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Kortekaas Krohn I, Badloe FMS, Herrmann N, Maintz L, De Vriese S, Ring J, Bieber T, Gutermuth J. Immunoglobulin E autoantibodies in atopic dermatitis associate with Type-2 comorbidities and the atopic march. Allergy 2023; 78:3178-3192. [PMID: 37489049 DOI: 10.1111/all.15822] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 05/24/2023] [Accepted: 06/12/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND Autoreactive immunoglobulin E (IgE) antibodies to self-peptides within the epidermis have been identified in patients with atopic dermatitis (AD). Prevalence, concomitant diseases, patient characteristics, and risk factors of IgE autoantibody development remain elusive. We aimed to determine IgE autoantibodies in serum samples (n = 672) from well-characterized patients with AD and controls (1.2-88.9 years). METHODS Atopic dermatitis patients were sub-grouped in AD with comorbid Type-2 diseases ("AD + Type 2"; asthma, allergic rhinitis, food allergy, n = 431) or "solely AD" (n = 115). Also, subjects without AD but with Type-2 diseases ("atopic controls," n = 52) and non-atopic "healthy controls" (n = 74) were included. Total proteins from primary human keratinocytes were used for the immunoassay to detect IgE autoantibodies. Values were compared to already known positive and negative serum samples. RESULTS Immunoglobulin E autoantibodies were found in 15.0% (82/546) of all analyzed AD-patients. "AD + Type 2" showed a higher prevalence (16.4%) than "solely AD" (9.6%). "Atopic controls" (9.6%) were comparable with "solely AD" patients, while 2.7% of healthy controls showed IgE autoantibodies. Of those with high levels of IgE autoantibodies, 15 out of 16 were patients with "AD + Type 2". AD patients with IgE autoantibodies were younger than those without. Patients with IgE autoreactivity also displayed higher total serum IgE levels. Factors that affected IgE autoantibody development were as follows: birth between January and June, cesarean-section and diversity of domestic pets. CONCLUSIONS Immunoglobulin E autoantibodies in AD seem to associate with the presence of atopic comorbidities and environmental factors. The potential value of IgE autoantibodies as a predictive biomarker for the course of AD, including the atopic march, needs further exploration.
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Affiliation(s)
- Inge Kortekaas Krohn
- Skin Immunology & Immune Tolerance (SKIN) Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Department of Dermatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Fariza Mishaal Saiema Badloe
- Skin Immunology & Immune Tolerance (SKIN) Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Department of Dermatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Nadine Herrmann
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
- Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| | - Laura Maintz
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
- Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| | - Shauni De Vriese
- Skin Immunology & Immune Tolerance (SKIN) Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Department of Dermatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Johannes Ring
- Department Dermatology and Allergy Biederstein, Technical University Munich, Munich, Germany
| | - Thomas Bieber
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
- Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
- Davos Biosciences, Davos, Switzerland
| | - Jan Gutermuth
- Skin Immunology & Immune Tolerance (SKIN) Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Department of Dermatology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Charles N, Kortekaas-Krohn I, Kocaturk E, Scheffel J, Altrichter S, Steinert C, Xiang YK, Gutermuth J, Reber LL, Maurer M. Autoreactive IgE: Pathogenic role and therapeutic target in autoimmune diseases. Allergy 2023; 78:3118-3135. [PMID: 37555488 DOI: 10.1111/all.15843] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/08/2023] [Accepted: 07/27/2023] [Indexed: 08/10/2023]
Abstract
Autoimmunity is the break of tolerance to self-antigens that leads to organ-specific or systemic diseases often characterized by the presence of pathogenic autoreactive antibodies (AAb) produced by plasmablast and/or plasma cells. AAb are prevalent in the general population and not systematically associated with clinical symptoms. In contrast, in some individuals, these AAb are pathogenic and drive the development of signs and symptoms of antibody-mediated autoimmune diseases (AbAID). AAb production, isotype profiles, and glycosylations are promoted by pro-inflammatory triggers linked to genetic, environmental, and hormonal parameters. Recent evidence supports a role for pathogenic AAb of the IgE isotype in a number of AbAID. Autoreactive IgE can drive the activation of mast cells, basophils, and other types of FcεRI-bearing cells and may play a role in promoting autoantibody production and other pro-inflammatory pathways. In this review, we discuss the current knowledge on the pathogenicity of autoreactive IgE in AbAID and their status as therapeutic targets. We also highlight unresolved issues including the need for assays that reproducibly quantify IgE AAbs, to validate their diagnostic and prognostic value, and to further study their pathophysiological contributions to AbAID.
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Affiliation(s)
- Nicolas Charles
- Faculté de Médecine site Bichat, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS EMR8252, Université Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Université Paris Cité, Paris, France
| | - Inge Kortekaas-Krohn
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Brussels, Belgium
- Department of Dermatology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Emek Kocaturk
- Department of Dermatology, Koç University School of Medicine, Istanbul, Turkey
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Jörg Scheffel
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Sabine Altrichter
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
- Departement of Dermatology and Venerology, Kepler University Hospital, Linz, Austria
| | - Carolin Steinert
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
- Freie Universität Berlin, Department of Biology, Chemistry and Pharmacy, Berlin, Germany
| | - Yi-Kui Xiang
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Jan Gutermuth
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Brussels, Belgium
- Department of Dermatology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Laurent L Reber
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), UMR 1291, University of Toulouse, INSERM, CNRS, Toulouse, France
| | - Marcus Maurer
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
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Zolotas M, Schleusener J, Lademann J, Meinke MC, Kokolakis G, Darvin ME. Atopic Dermatitis: Molecular Alterations between Lesional and Non-Lesional Skin Determined Noninvasively by In Vivo Confocal Raman Microspectroscopy. Int J Mol Sci 2023; 24:14636. [PMID: 37834083 PMCID: PMC10572245 DOI: 10.3390/ijms241914636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/14/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Atopic dermatitis (AD)/atopic eczema is a chronic relapsing inflammatory skin disease affecting nearly 14% of the adult population. An important pathogenetic pillar in AD is the disrupted skin barrier function (SBF). The atopic stratum corneum (SC) has been examined using several methods, including Raman microspectroscopy, yet so far, there is no depth-dependent analysis over the entire SC thickness. Therefore, we recruited 21 AD patients (9 female, 12 male) and compared the lesional (LAS) with non-lesional atopic skin (nLAS) in vivo with confocal Raman microspectroscopy. Our results demonstrated decreased total intercellular lipid and carotenoid concentrations, as well as a shift towards decreased orthorhombic lateral lipid organisation in LAS. Further, we observed a lower concentration of natural moisturising factor (NMF) and a trend towards increased strongly bound and decreased weakly bound water in LAS. Finally, LAS showed an altered secondary and tertiary keratin structure, demonstrating a more folded keratin state than nLAS. The obtained results are discussed in comparison with healthy skin and yield detailed insights into the atopic SC structure. LAS clearly shows molecular alterations at certain SC depths compared with nLAS which imply a reduced SBF. A thorough understanding of these alterations provides useful information on the aetiology of AD and for the development/control of targeted topical therapies.
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Affiliation(s)
- Michael Zolotas
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Johannes Schleusener
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Jürgen Lademann
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Martina C Meinke
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Georgios Kokolakis
- Psoriasis Research and Treatment Centre, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Maxim E Darvin
- Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Mucha J, Cho A, Weijler AM, Muckenhuber M, Hofmann AG, Wahrmann M, Heinzel A, Linhart B, Gattinger P, Valenta R, Berlakovich G, Zuckermann A, Jaksch P, Oberbauer R, Wekerle T. Prospective assessment of pre-existing and de novo anti-HLA IgE in kidney, liver, lung and heart transplantation. Front Immunol 2023; 14:1179036. [PMID: 37731514 PMCID: PMC10507692 DOI: 10.3389/fimmu.2023.1179036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 07/31/2023] [Indexed: 09/22/2023] Open
Abstract
Introduction Antibody mediated rejection (ABMR) is a major factor limiting outcome after organ transplantation. Anti-HLA donor-specific antibodies (DSA) of the IgG isotype are mainly responsible for ABMR. Recently DSA of the IgE isotype were demonstrated in murine models as well as in a small cohort of sensitized transplant recipients. In the present study, we aimed to determine the frequency of pre-existing and de novo anti-HLA IgE antibodies in a cohort of 105 solid organ transplant recipients. Methods We prospectively measured anti-HLA IgE antibodies in a cohort of kidney (n=60), liver, heart and lung (n=15 each) transplant recipients before and within one-year after transplantation, employing a single-antigen bead assay for HLA class I and class II antigens. Functional activity of anti-HLA IgE antibodies was assessed by an in vitro mediator release assay. Antibodies of the IgG1-4 subclasses and Th1 and Th2 cytokines were measured in anti-HLA IgE positive patients. Results Pre-existing anti-HLA IgE antibodies were detected in 10% of renal recipients (including 3.3% IgE-DSA) and in 4.4% of non-renal solid organ transplant recipients (heart, liver and lung cohort). Anti-HLA IgE occurred only in patients that were positive for anti-HLA IgG, and most IgE positive patients had had a previous transplant. Only a small fraction of patients developed de novo anti-HLA IgE antibodies (1.7% of kidney recipients and 4.4% of non-renal recipients), whereas no de novo IgE-DSA was detected. IgG subclass antibodies showed a distinct pattern in patients who were positive for anti-HLA IgE. Moreover, patients with anti-HLA IgE showed elevated Th2 and also Th1 cytokine levels. Serum from IgE positive recipients led to degranulation of basophils in vitro, demonstrating functionality of anti-HLA IgE. Discussion These data demonstrate that anti-HLA IgE antibodies occur at low frequency in kidney, liver, heart and lung transplant recipients. Anti-HLA IgE development is associated with sensitization at the IgG level, in particular through previous transplants and distinct IgG subclasses. Taken together, HLA specific IgE sensitization is a new phenomenon in solid organ transplant recipients whose potential relevance for allograft injury requires further investigation.
