Multi-omics segregate different transcriptomic impacts of anti-IL-17A blockade on type 17 T-cells and regulatory immune cells in psoriasis skin.
Multi-omics segregate different transcriptomic impacts of anti-IL-17A blockade on type 17 T-cells and regulatory immune cells in psoriasis skin.
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多组学分离了抗 IL-17A 阻断对银屑病皮肤中 17 型 T 细胞和调节性免疫细胞的不同转录组影响。
DOI：
10.3389/fimmu.2023.1250504
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发表时间：
2023
影响因子：
7.3
通讯作者：
Krueger, James G.
中科院分区：
文献类型：
--
作者：
Kim, Jaehwan;Lee, Jongmi;Li, Xuan;Kunjravia, Norma;Rambhia, Darshna;Cueto, Inna;Kim, Katherine;Chaparala, Vasuma;Ko, Younhee;Garcet, Sandra;Zhou, Wei;Cao, Junyue;Krueger, James G.
关键词：
据报道，在部分牛皮癣患者停用阻断IL-23/17型T细胞(T17)自身免疫轴的生物制剂治疗后，牛皮癣得到了持久的改善。然而，系统性阻断IL-23/T17轴是否能促进牛皮癣皮肤的免疫耐受尚不清楚。这项研究的目的是找到系统性IL-17A阻断促进银屑病皮肤免疫细胞亚群调节性转录组修饰的翻译证据。我们用多基因组学方法分析了系统性IL-17A阻断前后人类银屑病皮损皮肤6 mm穿孔活检组织，结合免疫细胞富集型scRNA-seq(n=18)、微阵列(n=61)和免疫组织化学(n=61)数据，并存储正常对照皮肤免疫细胞富集型scRNA-seq(n=10)和微阵列(n=8)数据。对于T17轴转录组，系统性IL-17A阻断可耗尽银屑病皮肤中100%的IL17A+T细胞和95%的IL17F+T细胞。IL-17A阻断可下调DC亚群中IL-23A的表达。IL-17驱动的炎症介质(IL36G、S100A8、DEFB4A和DEFB4B)在基底层角质形成细胞中的表达与银屑病的严重程度相关，并被IL-17A阻断而下调。对于调节性DC转录组，银屑病皮损治疗后皮肤中表达BDCA-3(THBD)和DCIR(CLEC4A)调节性DC标志物的调节性半表型DC比例较治疗前增加。此外，与治疗前相比，IL-17A阻断可诱导CD1c+CD14+树突状细胞(DC)亚群中抑制抗原特异性T细胞反应的CD1C和CD14的表达增加。综上所述，全身性IL-17A抑制不仅阻断了整个IL-23/T17细胞轴，而且促进了人类银屑病皮肤调节性树突状细胞中调节基因的表达。
Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (IL36G, S100A8, DEFB4A, and DEFB4B) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of BDCA-3 (THBD) and DCIR (CLEC4A) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14, which are markers of CD1c+ CD14+ dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.
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影响因子：
0.9
作者：
Farrag, Dina A.;Asaad, Marwa K.;Ghobrial, Christine K.
通讯作者：
Ghobrial, Christine K.
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
人白细胞介素17产生的细胞起源于CD161+ CD4+ T细胞前体。
影响因子：
15.3
作者：
Cosmi, Lorenzo;De Palma, Raffaele;Santarlasci, Veronica;Maggi, Laura;Capone, Manuela;Frosali, Francesca;Rodolico, Gabriella;Querci, Valentina;Abbate, Gianfranco;Angeli, Roberta;Berrino, Liberato;Fambrini, Massimiliano;Caproni, Marzia;Tonelli, Francesco;Lazzeri, Elena;Parronchi, Paola;Liotta, Francesco;Maggi, Enrico;Romagnani, Sergio;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
影响因子：
3
作者：
Cameron, AL;Kirby, B;Griffiths, CEM
通讯作者：
Griffiths, CEM
影响因子：
10.3
作者：
Gisondi, P.;Tessari, G.;Girolomoni, G.
通讯作者：
Girolomoni, G.