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Microenvironmental network of clonal CXCL13+CD4+ T cells and Tregs in pemphigus chronic blisters

 Dawoon Han  ;  A Yeong Lee  ;  Taehee Kim  ;  Ji Young Choi  ;  Mi Yeon Cho  ;  Ahreum Song  ;  Changhyeon Kim  ;  Joon Ho Shim  ;  Hyun Je Kim  ;  Honesty Kim  ;  Hillary Blaize D'Angio  ;  Ryan Preska  ;  Aaron T Mayer  ;  Miri Kim  ;  Eun-Ji Choi  ;  Tae-Gyun Kim  ;  Eui-Cheol Shin  ;  Kyemyung Park  ;  Do-Young Kim  ;  Soo-Chan Kim  ;  Jong Hoon Kim 
 JOURNAL OF CLINICAL INVESTIGATION, Vol.133(23) : e166357, 2023-12 
Journal Title
Issue Date
Adrenal Cortex Hormones ; Autoantibodies ; Autoimmune Diseases* / drug therapy ; Blister / drug therapy ; CD4-Positive T-Lymphocytes ; Chemokine CXCL13 ; Desmoglein 3 ; Humans ; Pemphigus* / drug therapy
Autoimmune diseases ; Autoimmunity ; Dermatology ; Skin ; T cells
BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-β stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영) ORCID logo https://orcid.org/0000-0002-0194-9854
Kim, Soo Chan(김수찬) ORCID logo https://orcid.org/0000-0002-2327-4755
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
Kim, Tae-Gyun(김태균) ORCID logo https://orcid.org/0000-0002-2116-4579
Song, Ahreum(송아름)
Cho, Mi Yeon(조미연) ORCID logo https://orcid.org/0000-0001-9676-6681
Choi, Jiyoung(최지영) ORCID logo https://orcid.org/0000-0003-0630-5860
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