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Affiliation(s)
- Jasmin Mucha
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Ara Cho
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Anna Marianne Weijler
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Moritz Muckenhuber
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Amun Georg Hofmann
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Markus Wahrmann
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Birgit Linhart
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Pia Gattinger
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Rudolf Valenta
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Karl Landsteiner University of Health Sciences, Krems, Austria
| | - Gabriela Berlakovich
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Andreas Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Peter Jaksch
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Rainer Oberbauer
- Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Thomas Wekerle
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
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Kolkhir P, Akdis CA, Akdis M, Bachert C, Bieber T, Canonica GW, Guttman-Yassky E, Metz M, Mullol J, Palomares O, Renz H, Ständer S, Zuberbier T, Maurer M. Type 2 chronic inflammatory diseases: targets, therapies and unmet needs. Nat Rev Drug Discov 2023; 22:743-767. [PMID: 37528191 DOI: 10.1038/s41573-023-00750-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2023] [Indexed: 08/03/2023]
Abstract
Over the past two decades, significant progress in understanding of the pathogenesis of type 2 chronic inflammatory diseases has enabled the identification of compounds for more than 20 novel targets, which are approved or at various stages of development, finally facilitating a more targeted approach for the treatment of these disorders. Most of these newly identified pathogenic drivers of type 2 inflammation and their corresponding treatments are related to mast cells, eosinophils, T cells, B cells, epithelial cells and sensory nerves. Epithelial barrier defects and dysbiotic microbiomes represent exciting future drug targets for chronic type 2 inflammatory conditions. Here, we review common targets, current treatments and emerging therapies for the treatment of five major type 2 chronic inflammatory diseases - atopic dermatitis, chronic prurigo, chronic urticaria, asthma and chronic rhinosinusitis with nasal polyps - with a high need for targeted therapies. Unmet needs and future directions in the field are discussed.
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Affiliation(s)
- Pavel Kolkhir
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany.
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF) Davos, University of Zürich, Davos, Switzerland
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF) Davos, University of Zürich, Davos, Switzerland
| | - Claus Bachert
- Department of Otorhinolaryngology - Head and Neck Surgery, University Hospital of Münster, Münster, Germany
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Division of ENT diseases, Karolinska Hospital, Stockholm, Sweden
| | - Thomas Bieber
- Department of Dermatology and Allergy, University Hospital, Bonn, Germany
- Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
- Davos Biosciences, Davos, Switzerland
| | - Giorgio Walter Canonica
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Asthma & Allergy Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Emma Guttman-Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Martin Metz
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Joaquim Mullol
- Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic Barcelona, FRCB-IDIBAPS, Universitat de Barcelona, CIBERES, Barcelona, Spain
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain
| | - Harald Renz
- Institute of Laboratory Medicine, member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University Marburg, Marburg, Germany
- Kilimanjaro Christian Medical University College (KCMUCo), Moshi, Tanzania
| | - Sonja Ständer
- Section Pruritus Medicine, Department of Dermatology and Center for Chronic Pruritus, University Hospital Münster, Münster, Germany
| | - Torsten Zuberbier
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Marcus Maurer
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany.
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Murashkin NN, Nezhvedilova RY, Fedorov DV, Epishev RV, Ivanov RA, Materikin AI, Opryatin LA, Savelova AA, Rusakova LL. Scientific and Practical Innovations in Restoring Skin Barrier Properties in Children with Atopic Dermatitis. CURRENT PEDIATRICS 2022. [DOI: 10.15690/vsp.v21i5.2457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Atopic dermatitis (AD) is a multifactorial inflammatory skin disease. Its pathogenetic basis is epidermal barrier dysfunction, immune system dysregulation, as well as skin microbiome diversity decrease that occurs due to genetic predisposition. Considering these factors, the skin of patients with AD requires constant care and use of medications with active regenerative properties. The inclusion of anti-inflammatory components in the composition of modern emollients (zinc sulfate and sucralfate) is crucial for restoring the microbiome and immune mechanisms controlling the skin. This article presents data on pathogenetic applicability and clinical efficacy of emollients with anti-inflammatory compounds in patients with AD.
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Affiliation(s)
- Nikolay N. Murashkin
- National Medical Research Center of Children’s Health; Sechenov First Moscow State Medical University; Central State Medical Academy of Department of Presidential Affairs
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7
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Shi L, Liu C, Xiong H, Shi D. Elevation of IgE in patients with psoriasis: Is it a paradoxical phenomenon? Front Med (Lausanne) 2022; 9:1007892. [PMID: 36314037 PMCID: PMC9606585 DOI: 10.3389/fmed.2022.1007892] [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: 07/31/2022] [Accepted: 09/26/2022] [Indexed: 11/25/2022] Open
Abstract
Immunoglobulin E (IgE) elevation is a hallmark of allergic conditions such as atopic dermatitis (AD). The pathogenesis of AD is typically associated with high levels of IL-4 and IL-13 produced by activated T helper 2 (Th2) cells. Psoriasis, on the other hand, is an inflammatory skin disease mainly driven by Th17 cells and their related cytokines. Although the immunopathologic reactions and clinical manifestations are often easily distinguished in the two skin conditions, patients with psoriasis may sometimes exhibit AD-like manifestations, such as elevated IgE and persistent pruritic lesions. Given the fact that the effective T cells have great plasticity to re-differentiate in response to innate and environmental factors, this unusual skin condition could be a consequence of a cross-reaction between distinct arms of T-cell and humoral immunity. Here we review the literature concerning the roles of IgE in the development of AD and psoriasis, showing that elevated IgE seems to be an important indicator for this non-typical psoriasis.
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Affiliation(s)
- Leyao Shi
- The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China,The Laboratory of Medical Mycology, Jining No. 1 People's Hospital, Jining, China
| | - Chen Liu
- The Laboratory of Medical Mycology, Jining No. 1 People's Hospital, Jining, China
| | - Huabao Xiong
- Basic Medical School, Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China,Huabao Xiong
| | - Dongmei Shi
- The Laboratory of Medical Mycology, Jining No. 1 People's Hospital, Jining, China,Department of Dermatology, Jining No.1 People's Hospital, Jining, China,*Correspondence: Dongmei Shi
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8
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Čelakovská J, Čermákova E, Vaňková R, Krejsek J, Andrýs C. Cluster analysis of allergen reagents in atopic dermatitis patients according to the specific IgE results in ALEX2 Allergy Explorer test. FOOD AGR IMMUNOL 2021. [DOI: 10.1080/09540105.2021.1978942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- J. Čelakovská
- Department of Dermatology and Venereology, Faculty Hospital and Medical Faculty of Charles University, Hradec Králové, Czech Republic
| | - E. Čermákova
- Department of Medical Biophysic, Medical Faculty of Charles University, Hradec Králové, Czech Republic
| | - R. Vaňková
- Department of Clinical Immunology and Allergy, Faculty Hospital and Medical Faculty of Charles University, Hradec Králové, Czech Republic
| | - J. Krejsek
- Department of Clinical Immunology and Allergy, Faculty Hospital and Medical Faculty of Charles University, Hradec Králové, Czech Republic
| | - C. Andrýs
- Department of Clinical Immunology and Allergy, Faculty Hospital and Medical Faculty of Charles University, Hradec Králové, Czech Republic
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9
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Chen KD, Huang YH, Guo MMH, Chang LS, Chu CH, Bu LF, Chu CL, Lee CH, Liu SF, Kuo HC. DNA Methylation Array Identifies Golli-MBP as a Biomarker for Disease Severity in Childhood Atopic Dermatitis. J Invest Dermatol 2021; 142:104-113. [PMID: 34293355 DOI: 10.1016/j.jid.2021.06.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 06/10/2021] [Accepted: 06/10/2021] [Indexed: 01/08/2023]
Abstract
In this study, we investigated the changes in global methylation status and its functional relevance in childhood atopic dermatitis (AD). Differences in epigenome-scale methylation events in peripheral blood associated with childhood AD were screened using DNA methylation arrays of 24 patients with AD compared with 24 control subjects. Of the 16,840 differentially methylated CpG regions between AD and control subjects, >97% CpG loci revealed hypomethylation in patients with childhood AD. Among the globally hypomethylated loci, we identified two CpG clusters within the golli-mbp locus of the MBP gene, which was functionally enriched by subnetwork enrichment analysis as an orchestrator among associated genes. The differential hypomethylation of the top-ranked cg24700313 cluster in the golli-mbp locus was validated by pyrosequencing in an independent cohort of 224 children with AD and 44 control subjects. DNA methylation was found to be negatively correlated with disease severity but showed no significant correlation with IgE levels after age adjustment. The multivariate correlation analysis represents a higher score in AD intensity with significantly increased IgE levels and decreased methylation levels in cg27400313. We concluded that methylation loss in the golli-mbp locus is an epigenetic factor associated with disease severity of childhood AD.
