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Jalili S, Hosn RR, Ko WC, Afshari K, Dhinakaran AK, Chaudhary N, Maiorino L, Haddadi N, Nathan A, Getz MA, Gaiha GD, Rashighi M, Harris JE, Hammond PT, Irvine DJ. Leveraging tissue-resident memory T cells for non-invasive immune monitoring via microneedle skin patches. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.17.25324099. [PMID: 40166546 PMCID: PMC11957092 DOI: 10.1101/2025.03.17.25324099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Detecting antigen-specific lymphocytes is crucial for immune monitoring in the setting of vaccination, infectious disease, cancer, and autoimmunity. However, their low frequency and dispersed distribution across lymphoid organs, peripheral tissues, and blood pose challenges for reliable detection. To address this issue, we developed a strategy exploiting the functions of tissue-resident memory T cells (TRMs) to concentrate target circulating immune cells in the skin and then sample these cells non-invasively using a microneedle (MN) skin patch. TRMs were first induced at a selected skin site through initial sensitization with a selected antigen. Subsequently, these TRMs were restimulated by intradermal inoculation of a small quantity of the same antigen to trigger the "alarm" and immune recruitment functions of these cells, leading to accumulation of antigen-specific T cells from the circulation over several days. In mouse models of vaccination, we show that application of MN patches coated with an optimized hydrogel layer for cell and fluid sampling to this skin site allowed effective isolation of thousands of live antigen-specific lymphocytes as well as innate immune cells. In a human subject with allergic contact dermatitis, stimulation of TRMs with allergen followed by MN patch application allowed the recovery of diverse lymphocyte populations that were absent from untreated skin sites. These results suggest that TRM restimulation coupled with microneedle patch sampling can be used to obtain a window into both local and systemic antigen-specific immune cell populations in a noninvasive manner that could be readily applied to a wide range of disease or vaccination settings.
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Affiliation(s)
- Sasan Jalili
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT, USA
| | - Ryan R. Hosn
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Wei-Che Ko
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Khashayar Afshari
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | | | - Namit Chaudhary
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
| | - Laura Maiorino
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
| | - Nazgol Haddadi
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Anusha Nathan
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA
- Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA
| | - Matthew A. Getz
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA
| | - Gaurav D. Gaiha
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Mehdi Rashighi
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - John E. Harris
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Paula T. Hammond
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Darrell J. Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA
- Departments of Biological Engineering and Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
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Yin H, Chen J, Li C. Immune Memory: A New Frontier in Treating Recurrent Inflammatory Skin Diseases. Clin Rev Allergy Immunol 2025; 68:31. [PMID: 40100550 DOI: 10.1007/s12016-025-09039-0] [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] [Accepted: 02/24/2025] [Indexed: 03/20/2025]
Abstract
The recurrence of inflammatory skin diseases represents a significant challenge in clinical practice, primarily mediated by immune memory. In inflammatory skin diseases, immune memory encompasses adaptive immune memory, trained immunity, and inflammatory memory, which are conducted by adaptive immune cells, innate immune cells, and structural cells, respectively. Adaptive immune memory is established through gene rearrangement, leading to antigen-specific immune memory. In contrast, trained immunity and inflammatory memory are formed through epigenetic and metabolic reprogramming, resulting in non-specific immune memory. Different types of immune memory work synergistically to aggravate localized inflammation in recurrent inflammatory skin diseases. However, immune memory in specific cells, such as macrophages, may also play an immunoregulatory role under certain conditions. We reviewed the immune memory mechanisms in different inflammatory skin diseases and discussed future strategies for targeted regulation of the molecular mechanisms underlying immune memory, such as targeted biological agents and epigenetic modifications. Additionally, we explored the potential for precise regulation of immune memory and its application in personalized treatment for recurrent inflammatory skin diseases.
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Affiliation(s)
- Hang Yin
- Department of Dermatology, Xijing Hospital, Forth Military Medical University, Xi'an, 710032, China
| | - Jianru Chen
- Department of Dermatology, Xijing Hospital, Forth Military Medical University, Xi'an, 710032, China.
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, 200433, China.
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Forth Military Medical University, Xi'an, 710032, China.
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Narla S, Chiesa Fuxench ZC, Abuabara K, Beck LA, Chovatiya R, Thaçi D, Silverberg JI. What Does Long-Term Control in Atopic Dermatitis Look Like? Dermatitis 2025. [PMID: 39925116 DOI: 10.1089/derm.2024.0121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
What defines long-term control in atopic dermatitis (AD) and why is it difficult to measure in AD? Why does long-term control matter? Herein, we critically examine these questions along with the clinical rationale, approaches for assessing long-term control in clinical practice, potential mechanistic underpinnings for AD long-term control, and evidence for long-term control with current systemic AD treatments. Currently, there is limited consensus on how to define flares and long-term control due to AD's heterogeneous nature, and AD being a disorder largely defined by patients' individual experience. An important part of long-term control is disease modification, which is made up of the impact on the disease itself and also its impact on AD's associated comorbidities. By focusing on the multiple facets of long-term control, possible deep/long-term remission or even therapy free remission may be achieved. While there is some research currently available on the long-term efficacy of current AD therapies, larger studies with longer follow-up periods are needed to adequately determine if reduced dosing can be applied to AD patients who have achieved deep/long-term remission. Future directions in AD may involve developing new therapies that target the innate and adaptive immune systems to bring about disease modification.
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Affiliation(s)
- Shanthi Narla
- From the Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Zelma C Chiesa Fuxench
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Katrina Abuabara
- Department of Dermatology, University of California, San Francisco, California, USA
| | - Lisa A Beck
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA
| | - Raj Chovatiya
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Diamant Thaçi
- Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany
| | - Jonathan I Silverberg
- Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
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Zhang J, Li G, Guo Q, Yang Y, Yang J, Feng X, Yao Z. Allergens in Atopic Dermatitis. Clin Rev Allergy Immunol 2025; 68:11. [PMID: 39924626 DOI: 10.1007/s12016-025-09024-7] [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] [Accepted: 01/20/2025] [Indexed: 02/11/2025]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex relationship to allergens. While AD itself is not an allergic reaction and does not necessarily involve allergen sensitization, AD patients show higher rates of sensitization to food and inhalant allergens compared to the general population. Recent evidence refining the "dual allergen exposure hypothesis" demonstrates that early oral exposure to allergens through an intact gastrointestinal barrier typically promotes tolerance, while exposure through compromised skin or respiratory barriers often leads to sensitization. Therefore, the impaired skin barrier function in AD patients increases the risk of transcutaneous sensitization and may interfere with oral tolerance development. Interestingly, AD patients' sensitivity to contact allergens (such as metals and fragrances) is not necessarily higher than that of the general population, which may be related to the inherent properties of these allergens. Personalized allergen testing can help guide appropriate allergen avoidance and reintroduction strategies in AD management. The insights into optimal allergen exposure conditions have also expanded the potential applications of allergen-specific immunotherapy in preventing AD onset in high-risk populations and halting the atopic march.
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Affiliation(s)
- Jiayan Zhang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Guofang Li
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Qiuyang Guo
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yijun Yang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Jinxiang Yang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xiaobo Feng
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Zhirong Yao
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
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Vaher H, Gadsbøll ASØ, Seibel AT, Kongsbak-Wismann M, Lohmann RKD, Mraz V, Funch AB, Jee MH, Ødum N, Woetmann A, Geisler C, Bonefeld CM. T Cells Induce Prolonged Downregulation of Barrier Molecules in a Mouse Model of Allergic Contact Dermatitis. Allergy 2024. [PMID: 39673368 DOI: 10.1111/all.16421] [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: 07/05/2024] [Revised: 10/04/2024] [Accepted: 11/03/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND Dysfunction of the skin barrier is regarded as a key event in the initiation and progression of inflammatory skin diseases. In many cases of allergic contact dermatitis (ACD), epidermal-resident memory CD8+ T (TRM) cells play a central role in the immune response to contact allergens. However, if and how allergen-specific CD8+ TRM cells affect the expression of skin barrier molecules is not known. METHODS The expression level of skin barrier molecules was determined by RT-qPCR and immunofluorescence in a mouse model of ACD. The role of CD8+ T cells on the expression of skin barrier molecules was investigated by depletion of CD8+ cells. Human primary keratinocytes were used to assess the direct effect of IFN-γ and contact allergen on their expression of skin barrier molecules. RESULTS Sensitization with the contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB) resulted in epidermal accumulation of CD8+ TRM cells and prolonged upregulation of Ifng and downregulation of keratin 5 (Krt5) and Krt14 even after complete macroscopic remission of the inflammatory response. Challenge with DNFB lead to an additionally rapid downregulation of Krt5 and Krt14 and the downregulation of several other skin barrier molecules. Depletion of CD8+ cells abolished both the prolonged and rapid downregulation of skin barrier molecules. In keratinocytes, IFN-γ and contact allergen synergistically down-regulated the expression of KRT5 and KRT14. CONCLUSION CD8+ TRM cells contribute to a prolonged reduction in the expression of skin barrier molecules, which might exacerbate allergen permeation and the inflammatory response during succeeding exposures of the skin to allergens and antigens.
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Affiliation(s)
- Helen Vaher
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne-Sofie Ø Gadsbøll
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Alexandra T Seibel
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Martin Kongsbak-Wismann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rebecca K D Lohmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders B Funch
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mia H Jee
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Ødum
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders Woetmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Liu Y, Yin M, Mao X, Wu S, Wei S, Heng S, Yang Y, Huang J, Guo Z, Li C, Ji C, Hu L, Liu W, Zhang LJ. Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics. eLife 2024; 13:RP94698. [PMID: 39213029 PMCID: PMC11364439 DOI: 10.7554/elife.94698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.
