was 20.5% (735/3593) and current eczema was 10.2% (388/3791), with 19.5% (736/3775) reporting history of ever doctor-diagnosed eczema. Among subjects with current itchy rash, nocturnal sleep disturbance due to itchy rash affected 21.7% (157/724) of participants for <1 night per week and affected 12.7% (92/724) of participants for ≥1 nights per week. Antihistamine use at least once per month increased as the frequency of nocturnal sleep disturbance due to itchy rash increased (Ptrend <0.001). Factors that demonstrated association with current eczema prevalence included underweight body mass index (aPR = 1.71, 95% CI: 1.16-2.53), Cesarean section delivery (1.29, 1.01-1.65), and maternal (1.72, 1.35-2.19) and paternal (1.83, 1.44-2.32) history of eczema. Frequent (≥1 nights per week) nocturnal sleep disturbance was associated with Cesarean section delivery (1.98, 1.37-2.85), exposure to household tobacco smoke (1.70, 1.18-2.47), and dog-keeping (1.93, 1.06-3.52). Conclusions Eczema symptoms are common among adolescents in Kuwait, with similar epidemiological patterns as those observed in western countries. A large proportion of affected adolescents reported nocturnal sleep disturbance due to itchy rash. Modifiable risk factors were associated increased prevalence of eczema and night awakenings.
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Affiliation(s)
- Ali H. Ziyab
- Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, Kuwait,Corresponding author. Department of Community Medicine and Behavioral Sciences, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat 13110, Kuwait
| | - John W. Holloway
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Yaser M. Ali
- Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Ministry of Health, Kuwait City, Kuwait
| | - Hongmei Zhang
- Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
| | - Wilfried Karmaus
- Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
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Muacevic A, Adler JR, Choday S, Kampa P, Ravi N, Sherpa ML, Agrawal H, Alfonso M. A Molecular Basis Approach of Eczema and Its Link to Depression and Related Neuropsychiatric Outcomes: A Review. Cureus 2022; 14:e32639. [PMID: 36660532 PMCID: PMC9845527 DOI: 10.7759/cureus.32639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
"What about my eczema do I love the most? The hurt? A scratch? The humiliation of the public? Oh, there are so many options available!" Studies have shown an association between atopic eczema (AE), a common inflammatory skin condition, and an increased risk of mental health problems. Despite this, experts are still examining the causes of the links between common mental diseases (such as depression and anxiety) and skin conditions. We collected studies that were published in the past 10 years. We searched the following databases: PubMed, PubMed Central, Science Direct, and Google Scholar. Further relevant research was assessed by examining the bibliographies of eligible studies and related ones. Two reviewers looked at the titles and abstracts of the studies to see if they were eligible, and then they read the full texts. We went through eczema and depression relationships, their etiopathogenesis, molecular basis, immune response, the role of genetic factors, and possible interactions between neurons and the immune system. Another possible contributing factor could be a change in cutaneous microbiota in eczema patients. Part of the initial connection could be explained by psychological stress, which further leads to depression in eczema patients. Healthcare professionals treating eczema patients must be aware of the comorbidity of mental problems and the potential that people with poor mental health may need social or emotional support. Patients with eczema, especially youngsters, can benefit from routine health checks since they can help identify neuropsychiatric issues like depression early and lessen the burden of both physical sickness and poor mental health. Given that AE is a condition that appears to be related to depression and anxiety, more research with larger samples is needed to determine a potential role for targeted mental health screening in people with AE, as well as the possibility of mental health modification through improved AE control (e.g., using new biologic agents).
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Miyake R, Iwamoto K, Sakai N, Matsunae K, Aziz F, Sugai M, Takahagi S, Tanaka A, Hide M. Uptake of Staphylococcus aureus by keratinocytes is reduced by interferon-fibronectin pathway and filaggrin expression. J Dermatol 2022; 49:1148-1157. [PMID: 35983802 DOI: 10.1111/1346-8138.16546] [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: 05/18/2022] [Revised: 07/16/2022] [Accepted: 07/28/2022] [Indexed: 11/27/2022]
Abstract
Staphylococcus aureus (S. aureus) is frequently detected in the skin of patients with atopic dermatitis (AD). AD skin-derived strains of S. aureus (AD strain) are selectively internalized into keratinocytes (HaCaT cells) compared to standard strains. However, the mechanism of AD strain internalization by keratinocytes and effect of the skin environment on internalization remain unclear. HaCaT cells were exposed to heat-killed AD or standard strains of fluorescently labeled S. aureus, with or without interferon (IFN)-γ, interleukin (IL)-4, and IL-13 cytokines, for 24 h. Filaggrin and fibronectin expression in HaCaT cells was knocked down using small interfering RNA. The amount of internalized S. aureus was evaluated using a cell imaging system. The effects of INF-γ, IL-4, and S. aureus exposure on mRNA expression in HaCaT cells were analyzed using single-cell RNA sequencing. AD strains adhered to HaCaT cells in approximately 15 min and were increasingly internalized for up to 3 h (2361 ± 467 spots/100 cells, mean ± SD), whereas the standard strain was not (991 ± 71 spots/100 cells). In the presence of IFN-γ, both the number of internalized strains and fibronectin expression significantly decreased compared to in the control, whereas Th2 cytokines had no significant effects. The number of internalized AD strains was significantly higher in filaggrin knockdown and lower in fibronectin knockdown HaCaT cells compared to in the control. RNA sequencing revealed that IFN-γ decreased both fibronectin and filaggrin expression. Keratinocyte internalization of the AD strain may be predominantly mediated by the INF-γ-fibronectin pathway and partially regulated by filaggrin expression.