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Affiliation(s)
- Kuang-Den Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Liver Transplantation Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ying-Hsien Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mindy Ming-Huey Guo
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ling-Sai Chang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chi-Hsiang Chu
- Department of Statistics, National Cheng-Kung University, Tainan, Taiwan; Institute of Statistics, National University of Kaohsiung, Kaohsiung, Taiwan
| | - Li-Feng Bu
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Liver Transplantation Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chiao-Lun Chu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Hung Lee
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital, Taiwan
| | - Shih-Feng Liu
- Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ho-Chang Kuo
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Division of Pulmonary & Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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10
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De Bruyn Carlier T, Badloe FMS, Ring J, Gutermuth J, Kortekaas Krohn I. Autoreactive T cells and their role in atopic dermatitis. J Autoimmun 2021; 120:102634. [PMID: 33892348 DOI: 10.1016/j.jaut.2021.102634] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023]
Abstract
Atopic dermatitis (AD) is an itchy, non-contagious relapsing and chronic inflammatory skin disease that usually develops in early childhood. This pathology is associated with food allergy, allergic asthma, allergic rhinitis and anaphylaxis which may persist in adulthood. The underlying mechanisms of AD (endotypes) are just beginning to be discovered and show a complex interaction of various pathways including skin barrier function and immune deviation. Immune reactions to self-proteins (autoantigens) of the skin have been identified in patients with inflammatory skin diseases, such as chronic spontaneous urticaria, connective tissue disease, pemphigus vulgaris and bullous pemphigoid. IgE antibodies and T cells directed against epitopes of the skin were observed in adult patients with severe and chronic AD as well. This was associated with disease severity and suggests a progression from allergic inflammation to severe autoimmune processes against the skin. IgE-mediated autoimmunity and self-reactive T cells might accelerate the ongoing skin inflammation or might contribute to the relapsing course of the disease. However, to date, the exact mechanisms of IgE-mediated autoimmunity and self-reactive T cells in the pathophysiology of AD are still unclear. The aim of this review is to evaluate the development of (autoreactive) T cells and their response to (auto)antigens, as well as the role of the peripheral tolerance in autoimmunity in the pathophysiology of AD, including the unmet needs and gaps.
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Affiliation(s)
- Tina De Bruyn Carlier
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Fariza Mishaal Saiema Badloe
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Johannes Ring
- Department of Dermatology and Allergology Biederstein, Technical University Munich, München, Germany.
| | - Jan Gutermuth
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
| | - Inge Kortekaas Krohn
- Vrije Universiteit Brussel (VUB), Skin Immunology & Immune Tolerance (SKIN) Research Group, Laarbeeklaan 103, 1090, Brussels, Belgium; Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
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11
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Elias PM, Wakefield JS. Provozieren konvergierende zelluläre und Signalübertragungs‐Störungen die atopische Dermatitis? J Dtsch Dermatol Ges 2020; 18:1215-1224. [DOI: 10.1111/ddg.14232_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/18/2020] [Indexed: 11/30/2022]
Affiliation(s)
- Peter M. Elias
- Dermatology Service Veterans Affairs Medical Center and Department of Dermatology University of California San Francisco CA USA
| | - Joan S. Wakefield
- Dermatology Service Veterans Affairs Medical Center and Department of Dermatology University of California San Francisco CA USA
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12
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Elias PM, Wakefield JS. Could cellular and signaling abnormalities converge to provoke atopic dermatitis? J Dtsch Dermatol Ges 2020; 18:1215-1223. [PMID: 33048449 PMCID: PMC11249044 DOI: 10.1111/ddg.14232] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/18/2020] [Indexed: 11/28/2022]
Abstract
Diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins compromise permeability, barrier function and antimicrobial defense in atopic dermatitis (AD). Though several mutations in filaggrin (FLG) predominate, alterations in other S-100, cornified envelope precursor proteins (hornerin [HRNR], filaggrin 2 [FLG2], SPRR3, mattrin) which regulate lamellar body formation; SPINK5, which encodes the serine protease inhibitor, LEKTI1, and a fatty acid transporter, FATP4, are all separately associated with an AD phenotype. Exogenous and endogenous stressors, such as prolonged psychological stress, a low environmental humidity, or exposure to basic soaps and surfactants can further compromise barrier function and are often required to trigger disease. In the immunologists' view, the barrier abnormality is relevant only because it allows antigen and pathogen access, while stimulating Th2 cytokine production. These proteins in turn downregulate lipid synthetic enzyme and antimicrobial peptide levels, as well as multiple epidermal structural proteins, including filaggrin. Each inherited and acquired abnormality can independently compromise lamellar body secretion production, resulting in defective lamellar membrane organization and antimicrobial defense. Furthermore, elevated pH of the SC is critical for AD pathogenesis, compromising post-secretory lipid processing, while also enhancing inflammation. There are various therapeutic options that interdict different stages in this pathogenic paradigm.
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Affiliation(s)
- Peter M Elias
- Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA
| | - Joan S Wakefield
- Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA
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13
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Pellefigues C. IgE Autoreactivity in Atopic Dermatitis: Paving the Road for Autoimmune Diseases? Antibodies (Basel) 2020; 9:E47. [PMID: 32911788 PMCID: PMC7551081 DOI: 10.3390/antib9030047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/20/2022] Open
Abstract
Atopic dermatitis (AD) is a common skin disease affecting 20% of the population beginning usually before one year of age. It is associated with the emergence of allergen-specific IgE, but also with autoreactive IgE, whose function remain elusive. This review discusses current knowledge relevant to the mechanisms, which leads to the secretion of autoreactive IgE and to the potential function of these antibodies in AD. Multiple autoantigens have been described to elicit an IgE-dependent response in this context. This IgE autoimmunity starts in infancy and is associated with disease severity. Furthermore, the overall prevalence of autoreactive IgE to multiple auto-antigens is high in AD patients. IgE-antigen complexes can promote a facilitated antigen presentation, a skewing of the adaptive response toward type 2 immunity, and a chronic skin barrier dysfunction and inflammation in patients or AD models. In AD, skin barrier defects and the atopic immune environment facilitate allergen sensitization and the development of other IgE-mediated allergic diseases in a process called the atopic march. AD is also associated epidemiologically with several autoimmune diseases showing autoreactive IgE secretion. Thus, a potential outcome of IgE autoreactivity in AD could be the development of further autoimmune diseases.
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Affiliation(s)
- Christophe Pellefigues
- INSERM UMRS1149-CNRS ERL8252, Team «Basophils and Mast cells in Immunopathology», Centre de recherche sur l'inflammation (CRI), Inflamex, DHU Fire, Université de Paris, 75018 Paris, France
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14
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Badloe FMS, De Vriese S, Coolens K, Schmidt-Weber CB, Ring J, Gutermuth J, Kortekaas Krohn I. IgE autoantibodies and autoreactive T cells and their role in children and adults with atopic dermatitis. Clin Transl Allergy 2020; 10:34. [PMID: 32774842 PMCID: PMC7398196 DOI: 10.1186/s13601-020-00338-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 07/27/2020] [Indexed: 12/14/2022] Open
Abstract
The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and self-reactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self-reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self-reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies.
