{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:24:18Z","timestamp":1789748658016,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T00:00:00Z","timestamp":1712275200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012331","name":"LEO Fondet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012331","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006286","name":"Kongelig Hofbuntmager Aage Bangs Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006286","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011055","name":"Milj\u00f8- og F\u00f8devareministeriet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Contact Dermatitis"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the clinical and subclinical immune response to low\u2010dose nickel exposure on nickel pre\u2010exposed skin to assess the adequacy of current regulatory limits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Nickel\u2010allergic and healthy controls were patch tested with nickel twice with a 3\u20134\u2009weeks interval. The first exposure used the diagnostic concentration of 2000\u2009\u03bcg\/cm<jats:sup>2<\/jats:sup> nickel sulphate, and the same skin areas were then re\u2010exposed to 0.2, 0.5, 12.8 and 370\u2009\u03bcg\/cm<jats:sup>2<\/jats:sup> nickel sulphate. After 48\u2009h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two nickel\u2010allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2\/0.5\u2009\u03bcg\/cm<jats:sup>2<\/jats:sup>) following re\u2010exposure. There was immune activation in all skin areas following re\u2010exposure to nickel, predominantly mediated by up\u2010regulation of cytokines and chemokines. In all nickel re\u2010exposed skin areas, 81 genes were up\u2010regulated independent from the clinical response. In skin areas exposed to 0.2\u2009\u03bcg\/cm<jats:sup>2<\/jats:sup>, 101 immune\u2010related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up\u2010regulation of three genes in response to nickel re\u2010exposures without any clinical reactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low\u2010dose exposures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cod.14549","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T08:45:03Z","timestamp":1712306703000},"page":"1-10","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Subclinical immune responses to nickel in sensitized individuals\u2014a dose\u2013response study"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5071-283X","authenticated-orcid":false,"given":"Michael","family":"Wennervaldt","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergy, National Allergy Research Centre Copenhagen University Hospital Herlev\u2010Gentofte  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8845-0326","authenticated-orcid":false,"given":"Helen","family":"Vaher","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2092-7826","authenticated-orcid":false,"given":"Malin G.","family":"Ahlstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, National Allergy Research Centre Copenhagen University Hospital Herlev\u2010Gentofte  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4929-4371","authenticated-orcid":false,"given":"Nuno","family":"Bischofberger","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torkil","family":"Menn\u00e9","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, National Allergy Research Centre Copenhagen University Hospital Herlev\u2010Gentofte  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3770-1743","authenticated-orcid":false,"given":"Jacob P.","family":"Thyssen","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, National Allergy Research Centre Copenhagen University Hospital Herlev\u2010Gentofte  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3537-8463","authenticated-orcid":false,"given":"Jeanne D.","family":"Johansen","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, National Allergy Research Centre Copenhagen University Hospital Herlev\u2010Gentofte  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0523-6229","authenticated-orcid":false,"given":"Charlotte M.","family":"Bonefeld","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.14167"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0536.2007.01257.x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/cod.12492"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/oem.60.12.954"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2020-0628"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljad488"},{"key":"e_1_2_11_8_1","first-page":"1","article-title":"Regulation (EC) No 1907\/2006 of the European Parliament and of the council of 18 December 2006 concerning the registration, evaluation, authorisation and restriction of chemicals (REACH)","volume":"396","author":"The Commission of the European Communities","year":"2006","journal-title":"Off J Eur Union"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cod.12775"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cod.13136"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.16935"},{"issue":"212","key":"e_1_2_11_12_1","first-page":"11","article-title":"Human stratum corneum adsorption of nickel salts. 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