Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.
Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.
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遗传性 PD-1 缺陷是儿童结核病和自身免疫性疾病的基础。
DOI：
10.1038/s41591-021-01388-5
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发表时间：
2021-09
期刊：
影响因子：
82.9
通讯作者：
Casanova JL
中科院分区：
文献类型：
--
作者：
Ogishi M;Yang R;Aytekin C;Langlais D;Bourgey M;Khan T;Ali FA;Rahman M;Delmonte OM;Chrabieh M;Zhang P;Gruber C;Pelham SJ;Spaan AN;Rosain J;Lei WT;Drutman S;Hellmann MD;Callahan MK;Adamow M;Wong P;Wolchok JD;Rao G;Ma CS;Nakajima Y;Yaguchi T;Chamoto K;Williams SC;Emile JF;Rozenberg F;Glickman MS;Rapaport F;Kerner G;Allington G;Tezcan I;Cagdas D;Hosnut FO;Dogu F;Ikinciogullari A;Rao VK;Kainulainen L;Béziat V;Bustamante J;Vilarinho S;Lifton RP;Boisson B;Abel L;Bogunovic D;Marr N;Notarangelo LD;Tangye SG;Honjo T;Gros P;Boisson-Dupuis S;Casanova JL
PD-1阻断后的不良事件，包括结核病和自身免疫，其病理生理学特征仍然很差。我们研究了一名遗传性PD-1缺乏症和肺结核患者，他死于肺自身免疫。患者的白细胞不表达PD-1，也不对PD-1介导的抑制反应。患者的淋巴细胞在分枝杆菌的刺激下只产生少量的干扰素-γ，类似于易患结核病的先天干扰素-γ产生错误的患者。这种表型是由于Vδ2+γδT、MAIT和CD5 6明亮的NK细胞的联合耗尽和其他T细胞亚群的功能障碍所致。此外，患者表现出肝脾肿大和总的、活化的、RORγT+CD4CD8双阴性αβT细胞的扩张，类似于表现为淋巴增殖性自身免疫的STAT3型功能获得突变患者。这种表型是由于活化的T淋巴细胞和单核细胞产生过多的STAT3激活的细胞因子IL-6和IL-23，以及活化的T淋巴细胞表达依赖STAT3的γT所致。我们的工作强调了人类PD-1在调节抗分枝杆菌免疫和自我耐受方面不可或缺的作用，同时确定了潜在的可操作的分子靶点，用于结核病的诊断和治疗管理以及接受PD-1阻断的患者的自身免疫。
The pathophysiology of adverse events following PD-1 blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient’s leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient’s lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similar to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, MAIT, and CD56bright NK lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated, and RORγT+ CD4-CD8- double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines IL-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.
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影响因子：
24.8
作者：
Kauffman KD;Sakai S;Lora NE;Namasivayam S;Baker PJ;Kamenyeva O;Foreman TW;Nelson CE;Oliveira-de-Souza D;Vinhaes CL;Yaniv Z;Lindestam Arleham CS;Sette A;Freeman GJ;Moore R;NIAID/DIR Tuberculosis Imaging Program;Sher A;Mayer-Barber KD;Andrade BB;Kabat J;Via LE;Barber DL
通讯作者：
Barber DL
影响因子：
30.8
作者：
Flanagan, Sarah E.;Haapaniemi, Emma;Russell, Mark A.;Caswell, Richard;Allen, Hana Lango;De Francol, Elisa;McDonald, Timothy J.;Rajala, Hanna;Ramelius, Anita;Barton, John;Heiskanen, Kaarina;Heiskanen-Kosmal, Tarja;Kajosaari, Merja;Murphyli, Nuala P.;Milenkovic, Tatjana;Seppanen, Mikko;Lemmark, Ake;Mustjoki, Satu;Otonkoski, Timo;Kere, Juha;Morgan, Noel G.;Ellard, Sian;Hattersley, Andrew T.
通讯作者：
Hattersley, Andrew T.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
17.1
作者：
Barber, Daniel L.;Sakai, Shunsuke;Sharon, Elad
通讯作者：
Sharon, Elad
影响因子：
56.9
作者：
Gentili, Matteo;Kowal, Joanna;Manel, Nicolas
通讯作者：
Manel, Nicolas