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Affiliation(s)
- Fariza Mishaal Saiema Badloe
- Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium
| | - Shauni De Vriese
- Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium
| | - Katarina Coolens
- Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium
| | - Carsten B Schmidt-Weber
- Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, Germany.,Member of the German Center of Lung Research (DZL) and the Helmholtz Initiative for Inflammation and Immunology (I&I), Munich, Germany
| | - Johannes Ring
- Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium.,Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, Germany
| | - Jan Gutermuth
- Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium
| | - Inge Kortekaas Krohn
- Department of Dermatology, SKIN Research Group, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 103, Building D, Room D148, 1090 Brussels, Belgium
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15
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Sánchez A, Cardona R, Munera M, Sánchez J. Identification of antigenic epitopes of thyroperoxidase, thyroglobulin and interleukin-24. Exploration of cross-reactivity with environmental allergens and possible role in urticaria and hypothyroidism. Immunol Lett 2020; 220:71-78. [PMID: 32027873 DOI: 10.1016/j.imlet.2020.02.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 01/30/2020] [Accepted: 02/02/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Human proteins such as interleukin-24 (IL24), thyroperoxidase (TPO) and thyroglobulin (Tg) are targets of IgE or IgG autoantibodies. Why these proteins are recognized by autoantibodies in some patients with chronic spontaneous urticaria (CSU) or hypothyroidism is unknown. OBJECTIVE Through in silico analysis, identify antigen patches of TPO, Tg and IL24 and compare the sequences of these human proteins with some prevalent allergens. METHODS The amino acids sequences of IL24, thyroperoxidase and thyroglobulin were compared between them and with 22 environmental allergens. Phylogenetic studies and multiple pairing were carried out to explore the degree of protein identity and cover. The proteins without 3D structure reported in the database, were modeled by homology with "Swiss Modeller" and compared through PYMOL. Residues conserved and accessible to the solvent (rASA> 0.25) were located in the 3D model to identify possible areas of cross-reactivity and antigen binding. RESULTS We build a 3D model of the TPO and thyroglobulin protein base on proteins closely related. Five epitopes for TPO, six for IL24 and six for thyroglobulin were predicted. The amino acid sequences of allergens from different sources (Dermatophagoides pteronyssinus, Blomia tropicalis, Betula verrucosa, Cynodon dactylon, Aspergillus fumigatus, Canis domesticus, Felis domesticus) were compared with human TPO, Tg and IL24. The cover and alignments between allergens and human proteins were low. CONCLUSION We identify possible linear and conformational epitopes of TPO, Tg and IL24 that could be the target of IgE or IgG binding in patients with urticaria or hypothyroidism; These epitopes do not appear to be present among common environmental allergens, suggesting that autoreactivity to these human proteins are not by cross-reactivity.
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Affiliation(s)
- Andrés Sánchez
- Medical Research Group (GINUMED) University Corporation Rafael Nuñez, Immunology Department, Faculty of medicine. Cartagena, Colombia; Group of Clinical and Experimental Allergy (GACE), IPS Universitaria, University of Antioquia. Medellín, Colombia
| | - Ricardo Cardona
- Group of Clinical and Experimental Allergy (GACE), IPS Universitaria, University of Antioquia. Medellín, Colombia
| | - Marlon Munera
- Medical Research Group (GINUMED) University Corporation Rafael Nuñez, Immunology Department, Faculty of medicine. Cartagena, Colombia
| | - Jorge Sánchez
- Group of Clinical and Experimental Allergy (GACE), IPS Universitaria, University of Antioquia. Medellín, Colombia.
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16
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Kamata A, Kurihara Y, Funakoshi T, Takahashi H, Kuroda K, Hachiya T, Amagai M, Yamagami J. Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results. Br J Dermatol 2019; 182:1221-1227. [PMID: 31330562 DOI: 10.1111/bjd.18364] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. OBJECTIVES To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. METHODS We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme-linked immunosorbent assay. RESULTS Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE- patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180-IgE levels were significantly higher among IgE+ patients than IgE± or IgE- patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE- patients. A significant correlation was detected between BP180-IgG and BP180-IgE, but not between BPDAI scores and any of BP180-IgG, BP180-IgE or blood eosinophil count. CONCLUSIONS IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic? BP180-IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add? Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180-specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.
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Affiliation(s)
- A Kamata
- Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Y Kurihara
- Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - T Funakoshi
- Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - H Takahashi
- Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - K Kuroda
- Medical and Biological Laboratories Co., Ltd, Nagoya, Japan
| | - T Hachiya
- Medical and Biological Laboratories Co., Ltd, Nagoya, Japan
| | - M Amagai
- Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - J Yamagami
- Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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17
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Wu W, Peng G, Yang F, Zhang Y, Mu Z, Han X. Sulforaphane has a therapeutic effect in an atopic dermatitis murine model and activates the Nrf2/HO‑1 axis. Mol Med Rep 2019; 20:1761-1771. [PMID: 31257541 PMCID: PMC6625393 DOI: 10.3892/mmr.2019.10405] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 05/14/2019] [Indexed: 12/11/2022] Open
Abstract
Atopic dermatitis (AD), a chronic inflammatory skin disease, is characterized by intense itching and recurrent eczematous lesions. Sulforaphane is known to attenuate oxidative stress, and tissue or cell damage in cerebral ischemia, brain inflammation and intracerebral hemorrhage. In the present study, a 2,4‑dinitrochlorobenzene (DNCB)‑induced AD mouse model was developed, and ear thickness, dermatitis score, eosinophil count, mast cell infiltration, and serum IgE levels were measured in DNCB‑induced AD and sulforaphane‑treated groups to demonstrate the therapeutic effects of sulforaphane. AD symptoms of DNCB‑induced mice were attenuated by sulforaphane treatment compared with those of negative control mice; furthermore, eosinophil count, mast cell infiltration and serum IgE levels were also reduced by sulforaphane treatment in DNCB‑induced AD mice. Western blot assays revealed that the expression levels of nuclear factor‑E2‑related factor 2 (Nrf2) and heme oxygenase-1 (HO‑1), which exhibit oxidation resistance, were increased by sulforaphane treatment in DNCB‑induced AD mice. The present study suggested that sulforaphane exerted a therapeutic effect in the AD mouse model through the activation of the Nrf2/HO‑1 axis as well as the suppression of Janus kinase 1/STAT3 signaling pathway.
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Affiliation(s)
- Wenqing Wu
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ge Peng
- Atopy (Allergy) Research Center, Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 1138642, Japan
| | - Fan Yang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yue Zhang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Zhenzhen Mu
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xiuping Han
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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18
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Abstract
Immunoglobulin E (IgE), though constitutively present at low levels, is most commonly studied in atopic disease where it plays a vital role in mast cell degranulation and in initiating a T helper 2 (Th2) response. With the advent of better detection assays, however, researchers are discovering the importance of IgE in actively contributing to many disease states and pathologies. This review will discuss the latest findings in IgE beyond its role in allergies and recently discovered roles for IgE in its cell-bound form on FcεRI-expressing effector cells like monocytes and dendritic cells. In terms of parasites, we will discuss helminth-induced IgE that appears to protect the worms from immune recognition and a tick-borne illness that elicits an IgE response against red meat. Next, we describe recent findings of how auto-reactive IgE can contribute to the progression of lupus and induce organ damage. Finally, we summarize the emerging roles of IgE in tumor surveillance and antibody-dependent cytotoxicity. We additionally discuss recent or ongoing clinical trials that either target harmful IgE or use the unique characteristics of the isotype.
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Affiliation(s)
- Andrea J Luker
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Joseph C Lownik
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.,Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, USA
| | - Daniel H Conrad
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Rebecca K Martin
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
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19
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Holmes J, Fairclough LC, Todd I. Atopic dermatitis and autoimmunity: the occurrence of autoantibodies and their association with disease severity. Arch Dermatol Res 2019; 311:141-162. [PMID: 30798353 PMCID: PMC7192884 DOI: 10.1007/s00403-019-01890-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 12/05/2018] [Accepted: 02/09/2019] [Indexed: 12/20/2022]
Abstract
Atopic dermatitis (AD) is a widespread condition that appears to be increasing in prevalence and severity worldwide, yet the underlying mechanisms are not well understood. Recent research has identified various similarities between AD and autoimmune conditions, as well as indicating that there may be an association between AD and autoimmunity. This systematic review evaluates the association between AD and autoimmunity, as well as between severity of disease in AD and autoimmunity, with an emphasis on the associations with autoantibodies. MEDLINE (1946 to December 2017) and Embase (1974 to December 2017) databases were searched. Further relevant articles were retrieved from reference lists. Only studies measuring direct indicators of autoimmunity, in humans, were included. Qualitative analysis was carried out for all studies. In addition, quantitative analysis was used to evaluate prevalence of IgE autoantibodies and anti-nuclear antibodies (ANAs) in AD patients and control subjects. The Mantel-Haenszel method was used with a random-effects model. 28 studies assessed the occurrence of autoantibodies in AD patients and 16 studies were used to evaluate association between disease severity and autoantibodies. Pooled analysis from 14 studies, involving 986 AD patients and 441 control subjects, showed that IgE autoantibodies were significantly more prevalent in patients with AD (P < 0.00001) than control subjects. Similar analysis was carried out for ANAs, with eight studies that involved 1045 AD patients and 1273 control subjects. ANAs were significantly more prevalent in patients with AD (P = 0.003). This quantitative analysis supported an association between AD and IgE autoantibodies, as well as between AD and ANAs. There was insufficient data to make similar conclusions for other indicators of autoimmunity. The weight of evidence also suggests an association between IgE autoantibodies and disease severity. There was insufficient evidence to make this link for other indicators of autoimmunity.
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Affiliation(s)
- James Holmes
- School of Life Sciences, University of Nottingham, Life Sciences Building, University Park, Nottingham, NG7 2RD, UK
| | - Lucy C Fairclough
- School of Life Sciences, University of Nottingham, Life Sciences Building, University Park, Nottingham, NG7 2RD, UK
| | - Ian Todd
- School of Life Sciences, University of Nottingham, Life Sciences Building, University Park, Nottingham, NG7 2RD, UK.