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Affiliation(s)
- Ryu Miyake
- Department of Dermatology, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan
| | - Kazumasa Iwamoto
- Department of Dermatology, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan
| | - Norio Sakai
- Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical & Health Sciences Hiroshima University, Hiroshima, Japan
| | - Kyoka Matsunae
- Department of Dermatology, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan
| | - Fatkhanuddin Aziz
- Department of Bioresources Technology and Veterinary, Vocational, College Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Motoyuki Sugai
- Antimicrobial Resistance Research Center National Institute of Infectious Diseases, Tokyo, Japan
| | - Shunsuke Takahagi
- Department of Dermatology, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan
| | - Akio Tanaka
- Department of Dermatology, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan
| | - Michihiro Hide
- Department of Dermatology, Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Japan.,Department of Dermatology Hiroshima Citizens Hospital, Hiroshima, Japan
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Genetic Variants in Epidermal Differentiation Complex Genes as Predictive Biomarkers for Atopic Eczema, Allergic Sensitization, and Eczema-Associated Asthma in a 6-Year Follow-Up Case-Control Study in Children. J Clin Med 2022; 11:jcm11164865. [PMID: 36013110 PMCID: PMC9410399 DOI: 10.3390/jcm11164865] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/04/2022] [Accepted: 08/16/2022] [Indexed: 11/29/2022] Open
Abstract
Atopic eczema is the most common chronic inflammatory skin disease of early childhood and is often the first manifestation of atopic march. Therefore, one challenge is to identify the risk factors associated with atopic eczema that may also be predictors of atopic disease progression. The aim of this study was to investigate the association of SNPs in hornerin (HRNR) and filaggrin-2 (FLG2) genes with childhood atopic eczema, as well as other atopic phenotypes. Genotyping for HRNR and FLG2 was performed in 188 children younger than 2 years of age, previously screened for the FLG null mutations, and followed at yearly intervals until the age of 6. We demonstrated that risk variants of HRNR rs877776[C] and FLG2 rs12568784[T] were associated with atopic eczema, allergic sensitization, and susceptibility to the complex phenotype—asthma plus eczema. These effects seem to be supplementary to the well-known associations for FLG mutations and may be modulated by gene–gene interactions. Additionally, in children with eczema, these genetic variants may also be considered, along with FLG mutations, as predictive biomarkers for eczema-associated asthma. In conclusion, our results indicate that genetic variants in the epidermal differentiation complex gene could contribute to the pathogenesis of atopic eczema and progression to subsequent allergic disease.
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Gao JF, Tang L, Luo F, Zhang YY, Chen L, Ding H, Meng ZD. Nicotinamide mononucleotide ameliorates DNFB-induced atopic dermatitis-like symptoms in mice by blocking activation of ROS-mediated JAK2/STAT5 signaling pathway. Int Immunopharmacol 2022; 109:108812. [DOI: 10.1016/j.intimp.2022.108812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 11/28/2022]
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Ma X, Ru Y, Luo Y, Kuai L, Chen QL, Bai Y, Liu YQ, Chen J, Luo Y, Song JK, Zhou M, Li B. Post-Translational Modifications in Atopic Dermatitis: Current Research and Clinical Relevance. Front Cell Dev Biol 2022; 10:942838. [PMID: 35874824 PMCID: PMC9301047 DOI: 10.3389/fcell.2022.942838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 06/16/2022] [Indexed: 11/20/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic and relapsing cutaneous disorder characterized by compromised immune system, excessive inflammation, and skin barrier disruption. Post-translational modifications (PTMs) are covalent and enzymatic modifications of proteins after their translation, which have been reported to play roles in inflammatory and allergic diseases. However, less attention has been paid to the effect of PTMs on AD. This review summarized the knowledge of six major classes (including phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, o-glycosylation, and glycation) of PTMs in AD pathogenesis and discussed the opportunities for disease management.