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Affiliation(s)
- Youxi Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen UniversityXiamenChina
| | - Meimei Yin
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen UniversityXiamenChina
| | - Xiaoting Mao
- Zhejiang Yangshengtang Institute of Natural Medication Co LtdHangzhouChina
| | - Shuai Wu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityXiamenChina
| | - Shuangping Wei
- Zhejiang Yangshengtang Institute of Natural Medication Co LtdHangzhouChina
- Yang Sheng Tang (Anji) Cosmetics Co LtdZhejiangChina
| | - Shujun Heng
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen UniversityXiamenChina
| | - Yichun Yang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen UniversityXiamenChina
| | - Jinwen Huang
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical UniversityFuzhouChina
| | - Zhuolin Guo
- Department of Dermatology, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghaiChina
| | - Chuan Li
- Zhejiang Yangshengtang Institute of Natural Medication Co LtdHangzhouChina
| | - Chao Ji
- Department of Dermatology, The First Affiliated Hospital of Fujian Medical UniversityFuzhouChina
| | - Liu Hu
- Zhejiang Yangshengtang Institute of Natural Medication Co LtdHangzhouChina
| | - Wenjie Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen UniversityXiamenChina
| | - Ling-juan Zhang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen UniversityXiamenChina
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Wennervaldt M, Vaher H, Ahlström MG, Bischofberger N, Menné T, Thyssen JP, Johansen JD, Bonefeld CM. Subclinical immune responses to nickel in sensitized individuals-a dose-response study. Contact Dermatitis 2024; 91:1-10. [PMID: 38577784 DOI: 10.1111/cod.14549] [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: 11/17/2023] [Revised: 02/10/2024] [Accepted: 03/08/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high. OBJECTIVE To investigate the clinical and subclinical immune response to low-dose nickel exposure on nickel pre-exposed skin to assess the adequacy of current regulatory limits. METHOD Nickel-allergic and healthy controls were patch tested with nickel twice with a 3-4 weeks interval. The first exposure used the diagnostic concentration of 2000 μg/cm2 nickel sulphate, and the same skin areas were then re-exposed to 0.2, 0.5, 12.8 and 370 μg/cm2 nickel sulphate. After 48 h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction. RESULTS Two nickel-allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2/0.5 μg/cm2) following re-exposure. There was immune activation in all skin areas following re-exposure to nickel, predominantly mediated by up-regulation of cytokines and chemokines. In all nickel re-exposed skin areas, 81 genes were up-regulated independent from the clinical response. In skin areas exposed to 0.2 μg/cm2, 101 immune-related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up-regulation of three genes in response to nickel re-exposures without any clinical reactions. CONCLUSION Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low-dose exposures.
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Affiliation(s)
- Michael Wennervaldt
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Helen Vaher
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Malin G Ahlström
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Nuno Bischofberger
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Torkil Menné
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Jacob P Thyssen
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Jeanne D Johansen
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Charlotte M Bonefeld
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
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8
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Macchione M, Yoshizaki K, Frias DP, Maier K, Smelan J, Prado CM, Mauad T. Fragrances as a trigger of immune responses in different environments. Toxicol In Vitro 2024; 96:105769. [PMID: 38142785 DOI: 10.1016/j.tiv.2023.105769] [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: 08/03/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023]
Abstract
Fragrances can cause allergic skin reactions, expressed as allergic contact dermatitis and reactions in the respiratory tract that range from acute temporary upper airway irritation to obstructive lung disease. These adverse health effects may result from the stimulation of a specific (adaptive) immune response. Th1 cells, which essentially produce interleukin-2 (IL-2) and interferon-γ (IFN-γ), play a key role in allergic contact dermatitis and also on allergic sensitization to common allergens (e.g., nickel and fragrance). It has been shown that fragrance allergy leads to Th2/Th22 production of IL-4, IL-5 and IL-13, controlling the development of IgE and mediating hypersensitivity reactions in the lung, such as asthma. Cytokines released during immune response modulate the expression of cytochrome P450 (CYPs) proteins, which can result in alterations of the pharmacological effects of substances in inflammatory diseases. The mechanisms linking environment and immunity are still not completely understood but it is known that aryl hydrocarbon receptor (AhR) is a sensor with conserved ligand-activated transcription factor, highly expressed in cells that controls complex transcriptional programs which are ligand and cell type specific, with CYPs as targeted genes. This review focuses on these important aspects of immune responses of the skin and respiratory tract cells, describing some in vitro models applied to evaluate the mechanisms involved in fragrance-induced allergy.
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Affiliation(s)
- M Macchione
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil.
| | - K Yoshizaki
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - D P Frias
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - K Maier
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - J Smelan
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - C M Prado
- Federal University of Sao Paulo, Santos, Brazil
| | - T Mauad
- Laboratory of Experimental Environmental Pathology, Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
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9
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Funch AB, Ahlström MG, Johansen JD, Geisler C, Bonefeld CM. Neutrophil infiltration in allergic contact dermatitis to nickel. Br J Dermatol 2024; 190:569-570. [PMID: 38175745 DOI: 10.1093/bjd/ljad499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/21/2023] [Accepted: 01/13/2024] [Indexed: 01/06/2024]
Abstract
Allergic contact dermatitis (ACD) is traditionally recognized as a T-cell-mediated delayed-type hypersensitivity reaction. However, many patients with ACD have been reported to experience rapid-onset ACD reactions within hours of re-exposure on skin areas previously exposed to the contact allergen. In this study, three nickel-allergic patients were patch tested for nickel twice at the same skin site over 21 days. The results demonstrated that neutrophils are rapidly recruited to the skin sites previously exposed to nickel, leading to the rapid onset of ACD. Considering that many patients with ACD are frequently re-exposed to contact allergens on the same skin areas in their daily lives, we propose that mechanisms involved in neutrophil recruitment could be potential targets for future ACD treatment.
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Affiliation(s)
- Anders B Funch
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
| | - Malin Glindvad Ahlström
- National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Jeanne D Johansen
- National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Carsten Geisler
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
| | - Charlotte M Bonefeld
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
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Ono E, Lenief V, Lefevre MA, Cuzin R, Guironnet-Paquet A, Mosnier A, Nosbaum A, Nicolas JF, Vocanson M. Topical corticosteroids inhibit allergic skin inflammation but are ineffective in impeding the formation and expansion of resident memory T cells. Allergy 2024; 79:52-64. [PMID: 37539746 DOI: 10.1111/all.15819] [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: 11/28/2022] [Revised: 04/28/2023] [Accepted: 05/23/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND Tissue-resident memory T (TRM ) cells are detrimental in allergic contact dermatitis (ACD), in which they contribute to the chronicity and severity of the disease. METHODS We assessed the impact of a standard topical corticosteroid (TCS) treatment, triamcinolone acetonide (TA), on the formation, maintenance and reactivation of epidermal TRM cells in a preclinical model of ACD to 2,4-dinitrofluorobenzene. TA 0.01% was applied at different time points of ACD response and we monitored skin inflammation and tracked CD8+ CD69+ CD103+ TRM by flow cytometry and RNA sequencing. RESULTS The impact of TA on TRM formation depended on treatment regimen: (i) in a preventive mode, that is, in sensitized mice before challenge, TA transiently inhibited the infiltration of effector T cells and the accumulation of TRM upon hapten challenge. In contrast, (ii) in a curative mode, that is, at the peak of the ACD response, TA blocked skin inflammation but failed to prevent the formation of TRM . Finally, (iii) in a proactive mode, that is, on previous eczema lesions, TA had no effect on the survival of skin TRM , but transiently inhibited their reactivation program upon allergen reexposure. Indeed, specific TRM progressively regained proliferative functions upon TA discontinuation and expanded in the tissue, leading to exaggerated iterative responses. Interestingly, TRM re-expansion correlated with the decreased clearance of hapten moieties from the skin induced by repeated TA applications. CONCLUSIONS Our results demonstrate that TCS successfully treat ACD inflammation, but are mostly ineffective in impeding the formation and expansion of allergen-specific TRM , which certainly restricts the induction of lasting tolerance in patients with chronic dermatitis.
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Affiliation(s)
- Emi Ono
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Vanina Lenief
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Marine-Alexia Lefevre
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Roxane Cuzin
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Aurélie Guironnet-Paquet
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
- Etablissement Français du Sang (EFS) Auvergne Rhône-Alpes, Apheresis Unit, Hôpital Lyon Sud, Pierre Bénite, France
| | - Amandine Mosnier
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
| | - Audrey Nosbaum
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
- Allergology and Clinical Immunology Department, Lyon Sud University Hospital, Pierre Bénite, France
| | - Jean-Francois Nicolas
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
- Allergology and Clinical Immunology Department, Lyon Sud University Hospital, Pierre Bénite, France
| | - Marc Vocanson
- CIRI-Centre International de Recherche en Infectiologie, INSERM, U1111, Université Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, CNRS UMR 5308, Lyon, France
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11
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Mraz V, Funch AB, Jee MH, Gadsbøll ASØ, Weber JF, Yeung K, Lohmann RKD, Hawkes A, Ødum N, Woetmann A, McKay D, Witherden D, Geisler C, Bonefeld CM. CD100 boosts the inflammatory response in the challenge phase of allergic contact dermatitis in mice. Contact Dermatitis 2023; 89:442-452. [PMID: 37700557 DOI: 10.1111/cod.14414] [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: 06/24/2023] [Revised: 08/18/2023] [Accepted: 08/29/2023] [Indexed: 09/14/2023]
Abstract
BACKGROUND Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8+ T (TRM ) cells play a key role. The mechanisms involved in the activation of CD8+ TRM cells during allergic flare-up responses are not understood. METHODS The expression of CD100 and its ligand Plexin B2 on CD8+ TRM cells and keratinocytes before and after allergen exposure was determined by flow cytometry and RT-qPCR. The role of CD100 in the inflammatory response during the challenge phase of ACD was determined in a model of ACD in CD100 knockout and wild-type mice. RESULTS We show that CD8+ TRM cells express CD100 during homeostatic conditions and up-regulate it following re-exposure of allergen-experienced skin to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB). Furthermore, Plexin B2 is up-regulated on keratinocytes following exposure to some contact allergens. We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1β and decreased recruitment of neutrophils to the epidermis. CONCLUSION Our study demonstrates that CD100 is expressed on CD8+ TRM cells and is required for full activation of CD8+ TRM cells and the flare-up response of ACD.