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20
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Crawford G, Hayes MD, Seoane RC, Ward S, Dalessandri T, Lai C, Healy E, Kipling D, Proby C, Moyes C, Green K, Best K, Haniffa M, Botto M, Dunn-Walters D, Strid J. Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response. Nat Immunol 2018; 19:859-870. [PMID: 30013146 PMCID: PMC6071860 DOI: 10.1038/s41590-018-0161-8] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 06/12/2018] [Indexed: 01/09/2023]
Abstract
IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.
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MESH Headings
- Animals
- Anthracenes/toxicity
- B-Lymphocytes/physiology
- Carcinoma, Squamous Cell/diagnosis
- Carcinoma, Squamous Cell/immunology
- Cell Death
- Cells, Cultured
- Complementarity Determining Regions/genetics
- DNA Damage
- Epithelial Cells/physiology
- Female
- High-Throughput Nucleotide Sequencing
- Immunoglobulin Class Switching
- Immunoglobulin E/genetics
- Immunoglobulin E/metabolism
- Immunologic Surveillance
- Intraepithelial Lymphocytes/physiology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neoplasms, Experimental/chemically induced
- Neoplasms, Experimental/immunology
- Piperidines/toxicity
- Prognosis
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Receptors, IgE/metabolism
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Affiliation(s)
- Greg Crawford
- Department of Medicine, Imperial College London, London, UK
| | | | | | - Sophie Ward
- Department of Medicine, Imperial College London, London, UK
| | | | - Chester Lai
- Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Eugene Healy
- Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - David Kipling
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Charlotte Proby
- Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK
| | - Colin Moyes
- Department of Pathology, Greater Glasgow and Clyde NHS, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kile Green
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Katie Best
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- Department of Dermatology and Newcastle Biomedical Research Centre, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Muzlifah Haniffa
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- Department of Dermatology and Newcastle Biomedical Research Centre, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Marina Botto
- Department of Medicine, Imperial College London, London, UK
| | - Deborah Dunn-Walters
- Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, Surrey, UK
| | - Jessica Strid
- Department of Medicine, Imperial College London, London, UK.
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Maurer M, Altrichter S, Schmetzer O, Scheffel J, Church MK, Metz M. Immunoglobulin E-Mediated Autoimmunity. Front Immunol 2018; 9:689. [PMID: 29686678 PMCID: PMC5900004 DOI: 10.3389/fimmu.2018.00689] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 03/20/2018] [Indexed: 12/13/2022] Open
Abstract
The study of autoimmunity mediated by immunoglobulin E (IgE) autoantibodies, which may be termed autoallergy, is in its infancy. It is now recognized that systemic lupus erythematosus, bullous pemphigoid (BP), and chronic urticaria, both spontaneous and inducible, are most likely to be mediated, at least in part, by IgE autoantibodies. The situation in other conditions, such as autoimmune uveitis, rheumatoid arthritis, hyperthyroid Graves’ disease, autoimmune pancreatitis, and even asthma, is far less clear but evidence for autoallergy is accumulating. To be certain of an autoallergic mechanism, it is necessary to identify both IgE autoantibodies and their targets as has been done with the transmembrane protein BP180 and the intracellular protein BP230 in BP and IL-24 in chronic spontaneous urticaria. Also, IgE-targeted therapies, such as anti-IgE, must have been shown to be of benefit to patients as has been done with both of these conditions. This comprehensive review of the literature on IgE-mediated autoallergy focuses on three related questions. What do we know about the prevalence of IgE autoantibodies and their targets in different diseases? What do we know about the relevance of IgE autoantibodies in different diseases? What do we know about the cellular and molecular effects of IgE autoantibodies? In addition to providing answers to these questions, based on a broad review of the literature, we outline the current gaps of knowledge in our understanding of IgE autoantibodies and describe approaches to address them.
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Affiliation(s)
- Marcus Maurer
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sabine Altrichter
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Schmetzer
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jörg Scheffel
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Martin K Church
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Martin Metz
- Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany
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23
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Kasperkiewicz M, Schmidt E, Ludwig RJ, Zillikens D. Targeting IgE Antibodies by Immunoadsorption in Atopic Dermatitis. Front Immunol 2018; 9:254. [PMID: 29520268 PMCID: PMC5827554 DOI: 10.3389/fimmu.2018.00254] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 01/29/2018] [Indexed: 11/24/2022] Open
Abstract
One major hallmark of atopic dermatitis (AD) is the elevated level of total serum IgE, which has been reported to be partly of the autoreactive type in a subset of patients. Immunoadsorption (IA) has been successfully applied in various classical autoantibody-mediated diseases such as pemphigus. Recent reports proposed the use of IA also for patients with severe AD and high total serum IgE levels. In this mini-review, we summarize the current knowledge about this novel treatment approach for AD and briefly discuss the so far incompletely known role of autoreactive IgE as potential target of IA therapy in this common inflammatory skin disorder.
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Affiliation(s)
| | - Enno Schmidt
- Department of Dermatology, University of Lübeck, Lübeck, Germany
- Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Ralf J. Ludwig
- Department of Dermatology, University of Lübeck, Lübeck, Germany
- Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Detlef Zillikens
- Department of Dermatology, University of Lübeck, Lübeck, Germany
- Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
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24
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Ettinger R, Karnell JL, Henault J, Panda SK, Riggs JM, Kolbeck R, Sanjuan MA. Pathogenic mechanisms of IgE-mediated inflammation in self-destructive autoimmune responses. Autoimmunity 2017; 50:25-36. [PMID: 28166684 DOI: 10.1080/08916934.2017.1280670] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Autoantibodies of the IgG subclass are pathogenic in a number of autoimmune disorders such as systemic lupus erythomatosus. The presence of circulating IgE autoantibodies in autoimmune patients has also been known for almost 40 years. Despite their role in allergies, IgE autoantibodies are not associated with a higher rate of atopy in these patients. However, recently they have been recognized as active drivers of autoimmunity through mechanisms involving the secretion of Type I interferons by plasmacytoid dendritic cells (pDC), the recruitment of basophils to lymph nodes, and the activation of adaptive immune responses through B and T cells. Here, we will review the formation, prevalence, affinity, and roles of the IgE autoantibodies that have been described in autoimmunity. We also present novel evidence supporting that triggering of IgE receptors in pDC induces LC3-associated phagocytosis, a cellular process also known as LAP that is associated with interferon responses. The activation of pDC with immune complexes formed by DNA-specific IgE antibodies also induce potent B-cell differentiation and plasma cell formation, which further define IgE's role in autoimmune humoral responses.
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Affiliation(s)
- Rachel Ettinger
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
| | - Jodi L Karnell
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
| | - Jill Henault
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
| | - Santosh K Panda
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
| | - Jeffrey M Riggs
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
| | - Roland Kolbeck
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
| | - Miguel A Sanjuan
- a Department of Respiratory , Inflammation & Autoimmunity, MedImmune LLC , Gaithersburg , MD , USA
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25
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Brunner PM, Emerson RO, Tipton C, Garcet S, Khattri S, Coats I, Krueger JG, Guttman-Yassky E. Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues. Allergy 2017; 72:2017-2025. [PMID: 28599078 DOI: 10.1111/all.13223] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and nonlesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to nonlesional skin remains unclear. METHODS We performed high-throughput deep sequencing of the β-TCR repertoire in 29 lesional and 19 nonlesional AD biopsies, compared to six healthy control and six cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts. RESULTS While greater T-cell infiltrates were observed in lesional vs nonlesional AD, TCR repertoire diversity was similar in lesional and nonlesional tissues, and absolute numbers of unique T-cell clones correlated with respective T-cell counts. Most (87%) top expanded lesional T-cell clones were shared with nonlesional tissues, and they were largely maintained after 16 weeks of successful treatment with topical triamcinolone. Nevertheless, both lesional and nonlesional AD showed a highly polyclonal TCR pattern, without evidence of oligoclonal expansion, or a preferred usage of certain V-β genes in AD skin. Size of the overall T-cell infiltrate, but not the level of clonality, correlated with mRNA levels of key inflammatory mediators (e.g., IL-13, CCL17, IL23p19, CXCL10). CONCLUSION While AD harbors a highly polyclonal T-cell receptor repertoire, and despite the lack of information on TCR antigen specificity, the sharing of top abundant clones between lesional and nonlesional skin, and their persistence after months of therapy, points to the continuous presence of potentially pathogenic skin resident memory T cells well beyond clinically inflamed lesions.
