Atopic dermatitis endotypes and implications for targeted therapeutics
2019; Elsevier BV; Volume: 143; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2018.10.032
ISSN1097-6825
AutoresTali Czarnowicki, Helen He, James G. Krueger, Emma Guttman‐Yassky,
Tópico(s)Asthma and respiratory diseases
ResumoRecent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional “one-size-fits-all” therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation. Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional “one-size-fits-all” therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: January 2019. Credit may be obtained for these courses until December 31, 2019.Copyright Statement: Copyright © 2019-2020. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Tali Czarnowicki, MD, MSc, Helen Y. He, BSc, James G. Krueger, MD, PhD, and Emma Guttman-Yassky, MD, PhD (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: J. G. Krueger has received research support (grants paid to his institution) and/or personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. E. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Celgene, Eli Lilly, Janssen, MedImmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB and is a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. The rest of the authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1.To describe the characteristics of intrinsic and extrinsic atopic dermatitis (AD).2.To identify the phenotypes and endotypes across ethnic groups.3.To distinguish the differences between AD in pediatric and adult patients.4.To list the current endotype-based targeted therapeutic approaches for AD.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Sasha Alvarado, DO, Diana Munoz-Mendoza, MD, Kim Jackson, MD, Rashmi D'Mello, MD, and Sami L. Bahna, MD, DrPHDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: January 2019. Credit may be obtained for these courses until December 31, 2019. Copyright Statement: Copyright © 2019-2020. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Tali Czarnowicki, MD, MSc, Helen Y. He, BSc, James G. Krueger, MD, PhD, and Emma Guttman-Yassky, MD, PhD (authors); Zuhair K. Ballas, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: J. G. Krueger has received research support (grants paid to his institution) and/or personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. E. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from Abbvie, Celgene, Eli Lilly, Janssen, MedImmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB and is a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. The rest of the authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships. Activity Objectives:1.To describe the characteristics of intrinsic and extrinsic atopic dermatitis (AD).2.To identify the phenotypes and endotypes across ethnic groups.3.To distinguish the differences between AD in pediatric and adult patients.4.To list the current endotype-based targeted therapeutic approaches for AD. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Sasha Alvarado, DO, Diana Munoz-Mendoza, MD, Kim Jackson, MD, Rashmi D'Mello, MD, and Sami L. Bahna, MD, DrPH Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. Atopic dermatitis (AD) is a highly heterogeneous inflammatory skin disorder.1Bieber T. D'Erme A.M. Akdis C.A. Traidl-Hoffmann C. Lauener R. Schappi G. et al.Clinical phenotypes and endophenotypes of atopic dermatitis: where are we, and where should we go?.J Allergy Clin Immunol. 2017; 139: S58-S64Abstract Full Text Full Text PDF PubMed Google Scholar Skin and blood phenotyping and genotyping advancements, as well as the development of targeted therapeutics over the past few years, portray a complex disease profile.2Czarnowicki T. Gonzalez J. Shemer A. Malajian D. Xu H. Zheng X. et al.Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population.J Allergy Clin Immunol. 2015; 136: 104-115Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 3Czarnowicki T. Esaki H. Gonzalez J. Malajian D. Shemer A. Noda S. et al.Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)(+) TH2/TH1 cell imbalance, whereas adults acquire CLA(+) TH22/TC22 cell subsets.J Allergy Clin Immunol. 2015; 136: 941-951Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 4Brunner P.M. Emerson R.O. Tipton C. Garcet S. Khattri S. Coats I. et al.Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues.Allergy. 