Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis.
Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis.
复制标题
DOI：
10.1038/s41467-021-25066-9
复制
发表时间：
2021-08-06
影响因子：
16.6
通讯作者：
PSORT Consortium
中科院分区：
文献类型：
--
作者：
Andres-Ejarque R;Ale HB;Grys K;Tosi I;Solanky S;Ainali C;Catak Z;Sreeneebus H;Saklatvala J;Dand N;de Rinaldis E;Chapman A;Nestle FO;Barnes MR;Warren RB;Reynolds NJ;Griffiths CEM;Barker JN;Smith CH;Di Meglio P;PSORT Consortium
生物疗法已经改变了银屑病的管理，但临床结果是可变的，留下了未满足的临床需求的预测生物标志物的反应。在此，我们对67例银屑病患者在抗TNF药物阿达木单抗治疗前和治疗期间的血液免疫细胞进行了深入的免疫监测，以确定临床反应的免疫介质并评估其预测价值。治疗前2型树突状细胞（DC）中TNF和LPS诱导的NF-κ Bp 65磷酸化增强与治疗12周后缺乏临床应答显著相关。NF-κB活化的增强与DC体外成熟的增加和治疗前无应答者血液中IL-17+ T细胞的频率有关。此外，无应答者的病变皮肤含有更高数量的表达成熟标志物CD 83并产生IL-23的真皮DC，以及增加数量的IL-17+ T细胞。最后，我们确定并临床验证了治疗前LPS诱导的NF-κ Bp 65磷酸化作为阿达木单抗无应答的预测生物标志物，在一个独立队列中具有100%的灵敏度和90.1%的特异性。我们的研究揭示了阿达木单抗在银屑病中作用机制的重要分子和细胞介质，并提出了一种预测临床结局的血液生物标志物。银屑病患者需要生物标志物来指示对生物疗法的潜在反应。在此，作者表明，治疗前cDC 2中NFκ Bp 65的磷酸化是银屑病患者对抗TNF治疗阿达木单抗无应答的指征。
Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome. Biomarkers to indicate potential response to biologic therapeutics are needed for patients with psoriasis. Here the authors show that phosphorylation of NFκBp65 in cDC2 before therapy is an indication of non-response to the anti-TNF therapy adalimumab in patients with psoriasis.
登录
查看更多内容
影响因子：
30.8
作者：
Nair RP;Duffin KC;Helms C;Ding J;Stuart PE;Goldgar D;Gudjonsson JE;Li Y;Tejasvi T;Feng BJ;Ruether A;Schreiber S;Weichenthal M;Gladman D;Rahman P;Schrodi SJ;Prahalad S;Guthery SL;Fischer J;Liao W;Kwok PY;Menter A;Lathrop GM;Wise CA;Begovich AB;Voorhees JJ;Elder JT;Krueger GG;Bowcock AM;Abecasis GR;Collaborative Association Study of Psoriasis
通讯作者：
Collaborative Association Study of Psoriasis
影响因子：
6.4
作者：
Collin M;Bigley V
通讯作者：
Bigley V
影响因子：
12.8
作者：
Hasegawa, D.;Bugarin, C.;Giordan, M.;Bresolin, S.;Longoni, D.;Micalizzi, C.;Ramenghi, U.;Bertaina, A.;Basso, G.;Locatelli, F.;Biondi, A.;te Kronnie, G.;Gaipa, G.
通讯作者：
Gaipa, G.
影响因子：
13.8
作者：
Menter, Alan;Tyring, Stephen K.;Papp, Kim
通讯作者：
Papp, Kim
影响因子：
4.4
作者：
Lyakh, LA;Koski, GK;Rice, NR
通讯作者：
Rice, NR