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Affiliation(s)
- P. M. Brunner
- The Laboratory for Investigative Dermatology; The Rockefeller University; New York NY USA
| | - R. O. Emerson
- Adaptive Biotechnologies Corporation; Seattle WA USA
| | - C. Tipton
- Adaptive Biotechnologies Corporation; Seattle WA USA
| | - S. Garcet
- The Laboratory for Investigative Dermatology; The Rockefeller University; New York NY USA
| | - S. Khattri
- Department of Dermatology and the Laboratory for Inflammatory Skin Diseases; Icahn School of Medicine at Mount Sinai; New York NY USA
| | - I. Coats
- The Laboratory for Investigative Dermatology; The Rockefeller University; New York NY USA
| | - J. G. Krueger
- The Laboratory for Investigative Dermatology; The Rockefeller University; New York NY USA
| | - E. Guttman-Yassky
- The Laboratory for Investigative Dermatology; The Rockefeller University; New York NY USA
- Department of Dermatology and the Laboratory for Inflammatory Skin Diseases; Icahn School of Medicine at Mount Sinai; New York NY USA
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26
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Wegner J, Weinmann-Menke J, von Stebut E. Immunoadsorption for treatment of severe atopic dermatitis. ATHEROSCLEROSIS SUPP 2017; 30:264-270. [DOI: 10.1016/j.atherosclerosissup.2017.05.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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27
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IgE autoantibodies and their association with the disease activity and phenotype in bullous pemphigoid: a systematic review. Arch Dermatol Res 2017; 310:11-28. [PMID: 29071428 PMCID: PMC5754504 DOI: 10.1007/s00403-017-1789-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 10/01/2017] [Accepted: 10/16/2017] [Indexed: 12/13/2022]
Abstract
Bullous pemphigoid (BP) is the most common autoimmune skin disease of blistering character. The underlying pathophysiological mechanism involves an immune attack, usually by IgG class autoantibodies, on the autoantigen BP 180/BPAg2, which is a type XVII collagen (COL17) protein acting as the adhesion molecule between the epidermis and the basement membrane of the dermis. About 40 years ago, following consistent findings of elevated total serum IgE levels in BP patients, it was hypothesized that IgE may be involved in the pathophysiology of BP. Our objective was to determine whether there is strong evidence for an association between IgE class autoantibodies and the clinical severity or phenotype of BP. Three databases were searched for relevant studies and appropriate exclusion and inclusion criteria were applied. Data was extracted and assessed in relation to the study questions concerning the clinical significance of IgE autoantibodies in BP. Nine studies found that anti-BP180 autoantibodies of IgE class are associated with increased severity of BP, whereas two studies did not find such an association. The number of studies which found an association between higher IgE autoantibody levels and the erythematous urticarial phenotype of BP (5) was equal in number to the studies which found no such association (5). In conclusion, higher serum IgE autoantibody levels are associated with more severe clinical manifestations of BP. There is insufficient evidence to support higher IgE autoantibody levels being associated with specific clinical phenotypes of BP.
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28
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Verzeaux L, Vyumvuhore R, Boudier D, Le Guillou M, Bordes S, Essendoubi M, Manfait M, Closs B. Atopic skin: In vivo Raman identification of global molecular signature, a comparative study with healthy skin. Exp Dermatol 2017; 27:403-408. [DOI: 10.1111/exd.13388] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2017] [Indexed: 12/31/2022]
Affiliation(s)
| | | | | | | | | | | | - Michel Manfait
- MéDIAN UMR CNRS 7369; University of Reims Champagne-Ardenne; Reims France
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29
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Bieber T, D'Erme AM, Akdis CA, Traidl-Hoffmann C, Lauener R, Schäppi G, Schmid-Grendelmeier P. Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go? J Allergy Clin Immunol 2017; 139:S58-S64. [PMID: 28390478 DOI: 10.1016/j.jaci.2017.01.008] [Citation(s) in RCA: 203] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 01/13/2017] [Accepted: 01/24/2017] [Indexed: 12/15/2022]
Abstract
Atopic dermatitis (AD) is a paradigmatic chronic inflammatory skin disease characterized by a complex pathophysiology and a wide spectrum of the clinical phenotype. Despite this high degree of heterogeneity, AD is still considered a single disease and usually treated according to the "one-size-fits-all" approach. Thus more tailored prevention and therapeutic strategies are still lacking. As for other disciplines, such as oncology or rheumatology, we have to approach AD in a more differentiated way (ie, to dissect and stratify the complex clinical phenotype into more homogeneous subgroups based on the endophenotype [panel of biomarkers]) with the aim to refine the management of this condition. Because we are now entering the era of personalized medicine, a systems biology approach merging the numerous clinical phenotypes with robust (ie, relevant and validated) biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD. This approach will not only allow an optimized prevention and treatment with the available drugs but also hopefully help assign newly developed medicinal products to those patients who will have the best benefit/risk ratio.
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Affiliation(s)
- Thomas Bieber
- Department of Dermatology and Allergy, University of Bonn, Bonn, Germany; Christine Kühne-Center for Allergy Research and Education (CK-CARE) Davos-Augsburg-Bonn-St Gallen-Zürich, St Gallen, Switzerland.
| | - Angelo M D'Erme
- Unit of Dermatology, Livorno Hospital, Livomo, Italy; Unit of Dermatology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cezmi A Akdis
- Christine Kühne-Center for Allergy Research and Education (CK-CARE) Davos-Augsburg-Bonn-St Gallen-Zürich, St Gallen, Switzerland; Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland
| | - Claudia Traidl-Hoffmann
- Christine Kühne-Center for Allergy Research and Education (CK-CARE) Davos-Augsburg-Bonn-St Gallen-Zürich, St Gallen, Switzerland; Institute for Environmental Medicine, Technische Universität München and Helmholtzzentrum München, Munich, Germany
| | - Roger Lauener
- Christine Kühne-Center for Allergy Research and Education (CK-CARE) Davos-Augsburg-Bonn-St Gallen-Zürich, St Gallen, Switzerland; Children's Hospital of Eastern Switzerland, St Gallen, and the University of Zurich, Zurich, Switzerland
| | - Georg Schäppi
- Christine Kühne-Center for Allergy Research and Education (CK-CARE) Davos-Augsburg-Bonn-St Gallen-Zürich, St Gallen, Switzerland
| | - Peter Schmid-Grendelmeier
- Christine Kühne-Center for Allergy Research and Education (CK-CARE) Davos-Augsburg-Bonn-St Gallen-Zürich, St Gallen, Switzerland; Allergy Unit, Department of Dermatology, University Hospital, Zurich, Switzerland
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Furue M, Chiba T, Tsuji G, Ulzii D, Kido-Nakahara M, Nakahara T, Kadono T. Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies. Allergol Int 2017; 66:398-403. [PMID: 28057434 DOI: 10.1016/j.alit.2016.12.002] [Citation(s) in RCA: 182] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 11/16/2016] [Indexed: 12/24/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder mostly associated with IgE elevation and skin barrier dysfunction due to decreased filaggrin expression. The lesional skin of AD exhibits Th2- and Th22-deviated immune reactions that are progressive during disease chronicity. Th2 and Th22 cytokines further deteriorate the skin barrier by inhibiting filaggrin expression. Some IgEs are reactive to self-antigens. The IgE autoreactivity may precipitate the chronicity of AD. Upon activation of the ORAI1 calcium channel, atopic epidermis releases large amounts of thymic stromal lymphopoietin (TSLP), which initiates the Th2 and Th22 immune response. Th2-derived interleukin-31 and TSLP induce an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD. Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.
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Abstract
BACKGROUND Comorbidities of cardiovascular diseases (CVDs), metabolic syndrome and autoimmune diseases with systemic inflammation are recent topics in medicine. Inflammatory skin diseases such as atopic dermatitis and psoriasis are an active source of diverse proinflammatory cytokines and chemokines, which are readily detectable in the circulation and are likely to be involved in developing comorbidities. EVIDENCE Both atopic dermatitis and psoriasis are frequently comorbid with CVD, metabolic syndrome and autoimmune diseases, the consequence of which is called "inflammatory skin march", "psoriatic march" or "march of psoriasis". CONCLUSION In this review, we summarize the epidemiological evidence and pathogenetic concepts regarding inflammatory skin march in atopic dermatitis and psoriasis.
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Affiliation(s)
- Masutaka Furue
- Department of Dermatology, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582, Japan.
| | - Takafumi Kadono
- Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan
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Elias MS, Long HA, Newman CF, Wilson PA, West A, McGill PJ, Wu KC, Donaldson MJ, Reynolds NJ. Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema. J Allergy Clin Immunol 2017; 140:1299-1309. [PMID: 28479159 PMCID: PMC5667587 DOI: 10.1016/j.jaci.2017.01.039] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 12/22/2016] [Accepted: 01/20/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood. OBJECTIVES We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin-equivalent (LSE) models and validate findings in skin of patients with AE. METHODS Differentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG]) LSEs were identified by means of proteomic analysis (liquid chromatography-mass spectrometry) and Ingenuity Pathway Analysis. Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence). RESULTS Proteomic analysis identified 17 (P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin. CONCLUSIONS For the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies.
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Affiliation(s)
- Martina S Elias
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Heather A Long
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Stiefel, a GlaxoSmithKline company, Stevenage, United Kingdom
| | | | | | - Andrew West
- GlaxoSmithKline R&D, Stevenage, United Kingdom
| | | | - Keith C Wu
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Nick J Reynolds
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.