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Affiliation(s)
- Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anders B Funch
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Allergy, National Allergy Research Center, Copenhagen University Hospital Gentofte, Hellerup, Denmark
| | - Mia H Jee
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anne-Sofie Ø Gadsbøll
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Julie F Weber
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Kelvin Yeung
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Allergy, National Allergy Research Center, Copenhagen University Hospital Gentofte, Hellerup, Denmark
| | - Rebecca K D Lohmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Alana Hawkes
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Niels Ødum
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anders Woetmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Dianne McKay
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Deborah Witherden
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
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12
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Pham JP, Wark KJL, Woods J, Frew JW. Resident cutaneous memory T cells: a clinical review of their role in chronic inflammatory dermatoses and potential as therapeutic targets. Br J Dermatol 2023; 189:656-663. [PMID: 37603832 DOI: 10.1093/bjd/ljad303] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 08/07/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023]
Abstract
Resident memory T cells (T-RMs) remain in epithelial barrier tissues after antigen exposure and the initial effector phase. These T-RMs provide effective antimicrobial and anticancer immunity; however, pathogenic T-RMs have been shown to mediate various chronic inflammatory disorders in a variety of tissue types. In the skin, T-RMs are referred to as resident cutaneous memory T cells (cT-RMs). Understanding the mechanisms leading to the development and establishment of these cT-RMs populations may allow for targeted treatments that provide durable responses in chronic immune-mediated skin diseases, even after cessation. In this review, we summarize the evidence on cT-RMs as drivers of chronic inflammatory dermatoses, including psoriasis, vitiligo, atopic dermatitis, cutaneous lupus erythematosus and alopecia areata, among others. Data from in vitro, animal model and ex vivo human studies are presented, with a focus on the potential for cT-RMs to trigger acute disease flares, as well as recurrent disease, by establishing an immune 'memory' in the skin. Furthermore, the available data on the potential for existing and novel treatments to affect the development or survival of cT-RMs in the skin are synthesized. The data suggest a dynamic and rapidly growing area in the field of dermatology; however, we also discuss areas in need of greater research to allow for optimal treatment selection for long-term disease control.
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Affiliation(s)
- James P Pham
- School of Clinical Medicine, UNSW Medicine and Health, Sydney, NSW, Australia
- Department of Dermatology, Liverpool Hospital, Liverpool, NSW, Australia
- Laboratory of Translational Cutaneous Medicine, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
| | - Kirsty J L Wark
- Department of Dermatology, Liverpool Hospital, Liverpool, NSW, Australia
| | - Jane Woods
- School of Clinical Medicine, UNSW Medicine and Health, Sydney, NSW, Australia
- Department of Dermatology, Liverpool Hospital, Liverpool, NSW, Australia
| | - John W Frew
- School of Clinical Medicine, UNSW Medicine and Health, Sydney, NSW, Australia
- Department of Dermatology, Liverpool Hospital, Liverpool, NSW, Australia
- Laboratory of Translational Cutaneous Medicine, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
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13
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Zheng C, Cao T, Ye C, Zou Y. Neutrophil recruitment by CD4 tissue-resident memory T cells induces chronic recurrent inflammation in atopic dermatitis. Clin Immunol 2023; 256:109805. [PMID: 37832861 DOI: 10.1016/j.clim.2023.109805] [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: 08/13/2023] [Revised: 09/18/2023] [Accepted: 10/07/2023] [Indexed: 10/15/2023]
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disease that continues to impose significant physical, mental, and economic burdens on patients. Recent research has suggested the significant role of tissue-resident memory (TRM) cells in AD. However, the precise role and mechanisms of action of TRM cells in AD remain unclear. A deeper understanding of the involvement of TRM cells in AD will unveil promising pathways for future innovative therapeutic strategies. METHODS To investigate the involvement of TRM cells in AD, we used diverse mouse models and employed experimental techniques to manipulate cell formation and depletion. We assessed the inflammatory response by analyzing mouse ear phenotype, measuring ear thickness, and performing hematoxylin and eosin staining. Flow cytometry and immunofluorescence staining were used to identify different cell types and evaluate changes in cell quantity. Additionally, we used qPCR to analyze gene expression of relevant chemokines and cytokines. RESULTS Our study revealed the presence of TRM cells in the skin after exposure to calcipotriol. After a 24-h re-challenge, we observed substantial neutrophil infiltration into the previously irritated skin. Neutrophil depletion prior to re-challenge effectively prevented early flare-up responses during AD recurrence. Furthermore, we demonstrate that CD4+TRM cells upregulate expression of cytokines INF-γ and TNF-α, which may induce the expression of CXCL1, thereby recruiting neutrophils and contributing to the chronic recurrent inflammation observed in AD. CONCLUSIONS We have established a novel, chronic recurrent mouse model for investigating TRM cells in AD. Our findings demonstrate that CD4+TRM cells in the skin mediate early flare-up response during AD recurrence and influence the chronic recurrent inflammation of AD by recruiting neutrophils. Targeting CD4+TRM cells may represent a promising approach for the treatment of chronic recurrent inflammation in AD.
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Affiliation(s)
- Chunjiao Zheng
- Skin and Cosmetic Research Department, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ting Cao
- Skin and Cosmetic Research Department, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chengbin Ye
- Skin and Cosmetic Research Department, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ying Zou
- Skin and Cosmetic Research Department, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China.
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14
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Mraz V, Lohmann RKD, Menzel M, Hawkes A, Vaher H, Funch AB, Jee MH, Gadsbøll ASØ, Weber JF, Yeung K, Ødum N, Woetmann A, McKay D, Witherden D, Geisler C, Bonefeld CM. The junctional adhesion molecule-like protein (JAML) is important for the inflammatory response during contact hypersensitivity. Contact Dermatitis 2023; 89:323-334. [PMID: 37619972 PMCID: PMC11034946 DOI: 10.1111/cod.14409] [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: 06/14/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND The junctional adhesion molecule-like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known. METHODS To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild-type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo. RESULTS JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8+ and CD4+ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1β (IL-1β) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8+ T cells express JAML and that JAML is essential for rapid flare-up responses to contact allergens. Finally, we show that keratinocytes up-regulate the JAML ligand CXADR following exposure to contact allergens. CONCLUSION Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans.
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Affiliation(s)
- Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Rebecca K. D. Lohmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Mandy Menzel
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark
| | - Alana Hawkes
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Helen Vaher
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anders B. Funch
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Allergy, National Allergy Research Center, Copenhagen University Hospital Gentofte, Hellerup, Denmark
| | - Mia H. Jee
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anne-Sofie Ø. Gadsbøll
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Julie F. Weber
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Kelvin Yeung
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Allergy, National Allergy Research Center, Copenhagen University Hospital Gentofte, Hellerup, Denmark
| | - Niels Ødum
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anders Woetmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Dianne McKay
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Deborah Witherden
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M. Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
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15
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Gatica-Ortega ME, Sanz-Sánchez T, Pastor-Nieto MA. Allergic contact dermatitis from hydroxyacetophenone in an anti-wrinkle facial serum with flare-up reactions triggered by the repeated open application test. Contact Dermatitis 2023; 88:407-409. [PMID: 36718024 DOI: 10.1111/cod.14284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023]
Affiliation(s)
- María E Gatica-Ortega
- Dermatology Department, Hospital Universitario de Toledo, Toledo, España, Spain.,Universidad de Castilla-La-Mancha, Ciudad Real, Spain
| | | | - María A Pastor-Nieto
- Universidad de Castilla-La-Mancha, Ciudad Real, Spain.,Dermatology Department, Hospital Universitario de Guadalajara, Guadalajara, Spain.,Facultad de Medicina y Ciencias de la Salud, Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Spain
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16
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Stănescu AMA, Cristea AMA, Bejan GC, Vieru M, Simionescu AA, Popescu FD. Allergic Contact Cell-Mediated Hypersensitivity in Psoriasis: A Narrative Minireview. Medicina (B Aires) 2022; 58:914. [PMID: 35888633 PMCID: PMC9324524 DOI: 10.3390/medicina58070914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 11/17/2022] Open
Abstract
The dysfunctionality of the protective skin barrier in psoriasis allows easier cutaneous penetration of various contact haptens; thus, such patients can develop allergic contact hypersensitivity as a comorbidity. Both skin conditions involve T-cell-mediated mechanisms. Dermatologists and allergists should consider assessing allergic contact cell-mediated hypersensitivity in selected psoriasis patients, especially those with palmoplantar psoriasis and who are refractory to topical treatments, and in patients with psoriasis, with or without arthritis, treated with biologics that present skin lesions clinically suggestive of contact dermatitis.
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Affiliation(s)
| | - Ana-Maria-Antoaneta Cristea
- Department of Allergology and Clinical Immunology, Nicolae Malaxa Clinical Hospital, 022441 Bucharest, Romania; (A.-M.-A.C.); (F.-D.P.)
| | - Gabriel Cristian Bejan
- Department of Family Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Mariana Vieru
- Department of Allergology and Clinical Immunology, Nicolae Malaxa Clinical Hospital, 022441 Bucharest, Romania; (A.-M.-A.C.); (F.-D.P.)
- Department of Allergology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Anca Angela Simionescu
- Department of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, 011132 Bucharest, Romania
| | - Florin-Dan Popescu
- Department of Allergology and Clinical Immunology, Nicolae Malaxa Clinical Hospital, 022441 Bucharest, Romania; (A.-M.-A.C.); (F.-D.P.)