2017; 72: 2017-2025Crossref PubMed Scopus (12) Google Scholar, 5Guttman-Yassky E. Waldman A. Ahluwalia J. Ong P.Y. Eichenfield L.F. Atopic dermatitis: pathogenesis.Semin Cutan Med Surg. 2017; 36: 100-103Crossref PubMed Scopus (2) Google Scholar, 6Brunner P.M. Guttman-Yassky E. Leung D.Y. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies.J Allergy Clin Immunol. 2017; 139: S65-S76Abstract Full Text Full Text PDF PubMed Google Scholar Endotype is defined as the molecular mechanisms underlying the disease's visible features/phenotype.7Agache I. Akdis C. Jutel M. Virchow J.C. Untangling asthma phenotypes and endotypes.Allergy. 2012; 67: 835-846Crossref PubMed Scopus (163) Google Scholar, 8Lotvall J. Akdis C.A. Bacharier L.B. Bjermer L. Casale T.B. Custovic A. et al.Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome.J Allergy Clin Immunol. 2011; 127: 355-360Abstract Full Text Full Text PDF PubMed Scopus (673) Google Scholar An example of an endotype that can control a phenotype is the presence of high IgE levels in patients with an allergic phenotype. AD is not only diverse phenotypically (children vs adults and white vs Asian patients) but is also characterized by a highly diverse endotype repertoire (TH1/TH2/TH17/TH22 immune activation with a compromised epidermal barrier, including terminal differentiation and lipid and tight junction abnormalities9Brunner P.M. Leung D.Y.M. Guttman-Yassky E. Immunologic, microbial, and epithelial interactions in atopic dermatitis.Ann Allergy Asthma Immunol. 2018; 120: 34-41Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). In patients with AD and other allergic disorders, few subendotypes comprised of several determinants with dynamic interactions can lead to a “complex endotype” that drives a specific phenotype.10Agache I. Akdis C.A. Endotypes of allergic diseases and asthma: an important step in building blocks for the future of precision medicine.Allergol Int. 2016; 65: 243-252Abstract Full Text Full Text PDF PubMed Google Scholar Despite these complexities, AD is generally managed according to a “one-size-fits-all” therapeutic approach, rather than adapting personalized, precision, endotype, and ethnicity-driven therapeutic strategies. Stratification of endotypes and definition of disease biomarkers specific to the different AD phenotypes might be important for developing personalized medicine approaches that can potentially improve therapeutic outcomes. There are 2 major approaches for characterization and stratification of AD endotypes. The first encompasses endotyping based on molecular profiling across the entire AD spectrum.11Thijs J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Csomor E. et al.Moving toward endotypes in atopic dermatitis: identification of patient clusters based on serum biomarker analysis.J Allergy Clin Immunol. 2017; 140: 730-737Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 12Thijs J.L. Herath A. de Bruin-Weller M.S. Hijnen D. Multiplex platform technology and bioinformatics are essential for development of biomarkers in atopic dermatitis.J Allergy Clin Immunol. 2017; 139: 1065Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 13Thijs J.L. van Seggelen W. Bruijnzeel-Koomen C. de Bruin-Weller M. Hijnen D. New developments in biomarkers for atopic dermatitis.J Clin Med. 2015; 4: 479-487Crossref PubMed Google Scholar Recent principal component analysis based on 147 serum mediators from 193 patients with AD and 30 healthy control subjects divided the AD population into 4 main clusters characterized by unique serum measures.11Thijs J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Csomor E. et al.Moving toward endotypes in atopic dermatitis: identification of patient clusters based on serum biomarker analysis.J Allergy Clin Immunol. 2017; 140: 730-737Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar This approach does not differentiate between ethnic groups, the patient's geographic origin, or other clinical or demographic characteristics and in the United States has to be performed in a Clinical Laboratory Improvement Amendments–certified facility if used for therapeutic decisions. Conversely, the alternative methodology includes detailed endotyping based on specific clinical, ethnic, or demographic patient groups, assuming AD is not one spectrum but rather comprises different disease phenotypes. According to the second approach, in this review we will describe different endotypes of specific clinical and ethnic AD subsets (summarized in Fig 1) and will discuss how they translate into advancing precision therapeutic approaches for AD. AD is characterized clinically by acute and chronic stages. Acute (new onset, within 72 hours) lesions are usually erythematous, wet, and highly inflammatory, turning lichenified, dry, thick, and hyperpigmented in patients with chronic disease.14Weidinger S. Beck L.A. Bieber T. Kabashima K. Irvine A.D. Atopic dermatitis.Nat Rev Dis Primers. 