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Affiliation(s)
- Xin Ma
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Yi Ru
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ying Luo
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Le Kuai
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Qi-Long Chen
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Yun Bai
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Ye-Qiang Liu
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Jia Chen
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Yue Luo
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Jian-Kun Song
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
| | - Mi Zhou
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Mi Zhou, ; Bin Li,
| | - Bin Li
- Shanghai Skin Disease Hospital of Tongji University, Shanghai, China
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Mi Zhou, ; Bin Li,
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Hawerkamp HC, Fahy CMR, Fallon PG, Schwartz C. Break on through: The role of innate immunity and barrier defence in atopic dermatitis and psoriasis. SKIN HEALTH AND DISEASE 2022; 2:e99. [PMID: 35677926 PMCID: PMC9168024 DOI: 10.1002/ski2.99] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 01/07/2022] [Accepted: 01/23/2022] [Indexed: 12/20/2022]
Abstract
The human skin can be affected by a multitude of diseases including inflammatory conditions such as atopic dermatitis and psoriasis. Here, we describe how skin barrier integrity and immunity become dysregulated during these two most common inflammatory skin conditions. We summarise recent advances made in the field of the skin innate immune system and its interaction with adaptive immunity. We review gene variants associated with atopic dermatitis and psoriasis that affect innate immune mechanisms and skin barrier integrity. Finally, we discuss how current and future therapies may affect innate immune responses and skin barrier integrity in a generalized or more targeted approach in order to ameliorate disease in patients.
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Affiliation(s)
- H C Hawerkamp
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland
| | - C M R Fahy
- Paediatric Dermatology Children's Health Ireland at Crumlin Dublin Ireland.,Royal United Hospitals NHS Foundation Trust Bath UK
| | - P G Fallon
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland.,National Children's Research Centre Our Lady's Children's Hospital Dublin Ireland.,Clinical Medicine Trinity College Dublin Dublin Ireland
| | - C Schwartz
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland.,Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg Erlangen Germany.,Medical Immunology Campus Erlangen FAU Erlangen-Nürnberg Erlangen Germany
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33
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Moosbrugger-Martinz V, Leprince C, Méchin MC, Simon M, Blunder S, Gruber R, Dubrac S. Revisiting the Roles of Filaggrin in Atopic Dermatitis. Int J Mol Sci 2022; 23:5318. [PMID: 35628125 PMCID: PMC9140947 DOI: 10.3390/ijms23105318] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/03/2022] [Accepted: 05/06/2022] [Indexed: 12/31/2022] Open
Abstract
The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.
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Affiliation(s)
- Verena Moosbrugger-Martinz
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
| | - Corinne Leprince
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse University, CNRS UMR5051, Inserm UMR1291, UPS, 31059 Toulouse, France; (C.L.); (M.-C.M.); (M.S.)
| | - Marie-Claire Méchin
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse University, CNRS UMR5051, Inserm UMR1291, UPS, 31059 Toulouse, France; (C.L.); (M.-C.M.); (M.S.)
| | - Michel Simon
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse University, CNRS UMR5051, Inserm UMR1291, UPS, 31059 Toulouse, France; (C.L.); (M.-C.M.); (M.S.)
| | - Stefan Blunder
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
| | - Robert Gruber
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
| | - Sandrine Dubrac
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria; (V.M.-M.); (S.B.); (R.G.)
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34
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Maiello N, Comberiati P, Giannetti A, Ricci G, Carello R, Galli E. New Directions in Understanding Atopic March Starting from Atopic Dermatitis. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9040450. [PMID: 35455494 PMCID: PMC9029734 DOI: 10.3390/children9040450] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/20/2022] [Accepted: 03/21/2022] [Indexed: 01/12/2023]
Abstract
Recent evidence showed that the postulated linear progression of the atopic march, from atopic dermatitis to food and respiratory allergies, does not capture the heterogeneity of allergic phenotypes, which are influenced by complex interactions between environmental, genetic, and psychosocial factors. Indeed, multiple atopic trajectories are possible in addition to the classic atopic march. Nevertheless, atopic dermatitis is often the first manifestation of an atopic march. Improved understanding of atopic dermatitis pathogenesis is warranted as this could represent a turning point in the prevention of atopic march. In this review, we outline the recent findings on the pathogenetic mechanisms leading to atopic dermatitis that could be targeted by intervention strategies for the prevention of atopic march.
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Affiliation(s)
- Nunzia Maiello
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 81100 Naples, Italy
- Correspondence:
| | - Pasquale Comberiati
- Department of Clinical and Experimental Medicine, Section of Pediatrics, University of Pisa, 56126 Pisa, Italy;
- Department of Clinical Immunology and Allergology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Arianna Giannetti
- Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Giampaolo Ricci
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy;
| | - Rossella Carello
- Pediatric Allergic Unit, S.Pietro Hospital FbF Roma, 00189 Rome, Italy; (R.C.); (E.G.)
| | - Elena Galli
- Pediatric Allergic Unit, S.Pietro Hospital FbF Roma, 00189 Rome, Italy; (R.C.); (E.G.)