- Department of Allergology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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17
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Goksøyr L, Funch AB, Okholm AK, Theander TG, de Jongh WA, Bonefeld CM, Sander AF. Preclinical Efficacy of a Capsid Virus-like Particle-Based Vaccine Targeting IL-1β for Treatment of Allergic Contact Dermatitis. Vaccines (Basel) 2022; 10:vaccines10050828. [PMID: 35632584 PMCID: PMC9143278 DOI: 10.3390/vaccines10050828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 02/05/2023] Open
Abstract
Hypersensitivity to a contact allergen is one of the most abundant forms of inflammatory skin disease. Today, more than 20% of the general population are sensitized to one or more contact allergens, making this disease an important healthcare issue, as re-exposure to the allergen can initiate the clinical disease termed allergic contact dermatitis (ACD). The current standard treatment using corticosteroids is effective, but it has side effects when used for longer periods. Therefore, there is a need for new alternative therapies for severe ACD. In this study, we used the versatile Tag/Catcher AP205 capsid virus-like particle (cVLP) vaccine platform to develop an IL-1β-targeted vaccine and to assess the immunogenicity and in vivo efficacy of the vaccine in a translational mouse model of ACD. We show that vaccination with cVLPs displaying full-length murine IL-1β elicits high titers of neutralizing antibodies, leading to a significant reduction in local IL-1β levels as well as clinical symptoms induced by treatment with 1-Fluoro-2,4-dinitrobenzene (DNFB). Moreover, we show that a single amino acid mutation in muIL-1β reduces the biological activity while maintaining the ability to induce neutralizing antibodies. Collectively, the data suggest that a cVLP-based vaccine displaying full-length IL-1β represents a promising vaccine candidate for use as an alternative treatment modality against severe ACD.
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Affiliation(s)
- Louise Goksøyr
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
- AdaptVac Aps, 2200 Copenhagen, Denmark;
| | - Anders B. Funch
- LEO Foundation Skin Immunology Research Center, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (A.B.F.); (C.M.B.)
| | - Anna K. Okholm
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
| | - Thor G. Theander
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
| | | | - Charlotte M. Bonefeld
- LEO Foundation Skin Immunology Research Center, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (A.B.F.); (C.M.B.)
| | - Adam F. Sander
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
- AdaptVac Aps, 2200 Copenhagen, Denmark;
- Correspondence:
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18
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Johansen JD, Bonefeld CM, Schwensen JFB, Thyssen JP, Uter W. Novel insights into contact dermatitis. J Allergy Clin Immunol 2022; 149:1162-1171. [PMID: 35183605 DOI: 10.1016/j.jaci.2022.02.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 11/30/2022]
Abstract
Contact dermatitis is a common disease, caused by repeated skin contact to contact allergens or irritants, resulting in allergic contact dermatitis (ACD) and/or irritant contact dermatitis. Attempts have been made to identify biomarkers to distinguish irritant and allergic patch test reactions, which could aid diagnosis. Some promising candidates have recently been identified, but verification and validation in clinical cases still need to be done. New causes of ACD are constantly recognized. In this review, 10 new contact allergens from recent years, were identified, several relating to anti-age products. Frequent allergens causing considerable morbidity in the population such as the preservative methylisothiazolinone (MI) have been regulated in EU. A significant drop in cases has been seen, while high rates are still occurring in other areas such as North America. Other frequent causes are fragrance allergens especially widely used terpenes and acrylates used in medical devises for control of diabetes. These represent unsolved problems. Recent advances in immunology have opened for a better understanding of the complexity of contact dermatitis, especially ACD. The disease may be more heterogenous that previous understood with several subtypes. With the rapidly evolving molecular understanding of the disease, the potential for development of new drugs for personalized treatment of contact dermatitis is considerable.
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Affiliation(s)
- J D Johansen
- National Allergy Research Centre, Department of Skin and Allergy. Gentofte Hospital University of Copenhagen, 2900 Hellerup, Denmark.
| | - C M Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology & Microbiology, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - J F B Schwensen
- National Allergy Research Centre, Department of Skin and Allergy. Gentofte Hospital University of Copenhagen, 2900 Hellerup, Denmark
| | - J P Thyssen
- National Allergy Research Centre, Department of Skin and Allergy. Gentofte Hospital University of Copenhagen, 2900 Hellerup, Denmark
| | - W Uter
- Dept. of Medical Informatics, Biometry and Epidemiology, Univ. Erlangen / Nürnberg; Waldstr. 6 91054 Erlangen, GERMANY
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Funch AB, Mraz V, Gadsbøll AØ, Jee MH, Weber JF, Ødum N, Woetmann A, Johansen JD, Geisler C, Bonefeld CM. CD8 + tissue-resident memory T cells recruit neutrophils that are essential for flare-ups in contact dermatitis. Allergy 2022; 77:513-524. [PMID: 34169536 DOI: 10.1111/all.14986] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/10/2021] [Accepted: 05/24/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Allergic contact dermatitis (ACD) is classically described as a delayed-type hypersensitivity reaction. However, patients often experience flare-ups characterized by itching erythema, edema, and often vesicles occurring within hours after re-exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin-resident memory T (TRM ) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen-induced flare-ups is not known. METHODS By the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare-up reactions to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene. The inflammatory response was measured by changes in ear thickness, and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils, and CXCL1/CXCL2 in the response. RESULTS We show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 h after re-exposure to the contact allergen. Depletion of neutrophils before re-exposure to the allergen abrogated the flare-up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C-X-C chemokine receptor type 1 and 2 inhibits flare-up reactions and neutrophil infiltration. CONCLUSION As the first, we show that epidermal CD8+ TRM cells cause ACD flare-ups by rapid recruitment of neutrophils to the epidermis.
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Affiliation(s)
- Anders B. Funch
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
- Department of Dermatology and Allergy National Allergy Research Center Copenhagen University Hospital Gentofte Hellerup Denmark
| | - Veronika Mraz
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
| | - Anne‐Sofie Ø. Gadsbøll
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
| | - Mia H. Jee
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
- Department of Dermatology and Allergy National Allergy Research Center Copenhagen University Hospital Gentofte Hellerup Denmark
| | - Julie F. Weber
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
| | - Niels Ødum
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
| | - Anders Woetmann
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
| | - Jeanne D. Johansen
- Department of Dermatology and Allergy National Allergy Research Center Copenhagen University Hospital Gentofte Hellerup Denmark
| | - Carsten Geisler
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
| | - Charlotte M. Bonefeld
- Department of Immunology and Microbiology Faculty of Health and Medical Sciences The LEO Foundation Skin Immunology Research Center University of Copenhagen Copenhagen Denmark
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Wu Y, Wang GJ, He HQ, Qin HH, Shen WT, Yu Y, Zhang X, Zhou ML, Fei JB. Low-dose intralesional injection of 5-fluorouracil and triamcinolone reduces tissue resident memory T cells in chronic eczema. World J Clin Cases 2022; 10:166-176. [PMID: 35071516 PMCID: PMC8727240 DOI: 10.12998/wjcc.v10.i1.166] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 10/29/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tissue resident memory T (TRM) cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.
AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil (5-FU) and triamcinolone (TA) with those associated with TA alone for the treatment of chronic eczema.
METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only. Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes. All patients were followed up monthly for up to 1 year.
RESULTS No serious adverse event was observed in either group. Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment, the relapse rate was significantly lower in the 5-FU+TA group than in the TA group. Histological examination showed significantly fewer CD8+ and CD103+ T cells but not CD4+ T cells in the 5-FU+TA group.
CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of TRM cells in the lesional skin and the relapse rate of chronic eczema.
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Affiliation(s)
- Yun Wu
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Guo-Jiang Wang
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Hui-Qiong He
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Hai-Hong Qin
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Wen-Tong Shen
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Yue Yu
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Xun Zhang
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Mao-Lin Zhou
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Jian-Biao Fei
- Department of Dermatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
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21
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Aparicio-Soto M, Curato C, Riedel F, Thierse HJ, Luch A, Siewert K. In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals-A Systematic Review. Cells 2021; 11:cells11010083. [PMID: 35011644 PMCID: PMC8750770 DOI: 10.3390/cells11010083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Chemical allergies are T cell-mediated diseases that often manifest in the skin as allergic contact dermatitis (ACD). To prevent ACD on a public health scale and avoid elicitation reactions at the individual patient level, predictive and diagnostic tests, respectively, are indispensable. Currently, there is no validated in vitro T cell assay available. The main bottlenecks concern the inefficient generation of T cell epitopes and the detection of rare antigen-specific T cells. Methods: Here, we systematically review original experimental research papers describing T cell activation to chemical skin sensitizers. We focus our search on studies published in the PubMed and Scopus databases on non-metallic allergens in the last 20 years. Results: We identified 37 papers, among them 32 (86%) describing antigen-specific human T cell activation to 31 different chemical allergens. The remaining studies measured the general effects of chemical allergens on T cell function (five studies, 14%). Most antigen-specific studies used peripheral blood mononuclear cells (PBMC) as antigen-presenting cells (APC, 75%) and interrogated the blood T cell pool (91%). Depending on the individual chemical properties, T cell epitopes were generated either by direct administration into the culture medium (72%), separate modification of autologous APC (29%) or by use of hapten-modified model proteins (13%). Read-outs were mainly based on proliferation (91%), often combined with cytokine secretion (53%). The analysis of T cell clones offers additional opportunities to elucidate the mechanisms of epitope formation and cross-reactivity (13%). The best researched allergen was p-phenylenediamine (PPD, 12 studies, 38%). For this and some other allergens, stronger immune responses were observed in some allergic patients (15/31 chemicals, 48%), illustrating the in vivo relevance of the identified T cells while detection limits remain challenging in many cases. Interpretation: Our results illustrate current hardships and possible solutions to monitoring T cell responses to individual chemical skin sensitizers. The provided data can guide the further development of T cell assays to unfold their full predictive and diagnostic potential, including cross-reactivity assessments.
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Affiliation(s)
- Marina Aparicio-Soto
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (F.R.); (H.-J.T.); (A.L.)
| | - Caterina Curato
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (F.R.); (H.-J.T.); (A.L.)
| | - Franziska Riedel
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (F.R.); (H.-J.T.); (A.L.)
- Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany
| | - Hermann-Josef Thierse
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (F.R.); (H.-J.T.); (A.L.)
| | - Andreas Luch
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (F.R.); (H.-J.T.); (A.L.)
- Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany
| | - Katherina Siewert
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (F.R.); (H.-J.T.); (A.L.)