2018; 4: 1Crossref PubMed Scopus (33) Google Scholar, 15Guttman-Yassky E. Nograles K.E. Krueger J.G. Contrasting pathogenesis of atopic dermatitis and psoriasis—part I: clinical and pathologic concepts.J Allergy Clin Immunol. 2011; 127: 1110-1118Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 16Bieber T. Atopic dermatitis.N Engl J Med. 2008; 358: 1483-1494Crossref PubMed Scopus (1260) Google Scholar Comparing the skin profile of nonlesional, acute, and chronic AD skin17Gittler J.K. Shemer A. Suarez-Farinas M. Fuentes-Duculan J. Gulewicz K.J. Wang C.Q. et al.Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.J Allergy Clin Immunol. 2012; 130: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar showed both barrier and immune disparities between disease stages. Chronic lesions are more hyperplastic and proliferative, with increased keratin 16 mRNA expression and Ki67 counts. The initiation of acute lesions is accompanied by marked increases in antimicrobial peptide (AMP) levels (S100A7/S100A8/S100A9) and TH2 and TH22 cytokine upregulation, with positive correlations between IL22 mRNA levels and AD severity determined based on SCORAD scores. Lesser inductions of TH17 markers are also observed in acute lesions. With disease chronicity, there is intensification of TH2 and TH22 cytokine axes, with significant increases in TH1 markers in patients with chronic AD but no further increases in TH17 markers. AD can be classified according to IgE levels into extrinsic and intrinsic subgroups. The classic (80%) extrinsic phenotype is characterized by high total and environmental serum IgE levels, eosinophilia, personal and family atopic background, and greater rate of filaggrin (FLG) mutation.18Karimkhani C. Silverberg J.I. Dellavalle R.P. Defining intrinsic vs. extrinsic atopic dermatitis.Dermatol Online J. 2015; 21Google Scholar, 19Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 20Tokura Y. Extrinsic and intrinsic types of atopic dermatitis.J Dermatol Sci. 2010; 58: 1-7Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Despite a similar clinical presentation, patients with intrinsic AD (20%) have normal IgE levels; have female predominance; show delayed disease onset and preserved barrier function, as measured based on transepidermal water loss (TEWL)20Tokura Y. Extrinsic and intrinsic types of atopic dermatitis.J Dermatol Sci. 2010; 58: 1-7Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar; have increased metal contact hypersensitivity20Tokura Y. Extrinsic and intrinsic types of atopic dermatitis.J Dermatol Sci. 2010; 58: 1-7Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar; and lack any other atopic background.21Akdis C.A. Akdis M. Immunological differences between intrinsic and extrinsic types of atopic dermatitis.Clin Exp Allergy. 2003; 33: 1618-1621Crossref PubMed Scopus (57) Google Scholar, 22Kulthanan K. Boochangkool K. Tuchinda P. Chularojanamontri L. Clinical features of the extrinsic and intrinsic types of adult-onset atopic dermatitis.Asia Pac Allergy. 2011; 1: 80-86Crossref PubMed Google Scholar In blood the intrinsic endotype includes TH1 but not TH2 or TH17 marker increases and low CCL17/thymus and activation-regulated chemokine levels.23Kabashima-Kubo R. Nakamura M. Sakabe J. Sugita K. Hino R. Mori T. et al.A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: possible immunological state of the intrinsic type.J Dermatol Sci. 2012; 67: 37-43Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar We compared molecular and cellular measures in lesional and nonlesional skin of 42 patients with extrinsic and 9 patients with intrinsic AD. Both disease forms showed increased T-cell and dendritic cell cutaneous infiltrates along with epidermal hyperplasia in lesional compared with nonlesional skin; however, greater cellular infiltrates (T cells, myeloid dendritic cells, and Langerhans cells) were seen in patients with intrinsic AD. Nonlesional measures were overall comparable between the 2 groups. Contrary to past studies,23Kabashima-Kubo R. Nakamura M. Sakabe J. Sugita K. Hino R. Mori T. et al.A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: possible immunological state of the intrinsic type.J Dermatol Sci. 2012; 67: 37-43Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 24Park J.H. Choi Y.L. Namkung J.H. Kim W.S. Lee J.H. Park H.J. et al.Characteristics of extrinsic vs. intrinsic atopic dermatitis in infancy: correlations with laboratory variables.Br J Dermatol. 