{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:40:12Z","timestamp":1791924012349,"version":"4.3.4"},"reference-count":73,"publisher":"National Academy of Sciences","issue":"48","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,11,26]]},"abstract":"<jats:p>\n                    Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease with a poorly understood immunopathogenesis. Here, we report that HS lesional skin is characterized by the expansion of innate lymphocytes and T cells expressing CD2, an essential activation receptor and adhesion molecule. Lymphocytes expressing elevated CD2 predominated with unique spatial distribution throughout the epidermis and hypodermis in the HS lesion. CD2\n                    <jats:sup>+<\/jats:sup>\n                    cells were mainly innate lymphocytes expressing the NK cell marker, CD56, and CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Importantly, these CD2\n                    <jats:sup>+<\/jats:sup>\n                    cells interacted with CD58 (LFA3) expressing epidermal keratinocytes and fibroblasts in the hypodermis. Granzyme A\n                    <jats:sup>bright<\/jats:sup>\n                    NKT cells (CD2\n                    <jats:sup>+<\/jats:sup>\n                    CD3\n                    <jats:sup>+<\/jats:sup>\n                    CD56\n                    <jats:sup>bright<\/jats:sup>\n                    ) clustered with \u03b1-SMA expressing fibroblasts juxtaposed to epithelialized tunnels and fibrotic regions of the hypodermis. Whereas NK cells (CD2\n                    <jats:sup>+<\/jats:sup>\n                    CD56\n                    <jats:sup>dim<\/jats:sup>\n                    ) were perforin\n                    <jats:sup>+<\/jats:sup>\n                    , granzymes A\n                    <jats:sup>+<\/jats:sup>\n                    and B\n                    <jats:sup>+<\/jats:sup>\n                    , and enriched adjacent to hyperplastic follicular epidermis and tunnels of HS showing presence of apoptotic cells. The cytokines IL-12, IL-15, and IL-18, which enhance NK cell maturation and function were significantly elevated in HS. Ex vivo HS skin explant cultures treated with CD2:CD58 interaction-blocking anti-CD2 monoclonal antibody attenuated secretion of inflammatory cytokines\/chemokines and suppressed inflammatory gene signature. Additionally, CD2:CD58 blockade altered miRNAs involved in NK\/NKT differentiation and\/or function. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation and is critical in the pathobiology of HS, including tunnel formation and fibrosis. Finally, CD2 blockade is a viable immunotherapeutic approach for the effective management of HS.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2409274121","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T10:46:41Z","timestamp":1732013201000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["CD2 expressing innate lymphoid and T cells are critical effectors of immunopathogenesis in hidradenitis suppurativa"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7924-4793","authenticated-orcid":false,"given":"Mahendra","family":"Pratap Kashyap","sequence":"first","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7505-5722","authenticated-orcid":false,"given":"Bharat","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Biology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-0839","authenticated-orcid":false,"given":"Rajesh","family":"Sinha","sequence":"additional","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6590-8755","authenticated-orcid":false,"given":"Lin","family":"Jin","sequence":"additional","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5466-7359","authenticated-orcid":false,"given":"YiFei","family":"Gou","sequence":"additional","affiliation":[{"name":"Department of Biology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6095-7902","authenticated-orcid":false,"given":"Nilesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6930-6636","authenticated-orcid":false,"given":"Kayla F.","family":"Goliwas","sequence":"additional","affiliation":[{"name":"Department of Medicine (Division of Pulmonary, Allergy and Critical Care Medicine) at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7162-731X","authenticated-orcid":false,"given":"Safiya","family":"Haque","sequence":"additional","affiliation":[{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessy","family":"Deshane","sequence":"additional","affiliation":[{"name":"Department of Medicine (Division of Pulmonary, Allergy and Critical Care Medicine) at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Berglund","sequence":"additional","affiliation":[{"name":"Department of Research and Development, ITB-MED AB, Stockholm 113 68, Sweden"},{"name":"Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, and Division of Transplantation Surgery, Karolinska Institute, Stockholm 171 76, Sweden"},{"name":"Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm 171 77, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Berglund","sequence":"additional","affiliation":[{"name":"Department of Research and Development, ITB-MED AB, Stockholm 113 68, Sweden"},{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 85, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1475-2874","authenticated-orcid":false,"given":"Boni E.","family":"Elewski","sequence":"additional","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7131-4697","authenticated-orcid":false,"given":"Craig A.","family":"Elmets","sequence":"additional","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5829-7992","authenticated-orcid":false,"given":"Mohammad","family":"Athar","sequence":"additional","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Shahid","family":"Mukhtar","sequence":"additional","affiliation":[{"name":"Department of Biology at the University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Genetics &amp; Biochemistry at Clemson University, Clemson, SC 29634"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7775-9988","authenticated-orcid":false,"given":"Chander","family":"Raman","sequence":"additional","affiliation":[{"name":"Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294"},{"name":"Department