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      Contribution of Antigen-Processing Machinery Genetic Polymorphisms to Atopic Dermatitis

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          Abstract

          Atopic dermatitis (AD) is a chronic and recurrent inflammatory dermatosis. We recently described an association of the C allele of the single nucleotide polymorphism (SNP) rs26618 in the ERAP1 gene and a synergism of ERAP1 and ERAP2 effects on AD risk. Here, we examined whether polymorphisms of other antigen-presenting machinery genes encoding immunoproteasome components LMP2 and LMP7 and peptide transporter components TAP1 and TAP2 may also affect susceptibility to AD or its outcome. We found that the LMP7 rs2071543*T allele decreased disease risk by about 1.5-fold (odds ratio 0.66, 95% confidence interval 0.44–0.99). On the other hand, the LMP2 rs1351383*C allele reduced the mean age at diagnosis from 23 to 15 years ( p < 0.001). Similarly, the TAP1 rs1135216*C allele decreased the mean age at diagnosis from almost 20 to 14 years ( p = 0.033). The results are discussed in light of other reports on the role of these polymorphisms in human disease.

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          Atopic Dermatitis: Global Epidemiology and Risk Factors

          Atopic dermatitis (AD) is a chronic inflammatory skin disease posing a significant burden on health-care resources and patients' quality of life. It is a complex disease with a wide spectrum of clinical presentations and combinations of symptoms. AD affects up to 20% of children and up to 3% of adults; recent data show that its prevalence is still increasing, especially in low-income countries. First manifestations of AD usually appear early in life and often precede other allergic diseases such as asthma or allergic rhinitis. Individuals affected by AD usually have genetically determined risk factors affecting the skin barrier function or the immune system. However, genetic mutations alone might not be enough to cause clinical manifestations of AD, and it is merely the interaction of a dysfunctional epidermal barrier in genetically predisposed individuals with harmful effects of environmental agents which leads to the development of the disease. AD has been described as an allergic skin disease, but today, the contribution of allergic reactions to the initiation of AD is challenged, and it is proposed that allergy is rather a consequence of AD in subjects with a concomitant underlying atopic constitution. Treatment at best achieves symptom control rather than cure; there is thus a strong need to identify alternatives for disease prevention.
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            Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population.

            Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (P(combined) = 8.36 × 10(-18)), the major histocompatibility complex (MHC) region (P = 8.38 × 10(-20)), OR10A3-NLRP10 (P = 1.54 × 10(-22)), GLB1 (P = 2.77 × 10(-16)), CCDC80 (P = 1.56 × 10(-19)), CARD11 (P = 7.83 × 10(-9)), ZNF365 (P = 5.85 × 10(-20)) and CYP24A1-PFDN4 (P = 1.65 × 10(-8)). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.
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              The immunoproteasome in antigen processing and other immunological functions.

              Treatment of cells with interferon-γ leads to the replacement of the constitutive catalytic proteasome subunits β1, β2, and β5 by the inducible subunits LMP2 (β1i), MECL-1 (β2i), and LMP7 (β5i), respectively, building the so-called immunoproteasome. The incorporation of these subunits is required for the production of numerous MHC class-I restricted T cell epitopes. Recently, new evidence for an involvement of the immunoproteasome in other facets of the immune response emerged. Investigations of autoimmune diseases in animal models and a genetic predisposition of β5i in human autoimmune disorders suggest a crucial function of the immunoproteasome in proinflammatory diseases. The recent elucidation of the high-resolution structure of the immunoproteasome will facilitate the design of immunoproteasome selective inhibitors for pharmacological intervention. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Life (Basel)
                Life (Basel)
                life
                Life
                MDPI
                2075-1729
                10 April 2021
                April 2021
                : 11
                : 4
                : 333
                Affiliations
                [1 ]Laboratory of Immunogenetics and Tissue Immunology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. Rudolfa Weigla 12, 53-114 Wrocław, Poland; wanda.niepieklo-miniewska@ 123456hirszfeld.pl (W.N.-M.); andrzej.wisniewski@ 123456hirszfeld.pl (A.W.)
                [2 ]Department of Dermatology, Venereology and Allergology, Medical University of Wroclaw, 50-368 Wrocław, Poland; luke71@ 123456interia.pl
                [3 ]Department of Dermatology, Pediatric Dermatology and Oncology Clinic, ul. Kniaziewicza 1/5, 91-347 Lódź, Poland; joanna.narbutt@ 123456umed.lodz.pl (J.N.); aleksandra.lesiak@ 123456umed.lodz.pl (A.L.)
                [4 ]2nd Department of Internal Medicine, Medical University of Łódź, al. Kościuszki 4, 90-419 Łódź, Poland; piotr.kuna@ 123456umed.lodz.pl
                [5 ]Division of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Łódź, ul. Kopcińskiego 22, 90-153 Łódź, Poland
                Author notes
                Author information
                https://orcid.org/0000-0003-2067-4929
                https://orcid.org/0000-0003-2401-0070
                https://orcid.org/0000-0002-9224-8921
                Article
                life-11-00333
                10.3390/life11040333
                8070454
                b3a73712-48c9-42cb-a5d3-3996bcfcb5f3
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 22 March 2021
                : 07 April 2021
                Categories
                Article

                atopic dermatitis,genetics,lmp2,lmp7,tap1,tap2
                atopic dermatitis, genetics, lmp2, lmp7, tap1, tap2

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