2006; 155: 778-783Crossref PubMed Scopus (0) Google Scholar data did not show a bias toward TH2 in patients with extrinsic AD, and TH2 marker increases were grossly similar between intrinsic and extrinsic lesional skin. Increased TH1 signal (IFN-γ, CXCL9, CXCL10, and MX-1) and more pronounced TH17/TH22 activation (IL-17A, CCL20, Elafin, and IL-22) historically linked to psoriasis25Guttman-Yassky E. Lowes M.A. Fuentes-Duculan J. Zaba L.C. Cardinale I. Nograles K.E. et al.Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis.J Immunol. 2008; 181: 7420-7427Crossref PubMed Google Scholar were significantly greater in patients with intrinsic AD. Parallel to these increases, levels of the antimicrobials S100A9 and S100A12, which are coregulated by IL-17/IL-22,26Kolls J.K. McCray Jr., P.B. Chan Y.R. Cytokine-mediated regulation of antimicrobial proteins.Nat Rev Immunol. 2008; 8: 829-835Crossref PubMed Scopus (218) Google Scholar were greater in intrinsic versus extrinsic lesions. Although TH2 markers in patients with extrinsic AD correlated positively with disease severity and negatively with barrier products (loricrin [LOR], periplakin, and FLG), TH1/interferon-related gene expression and levels of the TH17 chemokine CCL20 correlated with disease severity in patients with intrinsic AD. Later reports showed an inflammatory (IL-22, IL-36α/γ, IL-36RN, and CCL22) and lipid metabolism pathway overlap between intrinsic AD and psoriasis, further supporting TH17/IL-23 and IL-22 as common denominators of the 2 conditions.27Ewald D.A. Malajian D. Krueger J.G. Workman C.T. Wang T. Tian S. et al.Meta-analysis derived atopic dermatitis (MADAD) transcriptome defines a robust AD signature highlighting the involvement of atherosclerosis and lipid metabolism pathways.BMC Med Genomics. 2015; 8: 60Crossref PubMed Scopus (82) Google Scholar, 28Martel B.C. Litman T. Hald A. Norsgaard H. Lovato P. Dyring-Andersen B. et al.Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis.Exp Dermatol. 2016; 25: 453-459Crossref PubMed Scopus (21) Google Scholar Endotyping AD according to different ethnic backgrounds is critical for establishing disease biomarkers and nurturing precision therapeutic approaches. Although AD prevalence in European American (EA) adults is approximately 3% to 4%,29Hanifin J.M. Reed M.L. Eczema P. Impact Working G. A population-based survey of eczema prevalence in the United States.Dermatitis. 2007; 18: 82-91Crossref PubMed Scopus (208) Google Scholar, 30Silverberg J.I. Hanifin J.M. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study.J Allergy Clin Immunol. 2013; 132: 1132-1138Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar it is substantially greater in Asian countries (7% to 10%).31Torrelo A. Atopic dermatitis in different skin types. What is to know?.J Eur Acad Dermatol Venereol. 2014; 28: 2-4Crossref PubMed Scopus (18) Google Scholar, 32Saeki H. Tsunemi Y. Fujita H. Kagami S. Sasaki K. Ohmatsu H. et al.Prevalence of atopic dermatitis determined by clinical examination in Japanese adults.J Dermatol. 2006; 33: 817-819Crossref PubMed Scopus (46) Google Scholar, 33Sugiura H. Umemoto N. Deguchi H. Murata Y. Tanaka K. Sawai T. et al.Prevalence of childhood and adolescent atopic dermatitis in a Japanese population: comparison with the disease frequency examined 20 years ago.Acta Derm Venereol. 1998; 78: 293-294Crossref PubMed Scopus (125) Google Scholar Studying the Asian AD endotype, Koga et al34Koga C. Kabashima K. Shiraishi N. Kobayashi M. Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis.J Invest Dermatol. 2008; 128: 2625-2630Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar showed increased TH17 frequencies in blood and acute lesions of Japanese patients with AD, both of which are associated with AD severity. These results are in contrast to skin and blood data from EA patients with extrinsic AD who did not show TH17 axis activation.2Czarnowicki T. Gonzalez J. Shemer A. Malajian D. Xu H. Zheng X. et al.Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population.J Allergy Clin Immunol. 