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Navarrete-Dechent C, Pérez-Mateluna G, Silva-Valenzuela S, Vera-Kellet C, Borzutzky A. Humoral and Cellular Autoreactivity to Epidermal Proteins in Atopic Dermatitis. Arch Immunol Ther Exp (Warsz) 2016; 64:435-442. [PMID: 27147107 DOI: 10.1007/s00005-016-0400-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 03/08/2016] [Indexed: 12/20/2022]
Abstract
Atopic dermatitis (AD), a chronic relapsing inflammatory disease of the skin, is an important public health concern affecting 10-20 % of children worldwide. The etiology and pathogenesis of AD involve the interplay of genetic and environmental factors, including abnormalities in skin integrity and a skewed immune system usually driven by a Th2 phenotype in childhood with a switch to Th1 in the chronic phase of disease. Children and adults with AD commonly have elevated IgE levels directed to multiple different antigens, including aeroallergens, food allergens, and microbial proteins. IgE targeting self-antigens from epidermal proteins have been detected in up to 91 % of patients, particularly in severe persistent AD. It has been suggested that the occurrence of autoreactivity develops in early childhood. However, it is not clear yet if autoreactive IgEs in patients with AD are pathogenic or just an epiphenomenon. The fact that these autoantibodies are associated with severity and are not present in other allergic or skin diseases favors the pathogenicity of IgE-mediated autoreactivity in AD. In this review, we evaluate the pathogenesis of AD and the emerging role of autoreactivity to various keratinocyte antigens involving both the humoral and cellular components of the immune system.
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Affiliation(s)
- Cristián Navarrete-Dechent
- Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Guillermo Pérez-Mateluna
- Department of Pediatric Infectious Diseases and Immunology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Portugal 61, Santiago, 8330034, Chile
| | - Sergio Silva-Valenzuela
- Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cristián Vera-Kellet
- Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Arturo Borzutzky
- Department of Pediatric Infectious Diseases and Immunology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Portugal 61, Santiago, 8330034, Chile. .,Millennium Institute on Immunology and Immunotherapy, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Sanjuan MA, Sagar D, Kolbeck R. Role of IgE in autoimmunity. J Allergy Clin Immunol 2016; 137:1651-1661. [PMID: 27264000 DOI: 10.1016/j.jaci.2016.04.007] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 04/21/2016] [Accepted: 04/21/2016] [Indexed: 01/08/2023]
Abstract
There is accumulating evidence to suggest that IgE plays a significant role in autoimmunity. The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied. However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus. IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote TH2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies. More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity. Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells. The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid. In this review we summarize recent reports describing the prevalence of self-reactive IgE and discuss novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders.
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Affiliation(s)
- Miguel A Sanjuan
- Respiratory, Inflammation & Autoimmunity Department, Research, MedImmune, Gaithersburg, Md.
| | - Divya Sagar
- Respiratory, Inflammation & Autoimmunity Department, Research, MedImmune, Gaithersburg, Md
| | - Roland Kolbeck
- Respiratory, Inflammation & Autoimmunity Department, Research, MedImmune, Gaithersburg, Md
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Gillespie RMC, Brown SJ. From the outside-in: Epidermal targeting as a paradigm for atopic disease therapy. World J Dermatol 2015; 4:16-32. [DOI: 10.5314/wjd.v4.i1.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Revised: 11/29/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.
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Ota Y, Fujiwara M, Hirabayashi Y, Kumasaka T, Takemura T, Ota R, Suzuki M, Inokuma S. Eosinophilic granulomatosis with polyangiitis demonstrating IgE-immune complexes and the possible involvement of IgE autoantibodies. Intern Med 2015; 54:2687-91. [PMID: 26466712 DOI: 10.2169/internalmedicine.54.4588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We herein report a case of female eosinophilic granulomatosis with polyangiitis (EGPA) in which polyethylene glycol (PEG) precipitation was used to evaluate the patient's levels IgE-immune complexes (IC). Her serum IgE (7,110 IU/mL) and IgE-IC (1,880 IU/mL) levels were observed with an IgE PEG precipitated index of 26.4%. We speculate that the circulating IgE-IC were formed by anti-neutrophil IgE autoantibodies. Therefore, the large amount of IgE autoantibodies in the patient's serum appears to have induced a constant allergic pathology. This pathology may have resulted in a marked infiltration of eosinophils into the tissues, as well as intensified the EGPA pathology.
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Affiliation(s)
- Yasushi Ota
- Department of Otorhinolaryngology, Toho University Sakura Medical Center, Japan
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Elias PM, Wakefield JS. Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol 2014; 134:781-791.e1. [PMID: 25131691 DOI: 10.1016/j.jaci.2014.05.048] [Citation(s) in RCA: 159] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 04/29/2014] [Accepted: 05/07/2014] [Indexed: 12/22/2022]
Abstract
I review how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in patients with atopic dermatitis (AD). Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (ie, hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (ie, SPRR3); mattrin, which is encoded by TMEM79 and regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor lymphoepithelial Kazal-type trypsin inhibitor type 1; and the fatty acid transporter fatty acid transport protein 4 have all been linked to AD. Yet these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function, such as psychological stress, low ambient humidity, or high-pH surfactants, often are required to trigger disease. T(H)2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes, and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion, and/or extracellular lamellar membrane organization, as well as antimicrobial defense. Finally, I briefly review therapeutic options that address this new pathogenic paradigm.
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Affiliation(s)
- Peter M Elias
- Dermatology Service, Veterans Affairs Medical Center, and the Department of Dermatology, University of California, San Francisco, Calif.
| | - Joan S Wakefield
- Dermatology Service, Veterans Affairs Medical Center, and the Department of Dermatology, University of California, San Francisco, Calif
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Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 2014; 134:792-9. [PMID: 25065719 DOI: 10.1016/j.jaci.2014.06.014] [Citation(s) in RCA: 266] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 06/14/2014] [Accepted: 06/14/2014] [Indexed: 02/06/2023]
Abstract
The epidermis protects human subjects from exogenous stressors and helps to maintain internal fluid and electrolyte homeostasis. Filaggrin is a crucial epidermal protein that is important for the formation of the corneocyte, as well as the generation of its intracellular metabolites, which contribute to stratum corneum hydration and pH. The levels of filaggrin and its degradation products are influenced not only by the filaggrin genotype but also by inflammation and exogenous stressors. Pertinently, filaggrin deficiency is observed in patients with atopic dermatitis regardless of filaggrin mutation status, suggesting that the absence of filaggrin is a key factor in the pathogenesis of this skin condition. In this article we review the various causes of low filaggrin levels, centralizing the functional and morphologic role of a deficiency in filaggrin, its metabolites, or both in the etiopathogenesis of atopic dermatitis.
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Affiliation(s)
- Jacob P Thyssen
- National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, University of Copenhagen, Hellerup, Denmark.
| | - Sanja Kezic
- Coronel Institute of Occupational Health, Academic Medical Center, Amsterdam, The Netherlands
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Skin Barrier and Immune Dysregulation in Atopic Dermatitis: An Evolving Story with Important Clinical Implications. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2014; 2:371-9; quiz 380-1. [DOI: 10.1016/j.jaip.2014.03.006] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/20/2014] [Accepted: 03/20/2014] [Indexed: 12/21/2022]
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Cipriani F, Ricci G, Leoni MC, Capra L, Baviera G, Longo G, Maiello N, Galli E. Autoimmunity in atopic dermatitis: Biomarker or simply epiphenomenon? J Dermatol 2014; 41:569-76. [DOI: 10.1111/1346-8138.12464] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 01/31/2014] [Indexed: 01/09/2023]
Affiliation(s)
- Francesca Cipriani
- Pediatric Unit; Department of Medical and Surgical Sciences; University of Bologna; Bologna Italy
| | - Giampaolo Ricci
- Pediatric Unit; Department of Medical and Surgical Sciences; University of Bologna; Bologna Italy
| | - Maria Chiara Leoni
- Pediatric Unit; Department of Clinical-Surgical, Diagnostic and Pediatric Sciences; University of Pavia; Pavia Italy
| | - Lucetta Capra
- Department of Reproduction and Pediatrics; University Hospital S. Anna; Ferrara Italy
| | | | | | - Nunzia Maiello
- Department of Woman, Child and General and Specialized Surgery; Second University of Naples; Naples Italy
| | - Elena Galli
- Pediatric Allergy Unit; Research Center; San Pietro Hospital - Fatebenefratelli; Rome Italy
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41
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Tamari M, Hirota T. Genome-wide association studies of atopic dermatitis. J Dermatol 2014; 41:213-20. [DOI: 10.1111/1346-8138.12321] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Accepted: 09/19/2013] [Indexed: 12/23/2022]
Affiliation(s)
- Mayumi Tamari
- Laboratory for Respiratory and Allergic Diseases; Center for Integrative Medical Sciences; The Institute of Physical and Chemical Research (RIKEN); Kanagawa Japan
| | - Tomomitsu Hirota
- Laboratory for Respiratory and Allergic Diseases; Center for Integrative Medical Sciences; The Institute of Physical and Chemical Research (RIKEN); Kanagawa Japan
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Elias PM. Lipid abnormalities and lipid-based repair strategies in atopic dermatitis. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1841:323-30. [PMID: 24128970 DOI: 10.1016/j.bbalip.2013.10.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/27/2013] [Accepted: 10/01/2013] [Indexed: 01/30/2023]
Abstract
Prior studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes atopic dermatitis (AD). We review here increasing evidence that the inflammation in AD results primarily from inherited abnormalities in epidermal structural and enzymatic proteins that impact permeability barrier function. We also will show that the barrier defect can be attributed to a paracellular abnormality due to a variety of abnormalities in lipid composition, transport and extracellular organization. Accordingly, we also review the therapeutic implications of this emerging pathogenic paradigm, including several current and potentially novel, lipid-based approaches to corrective therapy. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
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Affiliation(s)
- Peter M Elias
- Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA.