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35
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Paternoster L, Budu-Aggrey A, Brown SJ. Imputation provides an opportunity to study filaggrin (FLG) null mutations in large population cohorts that lack bespoke genotyping. Wellcome Open Res 2022. [DOI: 10.12688/wellcomeopenres.17657.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background: Low frequency mutations within the filaggrin (FLG) gene are established genetic risk factors for atopic dermatitis. Studies of FLG have typically used sequencing or bespoke genotyping. Large-scale population cohorts with genome-wide imputed data offer powerful genetic analysis opportunities, but bespoke FLG genotyping is often not feasible in such studies. Therefore, we aimed to determine the quality of selected FLG null genotype data extracted from genome-wide imputed sources, focussing on UK population data. Methods: We compared the allele frequencies of three FLG null mutations (R501X, R2447X and S3247X) in directly genotyped and genome-wide imputed data in the ALSPAC cohort. Logistic regression analysis was used to test the association of atopic dermatitis with imputed and genotyped FLG null mutations in ALSPAC and UK Biobank to investigate the usefulness of imputed FLG data. Results: The three FLG null mutations appear to be well imputed in datasets that use the Haplotype Reference Consortium (HRC) for imputation (0.3% discordance compared with directly genotyped data). However, a greater proportion of null alleles failed imputation compared to wild-type alleles. Despite the calling of FLG mutations in imputed data being imperfect, they are still strongly associated with atopic dermatitis (p-values between 7x10-10 and 5x10-75 in UK Biobank). Conclusions: HRC imputed data appears to be adequate for UK population-based genetic analysis of selected FLG null mutations.
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36
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Arehart CH, Daya M, Campbell M, Boorgula MP, Rafaels N, Chavan S, David G, Hanifin J, Slifka MK, Gallo RL, Hata T, Schneider LC, Paller AS, Ong PY, Spergel JM, Guttman-Yassky E, Leung DYM, Beck LA, Gignoux CR, Mathias RA, Barnes KC. Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors. J Allergy Clin Immunol 2022; 149:145-155. [PMID: 34111454 PMCID: PMC8973457 DOI: 10.1016/j.jaci.2021.05.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 04/26/2021] [Accepted: 05/20/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. OBJECTIVES This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. METHODS AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. RESULTS Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36). CONCLUSIONS This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.
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Affiliation(s)
- Christopher H Arehart
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
| | - Michelle Daya
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
| | - Monica Campbell
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
| | | | - Nicholas Rafaels
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
| | - Sameer Chavan
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
| | | | - Jon Hanifin
- Department of Dermatology, Oregon Health and Science University, Portland, Ore
| | - Mark K Slifka
- Department of Dermatology, Oregon Health and Science University, Portland, Ore
| | - Richard L Gallo
- Department of Dermatology, University of California San Diego, San Diego, Calif
| | - Tissa Hata
- Department of Dermatology, University of California San Diego, San Diego, Calif
| | | | - Amy S Paller
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Pediatrics (Dermatology), Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill
| | - Peck Y Ong
- Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, Calif; Keck School of Medicine, University of Southern California, Los Angeles, Calif
| | - Jonathan M Spergel
- Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pa
| | | | - Donald Y M Leung
- Division of Allergy and Immunology, Department of Pediatrics, National Jewish Health, Denver, Colo
| | - Lisa A Beck
- Department of Dermatology, Medicine and Pathology, University of Rochester Medical Center, Rochester, NY
| | - Christopher R Gignoux
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo
| | - Rasika A Mathias
- Department of Medicine, Johns Hopkins University Department of Medicine, Baltimore, Md
| | - Kathleen C Barnes
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colo.
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37
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Jagadeesan S, Dhar S. Atopic March: Dermatologic perspectives. Indian J Dermatol 2022; 67:265-272. [PMID: 36386083 PMCID: PMC9644798 DOI: 10.4103/ijd.ijd_989_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The progression of allergic diseases with the development of atopic dermatitis and food allergy in infancy and subsequent asthma and allergic rhinitis in the later childhood is known as 'atopic march'. There have been many arguments in favour of and against this concept. This article reviews the latest epidemiology, immunological mechanisms and translational implications in clinical practice and research, which is relevant to the dermatologists. The role of skin as a site of initiation and the potential for interventions on skin that may prevent subsequent allergic diseases is also highlighted.
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38
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Dvornyk V, Ponomarenko I, Belyaeva T, Reshetnikov E, Churnosov M. Filaggrin gene polymorphisms are associated with atopic dermatitis in women but not in men in the Caucasian population of Central Russia. PLoS One 2021; 16:e0261026. [PMID: 34882715 PMCID: PMC8659355 DOI: 10.1371/journal.pone.0261026] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 11/22/2021] [Indexed: 11/18/2022] Open
Abstract
Background and purpose This study aimed to analyze the gender-specific association of the filaggrin (FLG) gene polymorphisms with atopic dermatitis (AD) in Caucasians from the central region of Russia. Methods The study sample consisted of 906 female (including 474 patients with AD and 432 controls) and 406 male (such as 226 patients with AD and 180 controls) participants. Genotyping of ten polymorphisms of the FLG gene was done. The logistic regression was used to analyze the associations. A total of 125 SNPs (seven AD-associated SNPs and 118 proxy SNPs, r2≥0.8) FLG gene were used for the in silico functional annotation analysis in the females. Results Significant associations were identified between seven SNPs of the FLG gene (rs12130219, rs61816761, rs558269137, rs12144049, rs3126085, rs471144, rs6661961) and AD in females: rs12144049 was associated independent individually (for allele C OR = 1.71, 95%Сl 1.19–2.46, рperm = 0.004 and OR = 1.76, 95%Сl 1.18–2.63, рperm = 0.006 according to the additive and dominant genetic models, respectively) and seven SNPs of the FLG gene within 14 haplotypes. Haplotype GGT [rs61816761-rs3126085-rs12144049] showed the strongest association (OR = 0.55, рperm = 0.001). No association between the analyzed SNPs and AD was determined in the male group. The subsequent bioinformatic analysis predicted the SNPs of the FLG gene that possessed epigenetic and non-synonymous effects, were involved in the control of gene expression and alternative splicing of genes that contribute to AD pathophysiology. Conclusion Polymorphisms of the FLG gene are associated with AD in females but not in males in the Caucasian population of Central Russia.