- Correspondence: ; Tel.: +49-(0)30-18412-57001
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22
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Riedel F, Aparicio-Soto M, Curato C, Thierse HJ, Siewert K, Luch A. Immunological Mechanisms of Metal Allergies and the Nickel-Specific TCR-pMHC Interface. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:10867. [PMID: 34682608 PMCID: PMC8535423 DOI: 10.3390/ijerph182010867] [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] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/03/2021] [Accepted: 10/11/2021] [Indexed: 12/19/2022]
Abstract
Besides having physiological functions and general toxic effects, many metal ions can cause allergic reactions in humans. We here review the immune events involved in the mediation of metal allergies. We focus on nickel (Ni), cobalt (Co) and palladium (Pd), because these allergens are among the most prevalent sensitizers (Ni, Co) and immediate neighbors in the periodic table of the chemical elements. Co-sensitization between Ni and the other two metals is frequent while the knowledge on a possible immunological cross-reactivity using in vivo and in vitro approaches remains limited. At the center of an allergic reaction lies the capability of a metal allergen to form T cell epitopes that are recognized by specific T cell receptors (TCR). Technological advances such as activation-induced marker assays and TCR high-throughput sequencing recently provided new insights into the interaction of Ni2+ with the αβ TCR-peptide-major histocompatibility complex (pMHC) interface. Ni2+ functionally binds to the TCR gene segment TRAV9-2 or a histidine in the complementarity determining region 3 (CDR3), the main antigen binding region. Thus, we overview known, newly identified and hypothesized mechanisms of metal-specific T cell activation and discuss current knowledge on cross-reactivity.
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Affiliation(s)
- Franziska Riedel
- Department for Chemicals and Product Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (H.-J.T.); (K.S.); (A.L.)
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2, 14195 Berlin, Germany
| | - Marina Aparicio-Soto
- Department for Chemicals and Product Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (H.-J.T.); (K.S.); (A.L.)
| | - Caterina Curato
- Department for Chemicals and Product Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (H.-J.T.); (K.S.); (A.L.)
| | - Hermann-Josef Thierse
- Department for Chemicals and Product Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (H.-J.T.); (K.S.); (A.L.)
| | - Katherina Siewert
- Department for Chemicals and Product Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (H.-J.T.); (K.S.); (A.L.)
| | - Andreas Luch
- Department for Chemicals and Product Safety, Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, 10589 Berlin, Germany; (M.A.-S.); (C.C.); (H.-J.T.); (K.S.); (A.L.)
- Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2, 14195 Berlin, Germany
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23
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Rühl-Muth AC, Maler MD, Esser PR, Martin SF. Feeding of a fat-enriched diet causes the loss of resistance to contact hypersensitivity. Contact Dermatitis 2021; 85:398-406. [PMID: 34218443 DOI: 10.1111/cod.13927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/23/2021] [Accepted: 07/02/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Low-molecular weight chemicals or metal ions can cause allergic contact dermatitis, an inflammatory skin disease. Mice lacking Toll-like receptors 2 and 4 (TLR2/4 mice) are resistant to contact hypersensitivity (CHS). In the Western population obesity is increasing, which is known to have a proinflammatory impact. OBJECTIVES The aim of this study was to investigate the impact of a high-fat diet (HFD) on the sensitization and elicitation of CHS. We hypothesized that a proinflammatory micromilieu can be caused by an increase in adipose tissue, which might be sufficient to break the resistance of TLR2/4 mice. METHODS Four weeks prior to sensitization, wild-type (wt) or TLR2/4 mice were fed normal chow (NC), control diet (CD), or HFD. The effects on CHS and inflammation were analysed by measuring the ear swelling response, using flow cytometry and enzyme-linked immunosorbent assay. RESULTS The reaction of wt mice to 2,4,6-trinitro-1-chlorobenzene (TNCB) was increased by HFD. While NC-fed TLR2/4 mice were still resistant to CHS, HFD and, unexpectedly, CD feeding broke the resistance of TLR2/4 mice to TNCB. CONCLUSIONS These experiments suggest that the increased fat content or the different fatty acid composition of the diets increases inflammation and, therefore, the likelihood of developing CHS.
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Affiliation(s)
- Anne-Catherine Rühl-Muth
- Allergy Research Group, Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Mareike D Maler
- Allergy Research Group, Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Philipp R Esser
- Allergy Research Group, Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg
| | - Stefan F Martin
- Allergy Research Group, Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg
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24
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Emmanuel T, Mistegård J, Bregnhøj A, Johansen C, Iversen L. Tissue-Resident Memory T Cells in Skin Diseases: A Systematic Review. Int J Mol Sci 2021; 22:ijms22169004. [PMID: 34445713 PMCID: PMC8396505 DOI: 10.3390/ijms22169004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/09/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
In health, the non-recirculating nature and long-term persistence of tissue-resident memory T cells (TRMs) in tissues protects against invading pathogens. In disease, pathogenic TRMs contribute to the recurring traits of many skin diseases. We aimed to conduct a systematic literature review on the current understanding of the role of TRMs in skin diseases and identify gaps as well as future research paths. EMBASE, PubMed, SCOPUS, Web of Science, Clinicaltrials.gov and WHO Trials Registry were searched systematically for relevant studies from their inception to October 2020. Included studies were reviewed independently by two authors. This study was conducted in accordance with the PRISMA-S guidelines. This protocol was registered with the PROSPERO database (ref: CRD42020206416). We identified 96 studies meeting the inclusion criteria. TRMs have mostly been investigated in murine skin and in relation to infectious skin diseases. Pathogenic TRMs have been characterized in various skin diseases including psoriasis, vitiligo and cutaneous T-cell lymphoma. Studies are needed to discover biomarkers that may delineate TRMs poised for pathogenic activity in skin diseases and establish to which extent TRMs are contingent on the local skin microenvironment. Additionally, future studies may investigate the effects of current treatments on the persistence of pathogenic TRMs in human skin.
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25
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Lefevre MA, Vocanson M, Nosbaum A. Role of tissue-resident memory T cells in the pathophysiology of allergic contact dermatitis. Curr Opin Allergy Clin Immunol 2021; 21:355-360. [PMID: 34155157 DOI: 10.1097/aci.0000000000000763] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW We bring updated knowledge on tissue-resident memory T cells (TRM), underlining their major role in the recurrence and the severity of allergic contact dermatitis (ACD). RECENT FINDINGS ACD is a frequently encountered skin disease. It is defined as a delayed-type hypersensitivity reaction initiated by the recruitment of antigen-specific T cells into the skin of sensitized patients. ACD lesions tend to develop on already-exposed areas and worsen over time. That clinical observation has raised questions on the contribution of TRM to ACD recurrence and severity. TRM are memory T cells that persist in peripheral tissues, such as the skin, without recirculating through the blood. These cells provide effective immune memory against pathogens, but they may also participate in the development or exacerbation of numerous inflammatory diseases, including skin allergies. Recent works have demonstrated a major role for TRM in ACD pathophysiology. SUMMARY In ACD, TRM accumulate preferentially at the allergen contact site during the sensitization phase. Thereafter, these cells cause a rapid and intense response to any new allergen exposure. They also play a key role in flare-ups of ACD and the chronicity and severity of the disease. These aspects suggest that TRM may have an interest as therapeutic targets.
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Affiliation(s)
- Marine-Alexia Lefevre
- CIRI, Centre International de Recherche en Infectiologie (Team Epidermal Immunity and Allergy), INSERM, U1111, Univ Lyon, Université de Lyon 1, Ecole Normale Supérieure de Lyon, CNRS, UMR 5308, Lyon
| | - Marc Vocanson
- CIRI, Centre International de Recherche en Infectiologie (Team Epidermal Immunity and Allergy), INSERM, U1111, Univ Lyon, Université de Lyon 1, Ecole Normale Supérieure de Lyon, CNRS, UMR 5308, Lyon
| | - Audrey Nosbaum
- CIRI, Centre International de Recherche en Infectiologie (Team Epidermal Immunity and Allergy), INSERM, U1111, Univ Lyon, Université de Lyon 1, Ecole Normale Supérieure de Lyon, CNRS, UMR 5308, Lyon
- Université de Lyon, Centre Hospitalier Lyon-Sud, Service d'Allergologie et d'Immunologie Clinique, Pierre-Benite, France
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26
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Yeung K, Mraz V, Geisler C, Skov L, Bonefeld CM. The role of interleukin-1β in the immune response to contact allergens. Contact Dermatitis 2021; 85:387-397. [PMID: 34324721 DOI: 10.1111/cod.13955] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/22/2021] [Accepted: 07/28/2021] [Indexed: 12/29/2022]
Abstract
Interleukin-1β (IL-1β) is an important pro-inflammatory cytokine that has an effect on almost every cell lineage in the body. By blocking IL-1β and investigating the IL-1β signaling pathway, several studies have demonstrated a central role of IL-1β in the response to contact allergens. This review summarizes the current literature regarding the basic immunological mechanisms mediated by IL-1β in the different phases of allergic contact dermatitis (ACD) and highlights potential IL-1β-targeted treatment options, which in the future may be relevant in the treatment of patients with ACD. This review is based primarily on studies using various mouse models and human in vitro studies, since clinical studies on the effect of IL-1β in ACD are lacking.
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Affiliation(s)
- Kelvin Yeung
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Dermatology and Allergy, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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27
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Scheinman PL, Vocanson M, Thyssen JP, Johansen JD, Nixon RL, Dear K, Botto NC, Morot J, Goldminz AM. Contact dermatitis. Nat Rev Dis Primers 2021; 7:38. [PMID: 34045488 DOI: 10.1038/s41572-021-00271-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 02/04/2023]
Abstract
Contact dermatitis (CD) is among the most common inflammatory dermatological conditions and includes allergic CD, photoallergic CD, irritant CD, photoirritant CD (also called phototoxic CD) and protein CD. Occupational CD can be of any type and is the most prevalent occupational skin disease. Each CD type is characterized by different immunological mechanisms and/or requisite exposures. Clinical manifestations of CD vary widely and multiple subtypes may occur simultaneously. The diagnosis relies on clinical presentation, thorough exposure assessment and evaluation with techniques such as patch testing and skin-prick testing. Management is based on patient education, avoidance strategies of specific substances, and topical treatments; in severe or recalcitrant cases, which can negatively affect the quality of life of patients, systemic medications may be needed.
