{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:01:02Z","timestamp":1765976462609,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1C1C1011296"],"award-info":[{"award-number":["2020R1C1C1011296"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>IL-31 is involved in pruritus in atopic dermatitis (AD) and the pathogenesis of AD. However, the mechanism of IL-31 production is not fully understood. We sought to investigate the association between CD45RO+CLA+H4R+ T cells and IL-31 production. Immunofluorescence studies were performed retrospectively on punch-biopsy specimens from five people with AD and three healthy controls. In addition, blood samples were collected prospectively from eight patients with AD and eight healthy controls for sorting CD45RO+CLA+H4R+ T cells. There was no overlap of patients between the biopsy group and the blood sampling group. Sorted cells were stimulated with 4-methylhistamine (4MH), and the level of IL-31 was measured by an enzyme-linked immunosorbent assay. Immunofluorescence showed co-localization of H4R and IL-31 in lesional AD skin but not in normal skin of healthy controls. The proportion of CLA+H4R+ T cells among CD3+CD45RO+ lymphocytes was 18.3 \u00b1 6.2% in patients with AD and 11.2 \u00b1 7.6% in healthy controls. In the AD group, production of IL-31 by CD45RO+CLA+H4R+ T cells increased from 32.4 \u00b1 13.3 pg\/mL to 47.5 \u00b1 18.7 pg\/mL by 4MH stimulation after 24 h (p &lt; 0.001). However, in the control group, production of IL-31 was 20.1 \u00b1 10.6 pg\/mL without and 22.1 \u00b1 9.3 pg\/mL with 4MH stimulation (p &gt; 0.05). According to our study, CD45RO+CLA+H4R+ T cells are an important source of IL-31 in AD, and may be a target for treatment of IL-31-induced pruritus.<\/jats:p>","DOI":"10.3390\/jcm10091976","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T11:06:01Z","timestamp":1620212761000},"page":"1976","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Production of IL-31 in CD45RO+CLA+H4R+ T Cells in Atopic Dermatitis"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6246-0331","authenticated-orcid":false,"given":"Chul Hwan","family":"Bang","sequence":"first","affiliation":[{"name":"Department of Dermatology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-3032","authenticated-orcid":false,"given":"Ji Young","family":"Song","sequence":"additional","affiliation":[{"name":"Program of Immunology &amp; Microbiology, Department of Biomedicine &amp; Health Science, Graduate School, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu Mee","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3671-502X","authenticated-orcid":false,"given":"Ji Hyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Min","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/ni1084","article-title":"Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice","volume":"5","author":"Dillon","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.jaci.2017.10.045","article-title":"IL-31: A new key player in dermatology and beyond","volume":"141","author":"Bagci","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1468-3083.2010.03794.x","article-title":"Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: Elevated levels correlate with severity scoring","volume":"25","author":"Ezzat","year":"2011","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1056\/NEJMoa1606490","article-title":"Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis","volume":"376","author":"Ruzicka","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.jaci.2005.10.046","article-title":"IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis","volume":"117","author":"Bilsborough","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jaci.2013.03.050","article-title":"Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation","volume":"132","author":"Stott","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.jaci.2013.10.048","article-title":"A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1","volume":"133","author":"Cevikbas","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"645","DOI":"10.4049\/jimmunol.1301836","article-title":"Human Th2 but not Th9 cells release IL-31 in a STAT6\/NF-kappaB-dependent way","volume":"193","author":"Maier","year":"2014","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1111\/j.1365-2133.2011.10487.x","article-title":"Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells","volume":"165","author":"Cornelissen","year":"2011","journal-title":"Br. J. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd2465","article-title":"The role of histamine H1 and H4 receptors in allergic inflammation: The search for new antihistamines","volume":"7","author":"Thurmond","year":"2008","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.jaci.2008.12.1110","article-title":"The histamine H4 receptor is functionally expressed on T(H)2 cells","volume":"123","author":"Gutzmer","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.2332\/allergolint.13-RA-0675","article-title":"The role of histamine H1 and H4 receptors in AD","volume":"63","author":"Ohsawa","year":"2014","journal-title":"Allergol. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/cea.12875","article-title":"Human basophils are a source of\u2014and are differentially activated by\u2014IL-31","volume":"47","author":"Raap","year":"2017","journal-title":"Clin. Exp. Allergy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.jaci.2016.02.020","article-title":"The pruritus- and TH2-associated cytokine IL-31 promotes growth of sensory nerves","volume":"138","author":"Feld","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1189\/jlb.0111020","article-title":"Transcriptional activation of the IL31 gene by NFAT and STAT6","volume":"91","author":"Park","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S0952-7915(02)00395-3","article-title":"Immune regulation by histamine","volume":"14","author":"Jutel","year":"2002","journal-title":"Curr. Opin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1016\/j.jaci.2018.07.047","article-title":"Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis","volume":"143","author":"Werfel","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1600-0625.2008.00762.x","article-title":"Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation","volume":"18","author":"Rossbach","year":"2009","journal-title":"Exp. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/j.1398-9995.2009.02240.x","article-title":"Histamine H(4) receptor antagonist ameliorates chronic allergic contact dermatitis induced by repeated challenge","volume":"65","author":"Seike","year":"2010","journal-title":"Allergy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jaci.2006.08.034","article-title":"Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus","volume":"119","author":"Dunford","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/1346-8138.12726","article-title":"Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis","volume":"42","author":"Murata","year":"2015","journal-title":"J. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1124\/jpet.114.215749","article-title":"The histamine H(4) receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects","volume":"350","author":"Kollmeier","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/sj.jid.5701250","article-title":"Human inflammatory dendritic epidermal cells express a functional histamine H4 receptor","volume":"128","author":"Dijkstra","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5224","DOI":"10.4049\/jimmunol.174.9.5224","article-title":"Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells","volume":"174","author":"Gutzmer","year":"2005","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.jaci.2013.06.023","article-title":"Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor","volume":"132","author":"Glatzer","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.phrs.2016.08.001","article-title":"Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes","volume":"113","author":"Schaper","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.anai.2019.10.005","article-title":"New treatments for atopic dermatitis targeting beyond IL-4\/IL-13 cytokines","volume":"124","year":"2020","journal-title":"Ann. Allergy Asthma. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0140-6736(15)00388-8","article-title":"Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: A randomised, placebo-controlled, dose-ranging phase 2b trial","volume":"387","author":"Simpson","year":"2016","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1056\/NEJMoa1610020","article-title":"Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis","volume":"375","author":"Simpson","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1016\/S0140-6736(17)31191-1","article-title":"Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): A 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial","volume":"389","author":"Blauvelt","year":"2017","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.jaad.2018.01.018","article-title":"Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study","volume":"80","author":"Silverberg","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/bjd.17932","article-title":"The oral Janus kinase\/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: Results from a randomized double-blind placebo-controlled study","volume":"181","author":"Bissonnette","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.jaci.2018.11.053","article-title":"GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis","volume":"144","author":"Pavel","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jaad.2018.01.016","article-title":"Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial","volume":"78","author":"Brunner","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaci.2018.10.032","article-title":"Atopic dermatitis endotypes and implications for targeted therapeutics","volume":"143","author":"Czarnowicki","year":"2019","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/9\/1976\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:09Z","timestamp":1760162229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/9\/1976"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["jcm10091976"],"URL":"https:\/\/doi.org\/10.3390\/jcm10091976","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}