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Affiliation(s)
- Volodymyr Dvornyk
- Department of Life Sciences, College of Science and General Studies, Alfaisal University, Riyadh, Saudi Arabia
| | - Irina Ponomarenko
- Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia
| | - Tatyana Belyaeva
- Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia
| | - Evgeny Reshetnikov
- Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia
- * E-mail:
| | - Mikhail Churnosov
- Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia
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39
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Wu J, Fang Z, Liu T, Hu W, Wu Y, Li S. Maximizing the Utility of Transcriptomics Data in Inflammatory Skin Diseases. Front Immunol 2021; 12:761890. [PMID: 34777377 PMCID: PMC8586455 DOI: 10.3389/fimmu.2021.761890] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory skin diseases are induced by disorders of the host defense system of the skin, which is composed of a barrier, innate and acquired immunity, as well as the cutaneous microbiome. These disorders are characterized by recurrent cutaneous lesions and intense itch, which seriously affecting life quality of people across all ages and ethnicities. To elucidate molecular factors for typical inflammatory skin diseases (such as psoriasis and atopic dermatitis), transcriptomic profiling assays have been largely performed. Additionally, single-cell RNA sequencing (scRNA-seq) as well as spatial transcriptomic profiling have revealed multiple potential translational targets and offered guides to improve diagnosis and treatment strategies for inflammatory skin diseases. High-throughput transcriptomics data has shown unprecedented power to disclose the complex pathophysiology of inflammatory skin diseases. Here, we will summarize discoveries from transcriptomics data and discuss how to maximize the transcriptomics data to propel the development of diagnostic biomarkers and therapeutic targets in inflammatory skin diseases.
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Affiliation(s)
- Jingni Wu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhixiao Fang
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Teng Liu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Hu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yangjun Wu
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Shengli Li
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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40
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Hassoun D, Malard O, Barbarot S, Magnan A, Colas L. Type 2 immunity-driven diseases: Towards a multidisciplinary approach. Clin Exp Allergy 2021; 51:1538-1552. [PMID: 34617355 PMCID: PMC9292742 DOI: 10.1111/cea.14029] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/23/2021] [Accepted: 09/08/2021] [Indexed: 12/31/2022]
Abstract
Asthma, atopic dermatitis and chronic rhinoconjunctivitis are highly heterogeneous. However, epidemiologic associations exist between phenotypic groups of patients. Atopic march is one such association but is not the only common point. Indeed, beyond such phenotypes, hallmarks of type 2 immunity have been found in these diseases involving immune dysregulation as well as environmental triggers and epithelial dysfunction. From the canonical Th2 cytokines (IL-4, IL-5, IL-13), new cellular and molecular actors arise, from the epithelium's alarmins to new innate immune cells. Their interactions are now better understood across the different environmental barriers, and slight differences appeared. In parallel, the development of type 2-targeting biotherapies not only raised hope to treat those diseases but also raised new questions regarding their true pathophysiological involvement. Here, we review the place of type 2 immunity in the different phenotypes of asthma, chronic rhinitis, chronic rhinosinusitis and atopic dermatitis, highlighting nuances between them. New hypotheses rising from the use of biotherapies will be discussed along with the uncertainties and unmet needs of this field.