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Affiliation(s)
- Pamela L Scheinman
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA
| | - Marc Vocanson
- CIRI - Centre International de Recherche en Infectiologie, INSERM, U1111; Univ Lyon; Université Claude Bernard Lyon 1; Ecole Normale Supérieure de Lyon; CNRS, UMR, 5308, Lyon, France
| | - Jacob P Thyssen
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jeanne Duus Johansen
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Rosemary L Nixon
- Skin Health Institute - Occupational Dermatology Research and Education Centre, Carlton, VIC, Australia
| | - Kate Dear
- Skin Health Institute - Occupational Dermatology Research and Education Centre, Carlton, VIC, Australia
| | - Nina C Botto
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Johanna Morot
- CIRI - Centre International de Recherche en Infectiologie, INSERM, U1111; Univ Lyon; Université Claude Bernard Lyon 1; Ecole Normale Supérieure de Lyon; CNRS, UMR, 5308, Lyon, France
| | - Ari M Goldminz
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.
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Weiß KT, Schreiver I, Siewert K, Luch A, Haslböck B, Berneburg M, Bäumler W. Tattoos – mehr als nur kolorierte Haut? Auf der Suche nach Tattoo‐Allergenen. J Dtsch Dermatol Ges 2021; 19:657-671. [PMID: 33979044 DOI: 10.1111/ddg.14436_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/14/2020] [Indexed: 11/30/2022]
Affiliation(s)
- Katharina T Weiß
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Regensburg
| | - Ines Schreiver
- Abteilung Chemikalien- und Produktsicherheit, Bundesinstitut für Risikobewertung (BfR), Berlin
| | - Katherina Siewert
- Abteilung Chemikalien- und Produktsicherheit, Bundesinstitut für Risikobewertung (BfR), Berlin
| | - Andreas Luch
- Abteilung Chemikalien- und Produktsicherheit, Bundesinstitut für Risikobewertung (BfR), Berlin
| | - Birgit Haslböck
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Regensburg
| | - Mark Berneburg
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Regensburg
| | - Wolfgang Bäumler
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Regensburg
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29
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Weiß KT, Schreiver I, Siewert K, Luch A, Haslböck B, Berneburg M, Bäumler W. Tattoos - more than just colored skin? Searching for tattoo allergens. J Dtsch Dermatol Ges 2021; 19:657-669. [PMID: 33955682 DOI: 10.1111/ddg.14436] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022]
Abstract
During tattooing, a high amount of ink is injected into the skin. Tattoo inks contain numerous substances such as the coloring pigments, impurities, solvents, emulsifiers, and preservatives. Black amorphous carbon particles (carbon black), white titanium dioxide, azo or polycyclic pigments create all varieties of color shades in the visible spectrum. Some ingredients of tattoo inks might be hazardous and allergenic chemicals of unknown potential. In Germany, about 20 % of the general population is tattooed and related adverse reactions are increasingly reported. Since tattoo needles inevitably harm the skin, microorganisms can enter the wound and may cause infections. Non-allergic inflammatory reactions (for example cutaneous granuloma and pseudolymphoma) as well as allergic reactions may emerge during or after wound healing. Especially with allergies occurring after weeks, months or years, it remains difficult to identify the specific ingredient(s) that trigger the reaction. This review summarizes possible adverse effects related to tattooing with a focus on the development of tattoo-mediated allergies. To date, relevant allergens were only identified in rare cases. Here we present established methods and discuss current experimental approaches to identify culprit allergens in tattoo inks - via testing of the patient and in vitro approaches.
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Affiliation(s)
- Katharina T Weiß
- Department of Dermatology and Allergology, University of Regensburg, Regensburg, Germany
| | - Ines Schreiver
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Katherina Siewert
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Andreas Luch
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Birgit Haslböck
- Department of Dermatology and Allergology, University of Regensburg, Regensburg, Germany
| | - Mark Berneburg
- Department of Dermatology and Allergology, University of Regensburg, Regensburg, Germany
| | - Wolfgang Bäumler
- Department of Dermatology and Allergology, University of Regensburg, Regensburg, Germany
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Mora-Buch R, Bromley SK. Discipline in Stages: Regulating CD8 + Resident Memory T Cells. Front Immunol 2021; 11:624199. [PMID: 33815352 PMCID: PMC8017121 DOI: 10.3389/fimmu.2020.624199] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Resident memory CD8+ T (TRM) cells are a lymphocyte lineage distinct from circulating memory CD8+ T cells. TRM lodge within peripheral tissues and secondary lymphoid organs where they provide rapid, local protection from pathogens and control tumor growth. However, dysregulation of CD8+ TRM formation and/or activation may contribute to the pathogenesis of autoimmune diseases. Intrinsic mechanisms, including transcriptional networks and inhibitory checkpoint receptors control TRM differentiation and response. Additionally, extrinsic stimuli such as cytokines, cognate antigen, fatty acids, and damage signals regulate TRM formation, maintenance, and expansion. In this review, we will summarize knowledge of CD8+ TRM generation and highlight mechanisms that regulate the persistence and responses of heterogeneous TRM populations in different tissues and distinct microenvironments.
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Affiliation(s)
- Rut Mora-Buch
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Shannon K Bromley
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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Wisgrill L, Werner P, Jalonen E, Berger A, Lauerma A, Alenius H, Fyhrquist N. Integrative transcriptome analysis deciphers mechanisms of nickel contact dermatitis. Allergy 2021; 76:804-815. [PMID: 32706929 PMCID: PMC7984291 DOI: 10.1111/all.14519] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 05/29/2020] [Accepted: 06/08/2020] [Indexed: 01/02/2023]
Abstract
Background Nickel‐induced allergic contact dermatitis (nACD) remains a major occupational skin disorder, significantly impacting the quality of life of suffering patients. Complex cellular compositional changes and associated immunological pathways are partly resolved in humans; thus, the impact of nACD on human skin needs to be further elucidated. Methods To decipher involved immunological players and pathways, human skin biopsies were taken at 0, 2, 48, and 96 hours after nickel patch test in six nickel‐allergic patients. Gene expression profiles were analyzed via microarray. Results Leukocyte deconvolution of nACD‐affected skin identified major leukocyte compositional changes at 48 and 96 hours, including natural killer (NK) cells, macrophage polarization, and T‐cell immunity. Gene set enrichment analysis mirrored cellular‐linked functional pathways enriched over time. NK cell infiltration and cytotoxic pathways were uniquely found in nACD‐affected skin compared to sodium lauryl sulfate–induced irritant skin reactions. Conclusion These results highlight key immunological leukocyte subsets as well as associated pathways in nACD, providing insights into pathophysiology with the potential to unravel novel therapeutic targets.
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Affiliation(s)
- Lukas Wisgrill
- Division of Neonatology Pediatric Intensive Care and Neuropediatrics Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria
- Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
| | - Paulina Werner
- Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
| | - Erja Jalonen
- Skin and Allergy Hospital Helsinki University Hospital Helsinki Finland
| | - Angelika Berger
- Division of Neonatology Pediatric Intensive Care and Neuropediatrics Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria
| | - Antti Lauerma
- Skin and Allergy Hospital Helsinki University Hospital Helsinki Finland
| | - Harri Alenius
- Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
- Human Microbiome Program (HUMI) MedicumUniversity of Helsinki Helsinki Finland
| | - Nanna Fyhrquist
- Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
- Human Microbiome Program (HUMI) MedicumUniversity of Helsinki Helsinki Finland
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Contact Allergy to Fragrances. Contact Dermatitis 2021. [DOI: 10.1007/978-3-030-36335-2_86] [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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Aparicio‐Soto M, Riedel F, Leddermann M, Bacher P, Scheffold A, Kuhl H, Timmermann B, Chudakov DM, Molin S, Worm M, Heine G, Thierse H, Luch A, Siewert K. TCRs with segment TRAV9-2 or a CDR3 histidine are overrepresented among nickel-specific CD4+ T cells. Allergy 2020; 75:2574-2586. [PMID: 32298488 DOI: 10.1111/all.14322] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 03/24/2020] [Accepted: 03/31/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Nickel is the most frequent cause of T cell-mediated allergic contact dermatitis worldwide. In vitro, CD4+ T cells from all donors respond to nickel but the involved αβ T cell receptor (TCR) repertoire has not been comprehensively analyzed. METHODS We introduce CD154 (CD40L) upregulation as a fast, unbiased, and quantitative method to detect nickel-specific CD4+ T cells ex vivo in blood of clinically characterized allergic and non allergic donors. Naïve (CCR7+ CD45RA+) and memory (not naïve) CD154+ CD4+ T cells were analyzed by flow cytometry after 5 hours of stimulation with 200 µmol/L NiSO4 ., TCR α- and β-chains of sorted nickel-specific and control cells were studied by high-throughput sequencing. RESULTS Stimulation of PBMCs with NiSO4 induced CD154 expression on ~0.1% (mean) of naïve and memory CD4+ T cells. In allergic donors with recent positive patch test, memory frequencies further increased ~13-fold and were associated with markers of in vivo activation. CD154 expression was TCR-mediated since single clones could be specifically restimulated. Among nickel-specific CD4+ T cells of allergic and non allergic donors, TCRs expressing the α-chain segment TRAV9-2 or a histidine in their α- or β-chain complementarity determining region 3 (CDR3) were highly overrepresented. CONCLUSIONS Induced CD154 expression represents a reliable method to study nickel-specific CD4+ T cells. TCRs with particular features respond in all donors, while strongly increased blood frequencies indicate nickel allergy for some donors. Our approach may be extended to other contact allergens for the further development of diagnostic and predictive in vitro tests.