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Tamari M, Tanaka S, Hirota T. Genome-wide association studies of allergic diseases. Allergol Int 2013; 62:21-28. [PMID: 23439055 DOI: 10.2332/allergolint.13-rai-0539] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Indexed: 12/12/2022] Open
Abstract
Allergic diseases are complex diseases caused by a combination of genetic and environmental factors. To determine the genetic components of these diseases and to discover the genes and cellular pathways underlying them, a large number of genetic studies have been conducted. Progress in genetics enables us to conduct genome-wide association studies (GWASs), which is a comprehensive and unbiased approach to identify susceptibility loci for multifactorial diseases. Recent GWASs have convincingly detected a large number of loci associated with allergic diseases. Candidate genes in the susceptibility loci suggest roles for epithelial barrier functions, innate-adaptive immunity, IL-1 family signaling, regulatory T cells and the vitamin D pathway in the pathogenesis of allergic diseases. Interestingly, the IL1RL1, HLA, IL13 and C11orf30 regions are overlapping susceptibility loci among atopic dermatitis and asthma or allergic rhinitis. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWASs improve our understanding of the pathophysiology of human allergic diseases and contribute to the development of better treatment and preventive strategies.
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Affiliation(s)
- Mayumi Tamari
- Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.
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Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Sakashita M, Yamada T, Fujieda S, Tanaka S, Doi S, Miyatake A, Enomoto T, Nishiyama C, Nakano N, Maeda K, Okumura K, Ogawa H, Ikeda S, Noguchi E, Sakamoto T, Hizawa N, Ebe K, Saeki H, Sasaki T, Ebihara T, Amagai M, Takeuchi S, Furue M, Nakamura Y, Tamari M. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 2012; 44:1222-6. [DOI: 10.1038/ng.2438] [Citation(s) in RCA: 253] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 09/11/2012] [Indexed: 12/12/2022]
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45
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Gittler JK, Krueger JG, Guttman-Yassky E. Atopic dermatitis results in intrinsic barrier and immune abnormalities: implications for contact dermatitis. J Allergy Clin Immunol 2012; 131:300-13. [PMID: 22939651 DOI: 10.1016/j.jaci.2012.06.048] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 06/29/2012] [Indexed: 01/14/2023]
Abstract
Atopic dermatitis (AD), as well as irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD), are common skin diseases. These diseases are characterized by skin inflammation mediated by activated innate immunity or acquired immune mechanisms. Although AD, ICD, and ACD can be encountered in pure forms by allergists and dermatologists, patients with AD often present with increased frequency of ICD and ACD. Although a disturbed barrier alone could potentiate immune reactivity in patients with AD through increased antigen penetration, additional immune mechanisms might explain the increased susceptibility of atopic patients to ICD and ACD. This review discusses cellular pathways associated with increased skin inflammation in all 3 conditions and presents mechanisms that might contribute to the increased rate of ICD and ACD in patients with AD.
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Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol 2012; 41:282-95. [PMID: 21174234 DOI: 10.1007/s12016-010-8231-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Excessive Th2 cell signaling and IgE production play key roles in the pathogenesis of atopic dermatitis (AD). Yet, recent information suggests that the inflammation in AD instead is initiated by inherited insults to the barrier, including a strong association between mutations in FILAGGRIN and SPINK5 in Netherton syndrome, the latter of which provides an important clue that AD is provoked by excess serine protease activity. But acquired stressors to the barrier may also be required to initiate inflammation in AD, and in addition, microbial colonization by Staphylococcus aureus both amplifies inflammation, but also further stresses the barrier in AD. Therapeutic implications of these insights are as follows: While current therapy has been largely directed toward ameliorating Th2-mediated inflammation and/or pruritus, these therapies are fraught with short-term and potential long-term risks. In contrast, "barrier repair" therapy, with a ceramide-dominant triple-lipid mixture of stratum corneum lipids, is more logical, of proven efficacy, and it provides a far-improved safety profile.
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48
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Liu FT, Goodarzi H, Chen HY. IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol 2012; 41:298-310. [PMID: 21249468 DOI: 10.1007/s12016-011-8252-4] [Citation(s) in RCA: 325] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific immune and inflammatory mechanisms. Atopy is among the major features of the diagnosis criteria for AD but is not an essential feature. Thus, patients diagnosed with AD can be atopic or non-atopic. This review focuses on the role of IgE, mast cells, and eosinophils in the pathogenesis of AD. The known functions of IgE in allergic inflammation suggest that IgE and IgE-mediated mast cell and eosinophil activation contribute to AD, but direct evidence supporting this is scarce. The level of IgE (thus the degree of allergic sensitization) is associated with severity of AD and contributed by abnormality of skin barrier, a key feature of AD. The function of IgE in development of AD is supported by the beneficial effect of anti-IgE therapy in a number of clinical studies. The role of mast cells in AD is suggested by the increase in the mast cell number and mast cell activation in AD lesions and the association between mast cell activation and AD. It is further suggested by their role in mouse models of AD as well as by the effect of therapeutic agents for AD that can affect mast cells. The role of eosinophils in AD is suggested by the presence of eosinophilia in AD patients and eosinophil infiltrates in AD lesions. It is further supported by information that links AD to cytokines and chemokines associated with production, recruitment, and activation of eosinophils.
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Affiliation(s)
- Fu-Tong Liu
- Department of Dermatology, University of California-Davis School of Medicine, Sacramento, CA 95816, USA.
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Does "autoreactivity" play a role in atopic dermatitis? J Allergy Clin Immunol 2012; 129:1209-1215.e2. [PMID: 22409986 DOI: 10.1016/j.jaci.2012.02.002] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 02/07/2012] [Accepted: 02/08/2012] [Indexed: 11/20/2022]
Abstract
The role of autoimmunity in atopic dermatitis (AD) is unclear. We sought to critically examine the occurrence, correlation with severity, and possible causative role of autoreactivity in patients with AD. Our systematic review of studies identified from MEDLINE included 31 experiments that described autoreactivity in patients with AD. We defined autoreactivity as in vitro or in vivo evidence of immune response to autologous human, generic human, or recombinant human proteins or other tissue/cellular components. Autoreactivity prevalence in patients with AD ranged from 23% to 91% in 14 studies involving 2644 participants, although it did not appear to vary with age, sex, or disease duration. In contrast to studies of AD, IgE autoreactivity was not found in healthy subjects or in those with allergic rhinoconjunctivitis, psoriasis, systemic lupus erythematosus, or other inflammatory diseases (8 studies of 816 participants). Two reports found a positive correlation between autoreactivity and AD severity. We suggest that autoreactivity might be playing a causative role in AD based on the magnitude and specificity of the associations found; plausible mechanisms through IgE autoantibodies, IgG autoantibodies, and T(H)1 autoreactivity; and experimental elicitation of eczematous lesions after provocation. Whether autoantibodies contribute to AD chronicity now needs to be examined in longitudinal studies.
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50
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Huang W, Hu C, Zeng H, Li P, Guo L, Zeng X, Liu G, Zhang F, Li Y, Wu L. Novel systemic lupus erythematosus autoantigens identified by human protein microarray technology. Biochem Biophys Res Commun 2012; 418:241-6. [PMID: 22266373 DOI: 10.1016/j.bbrc.2012.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2011] [Accepted: 01/03/2012] [Indexed: 10/14/2022]
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting many organs. Many autoantibodies have been associated with the disease, but either in low specificity or low sensitivity of detection. In an aim to screen for better autoantibodies, we profiled the autoantibody repertoire in sera from 30 SLE patients versus 30 healthy controls using a protein microarray containing 5011 non-redundant human proteins, and identified four candidates. We then selected CLIC2 for further verification by ELISA in an extended cohort including 110 SLE, 121 non-AD, 118 RA, 117 SSc, and 105 pSS patients. The positive rate of anti-CLIC2 was 28.18% in SLE patients, significantly higher than those in non-AD, RA, and SSc patients. The presence of anti-CLIC2 in SLE had positive correlation with disease activity in terms of SLEDAI score and several indexes (p<0.05).
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Affiliation(s)
- Wei Huang
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 101318, People's Republic of China
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