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Affiliation(s)
- Dorian Hassoun
- CHU Nantes, CNRS, INSERM, l'institut du Thorax, Université de Nantes, Nantes, France
| | - Olivier Malard
- Department of Otorhinolaryngology and Head and Neck Surgery, Nantes University Hospital, Nantes, France
| | - Sébastien Barbarot
- Department of Dermatology, CHU Nantes, UMR 1280 PhAN, INRA, Nantes Université, Nantes, France
| | - Antoine Magnan
- INRAe UMR_S 0892, Hôpital Foch, Université de Versailles Saint-Quentin, Paris Saclay, France
| | - Luc Colas
- Plateforme Transversale d'Allergologie et d'Immunologie Clinique, Institut du Thorax, CHU de Nantes, Nantes, France.,INSERM, CHU Nantes, Centre de Recherche en Transplantation et Immunologie UMR1064, Nantes Université, ITUN, Nantes, France
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41
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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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42
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Henderson I, Quenby S. Gestational hypertension and childhood atopy: a Millennium Cohort Study analysis. Eur J Pediatr 2021; 180:2419-2427. [PMID: 33770273 PMCID: PMC8285347 DOI: 10.1007/s00431-021-04012-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 02/28/2021] [Accepted: 03/04/2021] [Indexed: 11/16/2022]
Abstract
Gestational hypertension may confer risk of atopic disease in offspring through a direct biological mechanism, but another possibility is that risk is mediated through complications of pregnancy. To explore these associations, we conducted an analysis of a nationally representative birth cohort based in the UK involving children born 2000-2002. We included 12,450 mother-child pairs. We used logistic regression to estimate the association between hypertensive disease and asthma, hay fever, or eczema by age 5, and parentally reported early wheeze and severe wheeze. Mediation by gestation at delivery and caesarean delivery was explored using causal mediation analysis. Odds ratios (95% CI) for gestational hypertension and childhood asthma, hay fever, and eczema were 1.32 (1.09, 1.59), 1.22 (0.97, 1.55), and 1.12 (0.96, 1.32) respectively, adjusted for confounding. The population attributable fractions were 2.4% (1.0-3.8%), 0.9% (-0.3% to 2.1%), and 1.8% (0.0-3.7%), respectively. Accounting for mediation by gestational age and caesarean delivery, odds ratios (95% CI) for the potential direct effects of gestational hypertension were 1.21 (0.97, 1.50), 1.17 (0.91, 1.49), and 1.11 (0.94, 1.31) for the same.Conclusion: Gestational hypertension was weakly positively associated with asthma and this was partly mediated by earlier delivery. Only a small proportion of early childhood asthma was attributable to gestational hypertensive disease in this representative UK-based birth cohort. What is known: • Gestational hypertension has been shown to be an inconsistent risk factor for the atopic diseases. • The in utero immune environment may modify the risk of atopy in offspring; alternatively, complications of pregnancy including caesarean delivery and prematurity may explain an association between hypertensive disease and atopy. What is new: • Self-reported gestational hypertension was a weak risk factor for asthma and wheeze in the Millennium Cohort Study. • Part of the association between gestational hypertensive disease and asthma was explained by earlier delivery.
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Affiliation(s)
- Ian Henderson
- Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, UK.
- University Hospital Coventry, Coventry, CV2 2DX, UK.
| | - Siobhan Quenby
- Warwick Medical School, The University of Warwick, Coventry, CV4 7AL, UK
- University Hospital Coventry, Coventry, CV2 2DX, UK
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Looman KIM, van Mierlo MMF, van Zelm MC, Hu C, Duijts L, de Jongste JC, Nijsten T, Pardo LM, Kiefte-de Jong JC, Moll HA, Pasmans SGMA. Increased Th22 cell numbers in a general pediatric population with filaggrin haploinsufficiency: The Generation R Study. Pediatr Allergy Immunol 2021; 32:1360-1368. [PMID: 33715246 PMCID: PMC8451856 DOI: 10.1111/pai.13502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/09/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated whether school-aged children with and without FLG mutations have differences in T- and B-cell subsets. METHODS This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X, and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg), and CD27+ and CD27- memory B cells. Subset analysis was performed in 358 non-AD and 102 AD cases, assessed by parental questionnaires. RESULTS FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children in the general and non-AD population. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg, or memory B-cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cell subsets. CONCLUSIONS School-aged children of a general population with FLG mutations have higher Th22 cell numbers, which reflects the immunological response to the skin barrier dysfunction. FLG mutations did not otherwise affect the composition of the adaptive immunity in this general pediatric population.
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Affiliation(s)
- Kirsten I M Looman
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of General Pediatrics, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Minke M F van Mierlo
- Department of Dermatology, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital-Center of Pediatric Dermatology, Rotterdam, The Netherlands
| | - Menno C van Zelm
- Department Immunology and Pathology, Central Clinical School, Monash University and The Alfred Hospital, Melbourne, VIC, Australia
| | - Chen Hu
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Dermatology, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital-Center of Pediatric Dermatology, Rotterdam, The Netherlands
| | - Liesbeth Duijts
- Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Johan C de Jongste
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Tamar Nijsten
- Department of Dermatology, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital-Center of Pediatric Dermatology, Rotterdam, The Netherlands
| | - Luba M Pardo
- Department of Dermatology, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital-Center of Pediatric Dermatology, Rotterdam, The Netherlands
| | - Jessica C Kiefte-de Jong
- Department of Public Health and Primary Care, Leiden University Medical Center/LUMC Campus, Leiden, The Netherlands
| | - Henriëtte A Moll
- Department of General Pediatrics, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Suzanne G M A Pasmans
- Department of Dermatology, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital-Center of Pediatric Dermatology, Rotterdam, The Netherlands
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Chen KD, Huang YH, Guo MMH, Chang LS, Chu CH, Bu LF, Chu CL, Lee CH, Liu SF, Kuo HC. DNA Methylation Array Identifies Golli-MBP as a Biomarker for Disease Severity in Childhood Atopic Dermatitis. J Invest Dermatol 2021; 142:104-113. [PMID: 34293355 DOI: 10.1016/j.jid.2021.06.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 06/10/2021] [Accepted: 06/10/2021] [Indexed: 01/08/2023]
Abstract
In this study, we investigated the changes in global methylation status and its functional relevance in childhood atopic dermatitis (AD). Differences in epigenome-scale methylation events in peripheral blood associated with childhood AD were screened using DNA methylation arrays of 24 patients with AD compared with 24 control subjects. Of the 16,840 differentially methylated CpG regions between AD and control subjects, >97% CpG loci revealed hypomethylation in patients with childhood AD. Among the globally hypomethylated loci, we identified two CpG clusters within the golli-mbp locus of the MBP gene, which was functionally enriched by subnetwork enrichment analysis as an orchestrator among associated genes. The differential hypomethylation of the top-ranked cg24700313 cluster in the golli-mbp locus was validated by pyrosequencing in an independent cohort of 224 children with AD and 44 control subjects. DNA methylation was found to be negatively correlated with disease severity but showed no significant correlation with IgE levels after age adjustment. The multivariate correlation analysis represents a higher score in AD intensity with significantly increased IgE levels and decreased methylation levels in cg27400313. We concluded that methylation loss in the golli-mbp locus is an epigenetic factor associated with disease severity of childhood AD.