of Dermatology at the University of Alabama at Birmingham, Birmingham, AL 35294"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0149-1"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2009.00915.x"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2021.1677"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2022.01.006"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav5908"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.139932"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.139930"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.665873"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.05.012"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2021.07.187"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106896"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2315096120"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.36849\/JDD.6752"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.16691"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/dth.15116"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2023.07.023"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljad345"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0770-x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.599526"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljac096"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI169225"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01090"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.005"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI159402"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00763"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1159\/000477172"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-85960-6"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120944"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0261-x"},{"key":"e_1_3_4_31_2","article-title":"Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa","volume":"9","author":"Lowe M. M.","year":"2024","unstructured":"M. M. Lowe , Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa. JCI Insight 9, e169870 (2024).","journal-title":"JCI Insight"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.022"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646492"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-017-1074-y"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.10.008"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000699"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.09.009"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0995-x"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.12.651"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.627396"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.123253"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-78688-2"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000644"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.142067"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1814642116"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20212434"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI128678"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-022-01629-w"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.08.021"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100057"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111386"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00119"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.06.004"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/bjd\/ljad305"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz1965"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-1140"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150904"},{"key":"e_1_3_4_58_2","doi-asserted-by":"crossref","unstructured":"M. S. Mukhtar B. Mishra M. Athar Integrative systems biology framework discovers common gene regulatory signatures in multiple mechanistically distinct inflammatory skin diseases. Res. Sq. [Preprint] (2023). https:\/\/doi.org\/10.21203\/rs.3.rs-3611240\/v1 (Accessed 24 August 2024).","DOI":"10.21203\/rs.3.rs-3611240\/v1"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00847"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00974-6"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abq7991"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.11.049"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.11.018"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-01037-6"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.15533"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.592553"},{"key":"e_1_3_4_67_2","first-page":"411","article-title":"The safety and efficacy of alefacept in the treatment of chronic plaque psoriasis","volume":"3","author":"Jenneck C.","year":"2007","unstructured":"C. Jenneck, N. Novak, The safety and efficacy of alefacept in the treatment of chronic plaque psoriasis. Ther. Clin. Risk. Manag. 3, 411\u2013420 (2007).","journal-title":"Ther. Clin. Risk. Manag."},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.4110\/in.2018.18.e11"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3065"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01024-x"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1304410110"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2014.01.007"},{"key":"e_1_3_4_73_2","unstructured":"M. P. Kashyap CD2 expressing innate lymphoid and t cells are critical effectors of immunopathogenesis in hidradenitis suppurativa. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?&acc=GSE274880. Deposited 15 August 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2409274121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T10:47:34Z","timestamp":1732013254000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2409274121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":73,"journal-issue":{"issue":"48","published-print":{"date-parts":[[2024,11,26]]}},"alternative-id":["10.1073\/pnas.2409274121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2409274121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,19]]},"assertion":[{"value":"2024-05-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2409274121"}}