2015; 136: 104-115Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 19Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar A study comparing lesional and nonlesional skin of EA and Asian (Japanese and Koreans) patients with AD with that of patients with psoriasis and control subjects showed prominent epidermal hyperplasia and marked parakeratosis in Asian subject but relatively preserved barrier proteins (LOR and FLG). RT-PCR analysis revealed that although TH2 markers (IL-13, CCL17, CCL18, and CCL22) were similar between Asian and EA patients with AD, TH1 markers were significantly lower in lesional and nonlesional tissues of Asian patients with AD, possibly because of negative regulation by TH17 marker increased.35Mills K.H. Induction, function and regulation of IL-17-producing T cells.Eur J Immunol. 2008; 38: 2636-2649Crossref PubMed Scopus (0) Google Scholar, 36Damsker J.M. Hansen A.M. Caspi R.R. Th1 and Th17 cells: adversaries and collaborators.Ann N Y Acad Sci. 2010; 1183: 211-221Crossref PubMed Scopus (245) Google Scholar Importantly, greater expression of TH17-related cytokines (IL-17A and IL-19) and related markers (CCL20), as well as IL-22 and the IL-17/IL-22–induced S100A12, were seen in lesional and nonlesional skin of Asian patients with AD. Levels of IL-19, which was induced by IL-4, IL-13, and IL-17 and augments IL-17's effects on keratinocytes,37Witte E. Kokolakis G. Witte K. Philipp S. Doecke W.D. Babel N. et al.IL-19 is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis.J Invest Dermatol. 2014; 134: 2757-2767Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 38Huang F. Wachi S. Thai P. Loukoianov A. Tan K.H. Forteza R.M. et al.Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma.J Allergy Clin Immunol. 2008; 121: 1415-1421Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar were significantly greater in AD lesions of Asian versus EA patients. These data suggest that Asian patients with AD are characterized by a unique blended immune dysregulation and barrier feature phenotype between EA patients with AD and those with psoriasis. In line with their skin endotype, increased levels of TH2 cytokines and related chemokines were similarly seen in sera of EA and Asian patients with AD, correlating with AD severity and IgE levels.39Wen H.C. Czarnowicki T. Noda S. Malik K. Pavel A.B. Nakajima S. et al.Serum from Asian patients with atopic dermatitis is characterized by TH2/TH22 activation, which is highly correlated with nonlesional skin measures.J Allergy Clin Immunol. 2018; 142: 324-328Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Additionally, lower IFN-γ levels and levels of other TH1-related markers were detected in sera from Asian patients. IL-17 levels were equally increased in sera of EA and Asian patients, but levels of the hyperplasia-inducing cytokine IL-22 were substantially increased in the blood of Asian patients compared with that of EA patients. Eventually, levels of a series of TH2 markers and IL-22 in serum correlated positively with their mRNA expression specifically in nonlesional skin, supporting their potential as biomarkers reflecting overall rather than lesion-limited disease activity.39Wen H.C. Czarnowicki T. Noda S. Malik K. Pavel A.B. Nakajima S. et al.Serum from Asian patients with atopic dermatitis is characterized by TH2/TH22 activation, which is highly correlated with nonlesional skin measures.J Allergy Clin Immunol. 2018; 142: 324-328Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Studies suggest that Chinese patients with AD have a unique clinical phenotype compared with EA patients with AD.40Liu P. Zhao Y. Mu Z.L. Lu Q.J. Zhang L. Yao X. et al.Clinical features of adult/adolescent atopic dermatitis and chinese criteria for atopic dermatitis.Chin Med J (Engl). 2016; 129: 757-762Crossref PubMed Scopus (19) Google Scholar Our recent study41Chan T.C. Sanyal R.D. Pavel A.B. Glickman J. Zheng X. Cho Y. et al.Variable T(H)2/T(H)17-skewing places Chinese atopic dermatitis and psoriasis on an inflammatory spectrum.J Invest Dermatol. 2018; 138: S10Abstract Full Text Full Text PDF PubMed Google Scholar that compared Chinese patients with AD and patients with psoriasis versus control subjects showed that AD in Han Chinese patients is accompanied by remarkable epidermal hyperplasia, robust TH2 cytokine and chemokine activation (IL-4, IL-13, IL-5, IL-10, IL-31, and CCL13/17/18/22/26), and TH17/IL-23–induced (eg, IL-17F/IL-19/IL-21/CCL20) and TH17/TH22-induced (IL-22/S100As) marker upregulation. SCORAD scores correlated with IL-31, IL-5, and IL-17A levels. We also compared Chinese patients with AD with patients with the EA AD phenotype and found that lesional TH17 expression was greater, whereas levels of I
Referência(s)