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Affiliation(s)
- Kuang-Den Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Liver Transplantation Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ying-Hsien Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mindy Ming-Huey Guo
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ling-Sai Chang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chi-Hsiang Chu
- Department of Statistics, National Cheng-Kung University, Tainan, Taiwan; Institute of Statistics, National University of Kaohsiung, Kaohsiung, Taiwan
| | - Li-Feng Bu
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Liver Transplantation Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chiao-Lun Chu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Hung Lee
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital, Taiwan
| | - Shih-Feng Liu
- Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ho-Chang Kuo
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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Dębińska A. New Treatments for Atopic Dermatitis Targeting Skin Barrier Repair via the Regulation of FLG Expression. J Clin Med 2021; 10:jcm10112506. [PMID: 34198894 PMCID: PMC8200961 DOI: 10.3390/jcm10112506] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 12/16/2022] Open
Abstract
Atopic dermatitis (AD) is one of the most common chronic, inflammatory skin disorders with a complex etiology and a broad spectrum of clinical phenotypes. Despite its high prevalence and effect on the quality of life, safe and effective systemic therapies approved for long-term management of AD are limited. A better understanding of the pathogenesis of atopic dermatitis in recent years has contributed to the development of new therapeutic approaches that target specific pathophysiological pathways. Skin barrier dysfunction and immunological abnormalities are critical in the pathogenesis of AD. Recently, the importance of the downregulation of epidermal differentiation complex (EDC) molecules caused by external and internal stimuli has been extensively emphasized. The purpose of this review is to discuss the innovations in the therapy of atopic dermatitis, including biologics, small molecule therapies, and other drugs by highlighting regulatory mechanisms of skin barrier-related molecules, such as filaggrin (FLG) as a crucial pathway implicated in AD pathogenesis.
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Affiliation(s)
- Anna Dębińska
- 1st Department and Clinic of Paediatrics, Allergology and Cardiology, Wroclaw Medical University, Chałubińskiego 2a, 50-368 Wrocław, Poland
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Cheng J, Wu JJ, Han G. Epidemiology and Characterization of Atopic Dermatitis in East Asian Populations: A Systematic Review. Dermatol Ther (Heidelb) 2021; 11:707-717. [PMID: 33835410 PMCID: PMC8163933 DOI: 10.1007/s13555-021-00516-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction As atopic dermatitis (AD) grows increasingly prevalent in Asian populations worldwide, understanding how environmental, genetic, and cultural factors uniquely influence AD in Asians is essential for informing disease management. Our objectives were to characterize the epidemiology of AD in East Asian populations with sensitivity to the changing demographics of AD in these populations and the effects of urbanization and immigration. Methods A systematic review was performed on epidemiologic studies of AD in East Asian populations over the past 10 years. Results There is a rising prevalence of both pediatric and adult AD in Asian populations worldwide, particularly in Asians living in urban areas. Studies suggest that the children of Asian immigrants may be at higher risk for developing AD, potentially resulting from epigenetic phenomena unique to immigrant populations. A number of genetic polymorphisms implicated in AD are shared by Asian populations around the world and appear to be rare among other ethnic populations. Conclusions As the prevalence of AD continues to increase in Asian populations, it is important to understand its distinct genetic and pathophysiologic profile in these populations, as well as characterize the cultural beliefs and practices surrounding its treatment. Future research should aim to capitalize on our growing understanding of pathophysiologic differences to inform the most promising treatments for AD in Asians. Additionally, the impact of immigration on AD suggests that further investigation of these trends may lead to a greater understanding of the epigenetics of AD.