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Affiliation(s)
- Marina Aparicio‐Soto
- Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany
| | - Franziska Riedel
- Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany
| | - Melanie Leddermann
- Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany
| | - Petra Bacher
- Institute of Immunology Christian‐Albrechts Universität zu Kiel and Universitätsklinik Schleswig‐Holstein Kiel Germany
- Institute of Clinical Molecular Biology Christian‐Albrechts Universität zu Kiel Kiel Germany
| | - Alexander Scheffold
- Institute of Immunology Christian‐Albrechts Universität zu Kiel and Universitätsklinik Schleswig‐Holstein Kiel Germany
| | - Heiner Kuhl
- Sequencing Core Facility Max‐Planck‐Institute of Molecular Genetics Berlin Germany
| | - Bernd Timmermann
- Sequencing Core Facility Max‐Planck‐Institute of Molecular Genetics Berlin Germany
| | - Dmitriy M. Chudakov
- Genomics of Adaptive Immunity Department Shemyakin‐Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Science Moscow Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine Pirogov Russian National Research Medical University Moscow Russia
- Center of Molecular Medicine CEITEC Masaryk University Brno Czech Republic
| | - Sonja Molin
- Division of Dermatology Queen's University Kingston ON Canada
- Department of Dermatology and Allergy Ludwig Maximilian University Munich Germany
| | - Margitta Worm
- Division of Allergy and Immunology Department of Dermatology, Venerology, and Allergy Charité – Universitätsmedizin Berlin Berlin Germany
| | - Guido Heine
- Division of Allergy and Immunology Department of Dermatology, Venerology, and Allergy Charité – Universitätsmedizin Berlin Berlin Germany
- Department of Dermatology and Allergy University Hospital Schleswig‐Holstein Kiel Germany
| | - Hermann‐Josef Thierse
- Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany
| | - Andreas Luch
- Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany
| | - Katherina Siewert
- Department of Chemical and Product Safety German Federal Institute for Risk Assessment Berlin Germany
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Kato M, Oiso N, Yanagihara S, Kawada A. Long‐lasting allergic patch test reactions to dental metal allergens in a patient with palmoplantar pustulosis and pustulotic arthro‐osteitis. J Dermatol 2020; 47:e324-e325. [DOI: 10.1111/1346-8138.15471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Maiko Kato
- Department of Dermatology Kindai University Faculty of Medicine Osaka Japan
| | - Naoki Oiso
- Department of Dermatology Kindai University Faculty of Medicine Osaka Japan
| | - Shigeto Yanagihara
- Department of Dermatology Kindai University Faculty of Medicine Osaka Japan
| | - Akira Kawada
- Department of Dermatology Kindai University Faculty of Medicine Osaka Japan
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Jee MH, Mraz V, Geisler C, Bonefeld CM. γδ T cells and inflammatory skin diseases. Immunol Rev 2020; 298:61-73. [DOI: 10.1111/imr.12913] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/07/2020] [Accepted: 07/15/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Mia Hamilton Jee
- The LEO Foundation Skin Immunology Research Center Department of Immunology and Microbiology Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Veronika Mraz
- The LEO Foundation Skin Immunology Research Center Department of Immunology and Microbiology Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center Department of Immunology and Microbiology Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Charlotte Menné Bonefeld
- The LEO Foundation Skin Immunology Research Center Department of Immunology and Microbiology Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
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Caldarola G, Pirro F, Di Stefani A, Talamonti M, Galluzzo M, D'Adamio S, Magnano M, Bernardini N, Malagoli P, Bardazzi F, Potenza C, Bianchi L, Peris K, De Simone C. Clinical and histopathological characterization of eczematous eruptions occurring in course of anti IL-17 treatment: a case series and review of the literature. Expert Opin Biol Ther 2020; 20:665-672. [PMID: 32045273 DOI: 10.1080/14712598.2020.1727439] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 02/05/2020] [Indexed: 02/07/2023]
Abstract
Background: Real-life data often highlight the side effects of certain drugs not previously reported in randomized controlled trials (RCTs).Objective: To describe cutaneous inflammatory eruptions in psoriatic patients treated with an anti IL-17A agent (secukinumab or ixekizumab).Methods: Retrospective analysis of a cohort of patients with chronic plaque psoriasis who started an anti IL-17A agent between September 2016-February 2019 and who developed cutaneous inflammatory eruptions during treatment. A systematic review of similar events reported in the literature was performed.Results: Data of 468 patients were reviewed and 27 cutaneous inflammatory eruptions of 27 (5.8%) patients were collected. The eruptions appeared after a mean of 16.9 ± 17.0 weeks of therapy showing a classical acute eczema in 11 patients (40.7%), an atopic dermatitis-like rash in 11 patients (40.7%) and a psoriasiform eruption in 5 patients (18.5%). Histopathology of 12/27 cases showed epidermal spongiosis in all these variants.Conclusion: We described the clinic-pathologic features of some eczematous eruptions occurring in psoriatic patients, 3-4 months after treatment initiation with an anti IL-17A agent. Further investigations are needed to explain this phenomenon, that might be defined a paradoxical adverse event, based upon the role of IL17 in eczema pathogenesis.
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Affiliation(s)
- G Caldarola
- Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - F Pirro
- Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - A Di Stefani
- Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - M Talamonti
- Dermatology Unit, University of Rome "Tor Vergata", Rome, Italy
| | - M Galluzzo
- Dermatology Unit, University of Rome "Tor Vergata", Rome, Italy
| | - S D'Adamio
- Dermatology Unit, University of Rome "Tor Vergata", Rome, Italy
| | - M Magnano
- Division of Dermatology, Department of Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy
| | - N Bernardini
- Dermatology Unit, Sapienza University of Rome, Polo Pontino, Terracina, Italy
| | - P Malagoli
- Dermatology Unit, Azienda Ospedaliera San Donato Milanese, Milan, Italy
| | - F Bardazzi
- Division of Dermatology, Department of Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy
| | - C Potenza
- Dermatology Unit, Sapienza University of Rome, Polo Pontino, Terracina, Italy
| | - L Bianchi
- Dermatology Unit, University of Rome "Tor Vergata", Rome, Italy
| | - K Peris
- Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - C De Simone
- Institute of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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Murata A, Hayashi SI. CD4 + Resident Memory T Cells Mediate Long-Term Local Skin Immune Memory of Contact Hypersensitivity in BALB/c Mice. Front Immunol 2020; 11:775. [PMID: 32508808 PMCID: PMC7248184 DOI: 10.3389/fimmu.2020.00775] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/06/2020] [Indexed: 12/23/2022] Open
Abstract
In allergic contact dermatitis (ACD) and contact hypersensitivity (CHS), the healed skin shows greater swelling than the naïve skin in the same individual upon re-exposure to the same hapten. This “local skin memory” (LSM) in healed skin was maintained for a prolonged period of time and mediated by skin CD8+-resident memory T (TRM) cells in C57BL/6 mice. However, the number of CD4+ T cells is elevated in ACD-healed human skin, and the contribution of CD4+ TRM cells to the formation of LSM currently remains unclear. We herein demonstrated that immediately after CHS subsided, the healed skin in BALB/c mice showed an accumulation of hapten-specific CD4+ and CD8+ TRM cells, with a predominance of CD4+ TRM cells. The presence of CD4+ or CD8+ TRM cells in the healed skin was sufficient for the induction of a flare-up reaction upon a re-challenge. The CD4+ and CD8+ TRM cells both produced interferon-γ and tumor necrosis factor early after the re-challenge. Moreover, while CD8+ TRM cells gradually decreased over time and were eventually lost from the healed skin at 40–51 weeks after the resolution of CHS, the CD4+ TRM cell numbers remained elevated during this period. The present results indicate that the long-term maintenance of LSM is mediated by CD4+ TRM cells, and thus CD4+ TRM cells are an important target for the treatment of recurrent human ACD.
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Affiliation(s)
- Akihiko Murata
- Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Shin-Ichi Hayashi
- Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Japan
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Mraz V, Geisler C, Bonefeld CM. Dendritic Epidermal T Cells in Allergic Contact Dermatitis. Front Immunol 2020; 11:874. [PMID: 32508820 PMCID: PMC7248261 DOI: 10.3389/fimmu.2020.00874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/16/2020] [Indexed: 01/25/2023] Open
Abstract
Allergic contact dermatitis (ACD) is a common inflammatory skin disease with a prevalence of approximately 20% in the European population. ACD is caused by contact allergens that are reactive chemicals able to modify non-immunogenic self-proteins to become immunogenic proteins. The most frequent contact allergens are metals, fragrances, and preservatives. ACD clinically manifests as pruritic eczematous lesions, erythema, local papules, and oedema. ACD is a T cell-mediated disease, involving both CD4+ and CD8+ T cells. In addition, γδ T cells appear to play an important role in the immune response to contact allergens. However, it is debated whether γδ T cells act in a pro- or anti-inflammatory manner. A special subset of γδ T cells, named dendritic epidermal T cells (DETC), is found in the epidermis of mice and it plays an important role in immunosurveillance of the skin. DETC are essential in sensing the contact allergen-induced stressed environment. Thus, allergen-induced activation of DETC is partly mediated by numerous allergen-induced stress proteins expressed on the keratinocytes (KC). Several stress proteins, like mouse UL-16-binding protein-like transcript 1 (Mult-1), histocompatibility 60 (H60) and retinoic acid early inducible-1 (Rae-1) α-ε family in mice and major histocompatibility complex (MHC) class I-chain-related A (MICA) in humans, are upregulated on allergen-exposed KC. Allergen-induced stress proteins expressed on the KC are consequently recognized by NKG2D receptor on DETC. This review focuses on the role of γδ T cells in ACD, with DETC in the spotlight, and on the role of stress proteins in contact allergen-induced activation of DETC.
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Affiliation(s)
- Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte Menné Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Gadsbøll ASØ, Jee MH, Funch AB, Alhede M, Mraz V, Weber JF, Callender LA, Carroll EC, Bjarnsholt T, Woetmann A, Ødum N, Thomsen AR, Johansen JD, Henson SM, Geisler C, Bonefeld CM. Pathogenic CD8+ Epidermis-Resident Memory T Cells Displace Dendritic Epidermal T Cells in Allergic Dermatitis. J Invest Dermatol 2020; 140:806-815.e5. [DOI: 10.1016/j.jid.2019.07.722] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/12/2019] [Accepted: 07/16/2019] [Indexed: 12/19/2022]
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Abstract
BACKGROUND While the pathogenesis of contact allergy in recent years has increasingly focused on the mechanisms of the innate immune response, valid therapeutic options are still lacking. AIMS This article intends to shed light on the background of contact allergy development as well as possible risk factors and to highlight potential new therapeutic options. MATERIALS AND METHODS Allergic contact dermatitis (ACD) as well as the sensitization and trigger phase, potential risk factors as well as the therapy options including (current) PubMed-listed literature are described. RESULTS Inflammation plays a central role in ACD. The innate immune system responds to contact allergens as well as to infection. Elucidation of the mechanisms will enable a targeted therapeutic intervention in the future. CONCLUSION Although there is still a need for research, many parts of the contact allergy pathogenesis are now better understood. In particular, the essential role of the innate immune response not only for the sensitization but also for the elicitation phase seems to be established. Implementation of today's knowledge into new therapeutic approaches and their application testing remains important and exciting.
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Affiliation(s)
- Philipp R Esser
- Klinik für Dermatologie und Venerologie, Forschergruppe Allergologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hauptstr. 7, 79104, Freiburg im Breisgau, Deutschland.
| | - Stefan F Martin
- Klinik für Dermatologie und Venerologie, Forschergruppe Allergologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Hauptstr. 7, 79104, Freiburg im Breisgau, Deutschland.
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Contact Allergy to Fragrances. Contact Dermatitis 2020. [DOI: 10.1007/978-3-319-72451-5_86-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Martin SF, Bonefeld CM. Mechanisms of Irritant and Allergic Contact Dermatitis. Contact Dermatitis 2020. [DOI: 10.1007/978-3-319-72451-5_59-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Chen L, Shen Z. Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders. Cell Mol Immunol 2019; 17:64-75. [PMID: 31595056 DOI: 10.1038/s41423-019-0291-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 08/25/2019] [Indexed: 11/09/2022] Open
Abstract
The skin is the largest organ of the body. The establishment of immunological memory in the skin is a crucial component of the adaptive immune response. Once naive T cells are activated by antigen-presenting cells, a small fraction of them differentiate into precursor memory T cells. These precursor cells ultimately develop into several subsets of memory T cells, including central memory T (TCM) cells, effector memory T (TEM) cells, and tissue resident memory T (TRM) cells. TRM cells have a unique transcriptional profile, and their most striking characteristics are their long-term survival (longevity) and low migration in peripheral tissues, including the skin. Under physiological conditions, TRM cells that reside in the skin can respond rapidly to pathogenic challenges. However, there is emerging evidence to support the vital role of TRM cells in the recurrence of chronic inflammatory skin disorders, including psoriasis, vitiligo, and fixed drug eruption, under pathological or uncontrolled conditions. Clarifying and characterizing the mechanisms that are involved in skin TRM cells will help provide promising strategies for reducing the frequency and magnitude of skin inflammation recurrence. Here, we discuss recent insights into the generation, homing, retention, and survival of TRM cells and share our perspectives on the biological characteristics of TRM cells in the recurrence of inflammatory skin disorders.
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Affiliation(s)
- Ling Chen
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Zhu Shen
- Department of Dermatology, Institute of Dermatology and Venereology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital; School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Ahlström MG, Thyssen JP, Wennervaldt M, Menné T, Johansen JD. Nickel allergy and allergic contact dermatitis: A clinical review of immunology, epidemiology, exposure, and treatment. Contact Dermatitis 2019; 81:227-241. [DOI: 10.1111/cod.13327] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/23/2019] [Accepted: 05/24/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Malin G. Ahlström
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte HospitalUniversity of Copenhagen Hellerup Denmark
| | - Jacob P. Thyssen
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte HospitalUniversity of Copenhagen Hellerup Denmark
- Department of Dermatology and Allergy, Herlev and Gentofte HospitalUniversity of Copenhagen Hellerup Denmark
| | - Michael Wennervaldt
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte HospitalUniversity of Copenhagen Hellerup Denmark
| | - Torkil Menné
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte HospitalUniversity of Copenhagen Hellerup Denmark
| | - Jeanne D. Johansen
- National Allergy Research Centre, Department of Dermatology and Allergy, Herlev and Gentofte HospitalUniversity of Copenhagen Hellerup Denmark
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Gamradt P, Laoubi L, Nosbaum A, Mutez V, Lenief V, Grande S, Redoulès D, Schmitt AM, Nicolas JF, Vocanson M. Inhibitory checkpoint receptors control CD8+ resident memory T cells to prevent skin allergy. J Allergy Clin Immunol 2019; 143:2147-2157.e9. [DOI: 10.1016/j.jaci.2018.11.048] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 10/13/2018] [Accepted: 11/16/2018] [Indexed: 01/08/2023]
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Reis J, Duarte S, Sardoeira A, Santos E, Sanches M, Lobo I, Selores M. Case report of recalcitrant allergic contact eczema successfully treated with teriflunomide. Dermatol Ther 2019; 32:e12947. [PMID: 31025527 DOI: 10.1111/dth.12947] [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: 01/04/2019] [Revised: 03/25/2019] [Accepted: 04/05/2019] [Indexed: 11/27/2022]
Abstract
Allergic contact dermatitis (ACD) is a type IV, delayed-type reaction caused by skin contact with low-molecular-weight organic chemicals and metal ions that activate antigen-specific T cells, primarily T-helper 1 (Th1), in a sensitized individual, leading to skin eczema.First-line treatments are based on avoidance of causal agents and topical corticosteroids/immunomodulators. In recalcitrant cases, chronic oral immunosuppressive agents may be used, but they may have serious adverse effects and do not address the immunological disfunction. We report a case of severe ACD, unresponsive to topical or oral immunosuppressive therapy, which resolved itself after treatment with teriflunomide (TF) 14 mg/daily used for multiple sclerosis. TF is a once-daily, oral selective and reversible dihydroorotate dehydrogenase inhibitor, revealing a new treatment option for ACD.
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Affiliation(s)
- Joel Reis
- Department of Dermatology, Centro Hospitalar Universitário do Porto, Portugal
| | - Sara Duarte
- Department of Neurology, Centro Hospitalar Universitário do Porto, Portugal
| | - Ana Sardoeira
- Department of Neurology, Centro Hospitalar Universitário do Porto, Portugal
| | - Ernestina Santos
- Department of Neurology, Centro Hospitalar Universitário do Porto, Portugal
| | - Madalena Sanches
- Department of Dermatology, Centro Hospitalar Universitário do Porto, Portugal
| | - Inês Lobo
- Department of Dermatology, Centro Hospitalar Universitário do Porto, Portugal
| | - Manuela Selores
- Department of Dermatology, Centro Hospitalar Universitário do Porto, Portugal
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Todberg T, Zachariae C, Krustrup D, Skov L. The effect of treatment with anti-interleukin-17 in patients with allergic contact dermatitis. Contact Dermatitis 2019; 78:431-432. [PMID: 29722024 DOI: 10.1111/cod.12988] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 02/05/2018] [Accepted: 02/08/2018] [Indexed: 02/02/2023]
Affiliation(s)
- Tanja Todberg
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Claus Zachariae
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Dorrit Krustrup
- Department of Pathology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Furusawa E, Ohno T, Nagai S, Noda T, Komiyama T, Kobayashi K, Hamamoto H, Miyashin M, Yokozeki H, Azuma M. Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity. J Invest Dermatol 2019; 139:2164-2173.e1. [PMID: 30978356 DOI: 10.1016/j.jid.2019.02.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 11/25/2022]
Abstract
PD-L2 is a ligand for the immune checkpoint receptor PD-1; however, its regulatory function is unclear. We previously reported that silencing of CD86 in cutaneous dendritic cells by topical application of small interfering RNA (siRNA) inhibits the elicitation of contact hypersensitivity (CHS). Here, we investigated the effects of topical application of PD-L2 siRNA on allergic skin disease. PD-L2 was induced in dendritic cells concurrently with the elevation of major histocompatibility complex class II and CD86 expression. Topical application of PD-L2 siRNA inhibited the elicitation of CHS by suppressing early proinflammatory cytokine expression and migration of hapten-carrying dendritic cells into lymph nodes. Local injection of neutralizing anti-PD-L2 mAb inhibited CHS to the same extent. PD-L2 siRNA treatment inhibited CHS in PD-1/PD-L1 double knockout mice and in the sensitized T-cell-transferred skin. These results suggest that the effects of PD-L2 silencing are independent of PD-1 but dependent on local memory T cells. Most of the inhibitory effects of PD-L2 and CD86 silencing on CHS were comparable, but PD-L2 siRNA treatment did not inhibit atopic disease-like manifestations and T helper type 2 responses in NC/Nga mice. Our results suggest that PD-L2 in cutaneous dendritic cells acts as a costimulator rather than a regulator. Local PD-L2 silencing by topical application of siRNA represents a therapeutic approach for contact allergy.
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Affiliation(s)
- Emi Furusawa
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Pediatric Dentistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsukuni Ohno
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigenori Nagai
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taisei Noda
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takuya Komiyama
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | - Michiyo Miyashin
- Department of Pediatric Dentistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroo Yokozeki
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miyuki Azuma
- Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
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Martinez-Mera C, González MA, Hospital M, Turrión-Merino L. Isothiazolinones in paint as a cause of airborne contact dermatitis in a patient with psoriasis receiving anti-interleukin-17 therapy. Contact Dermatitis 2019; 80:328-329. [PMID: 30578553 DOI: 10.1111/cod.13203] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/17/2018] [Accepted: 12/18/2018] [Indexed: 11/30/2022]
Affiliation(s)
- Constanza Martinez-Mera
- Department of Dermatology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Maria A González
- Department of Dermatology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Mercedes Hospital
- Department of Dermatology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Lucia Turrión-Merino
- Department of Dermatology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
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