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Affiliation(s)
- Julia Cheng
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jashin J Wu
- Dermatology Research and Education Foundation, Irvine, CA, USA
| | - George Han
- Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Salama RH, Rasheed Z, Ahmed AA, Bin Saif GA, Elkholy MM, Abd El-Moniem AE, Salem T, Zedan K, Al Robaee AA, Alzolibani AA. Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2021; 40:357-367. [PMID: 33538231 DOI: 10.1080/15257770.2021.1880009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
This study investigated the atopic march on the basis of genetics. This research detected 227 variants in the filaggrin gene (FLG gene). Missense, silent, non-sense, frame-shift and non-coding mutations were detected in exon 3 of the FLG gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. Missense mutation was detected at c.8343 G > C (p. Asp2781Glu) in all adult asthmatic and allergic rhinitis patients. Whereas, mutation at c.8360 C > T/A (p. Arg2787 His/Leu) was detected in all childhood asthmatic and mixed atopic patients. A non-coding mutation was detected at c.12365 in atopic dermatitis and bronchial asthma patients. Furthermore, DNA sequencing of asthmatic and mixed atopic patients showed missense mutations at c.6073 C > T (p. Gly2025Glu) and a silent mutation at c. 8341 G > A (p. Asp2781Asp).
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Affiliation(s)
- Ragaa H Salama
- Department of Medical Biochemistry, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Zafar Rasheed
- Department of Medical Biochemistry, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Ahmed A Ahmed
- Research Center, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Ghada A Bin Saif
- Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Maha M Elkholy
- Department of Medicine, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Alaa E Abd El-Moniem
- Department of Medicine, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Tarek Salem
- Department of Medical Biochemistry, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Khaled Zedan
- Department of Pediatrics, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Ahmad A Al Robaee
- Department of Dermatology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
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Current insights into the genetics of food allergy. J Allergy Clin Immunol 2021; 147:15-28. [PMID: 33436162 DOI: 10.1016/j.jaci.2020.10.039] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/02/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022]
Abstract
Food allergy (FA), a growing public health burden in the United States, and familial aggregation studies support strong roles for both genes and environment in FA risk. Deepening our understanding of the molecular and cellular mechanisms driving FAs is paramount to improving its prevention, diagnosis, and clinical management. In this review, we document lessons learned from the genetics of FA that have aided our understanding of these mechanisms. Although current genetic association studies suffer from low power, heterogeneity in definition of FA, and difficulty in our ability to truly disentangle FA from food sensitization (FS) and general atopy genetics, they reveal a set of genetic loci, genes, and variants that continue to implicate the importance of barrier and immune function genes across the atopic march, and FA in particular. The largest reported effects on FA are from MALT1 (odds ratio, 10.99), FLG (average odds ratio, ∼2.9), and HLA (average odds ratio, ∼2.03). The biggest challenge in the field of FA genetics is to elucidate the specific mechanism of action on FA risk and pathogenesis for these loci, and integrative approaches including genetics/genomics with transcriptomics, proteomics, and metabolomics will be critical next steps to translating these genetic insights into practice.
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Yang YB, Gohari A, Lam J. Brief Academic Review and Clinical Practice Guidelines for Pediatric Atopic Dermatitis. Curr Pediatr Rev 2021; 17:229-237. [PMID: 32867653 DOI: 10.2174/1573396316999200820163434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/21/2020] [Accepted: 06/10/2020] [Indexed: 11/22/2022]
Abstract
In this clinical guidelines article, we first include a brief review of the epidemiology, pathogenesis, clinical diagnoses, and scoring-scales for pediatric atopic dermatitis (AD). We then offer a set of pharmacologic treatment guidelines for infants and toddlers (<2 years), children (2-12 years), and adolescents (>12 years). We recommend irritant avoidance and liberal emollient usage as the cornerstone of treatment in all age-groups. In infants <2 years, we recommend topical corticosteroids as first-line medication-based therapy. In infants as young as 3 months, pimecrolimus, a topical calcineurin inhibitor, may also be used. As a last resort in patients <2 years, non-traditional therapies, such as the Aron regime, may be a safer option for refractory or resistant AD before off- label medications are considered. In children and adolescents >2 years, topical corticosteroids are still considered first-line therapies, but there is sufficient safety data to utilize topical calcineurin inhibitors and topical PDE4 inhibitors as well. In children ages 2-12 years whose atopic dermatitis fails to respond to prior treatments, oral systemic immunosuppressants can be used. For adolescents >12, the biologic, dupilumab, is an additional therapeutic option. A trial of phototherapy may also be utilized in children, particularly in adolescents >12 years, if they have access to treatment. Although not currently approved for the treatment of AD, Janus-kinase (JAK) inhibitors represent a promising new class of biologics with recently completed phase III clinical trials (JADE-- MONO1/2).
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Affiliation(s)
- Yue Bo Yang
- Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Amir Gohari
- Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Joseph Lam
- Departments of Paediatrics and Dermatology and Skin Sciences, Faculty of Medicine, University of British Columbia, Vancouver, Canada
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Ulrich NH, Thyssen JP, Mizutani H, Nixon RL. Hand Eczema: Causative Factors, Diagnosis, Personal and Societal Consequences. Contact Dermatitis 2021. [DOI: 10.1007/978-3-030-36335-2_61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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