美国洛克菲勒大学Jean-Laurent Casanova和Stéphanie Boisson-Dupuis研究组等合作取得一项新突破。他们发现遗传性程序性细胞死亡蛋白 1 (PD-1)缺乏是儿童结核病 (TB)和自身免疫的基础。相关论文于2021年6月28日发表在《自然-医学》杂志上。
他们研究了一名死于肺自身免疫的遗传性 PD-1 缺乏症和结核病患者。患者的白细胞不表达 PD-1 或??应答 PD-1 介导的抑制。患者的淋巴细胞在分枝杆菌刺激下仅产生少量干扰素 (IFN)-γ,类似于易患结核病的先天性 IFN-γ 产生错误的患者。这种表型是由 Vδ2+ γδ T、粘膜相关不变 T 和 CD56 明亮自然杀伤淋巴细胞的联合消耗以及其他 T 淋巴细胞亚群的功能障碍引起的。此外,该患者表现出肝脾肿大和总的、激活的和 RORγT+ CD4-CD8- 双阴性 αβ T 细胞的扩增,类似于显示淋巴组织增殖性自身免疫的 STAT3 功能获得性突变患者。
这种表型是由活化的 T 淋巴细胞和单核细胞产生过量的 STAT3 激活细胞因子白细胞介素 (IL)-6 和 IL-23,以及活化的 T 淋巴细胞 RORγT 的 STAT3 依赖性表达造成的。他们的工作强调了人类 PD-1 在控制抗分枝杆菌免疫和自我耐受方面不可或缺的作用,同时为患者结核病和自身免疫PD-1 阻断的诊断和治疗管理确定了潜在的可操作分子靶标。
研究人员表示,PD-1 阻断后不良事件的病理生理学,包括TB 和自身免疫,仍未得到很好的表征。
附:英文原文
Title: Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child
Author: Masato Ogishi, Rui Yang, Caner Aytekin, David Langlais, Mathieu Bourgey, Taushif Khan, Fatima Al Ali, Mahbuba Rahman, Ottavia M. Delmonte, Maya Chrabieh, Peng Zhang, Conor Gruber, Simon J. Pelham, Andrs N. Spaan, Jrmie Rosain, Wei-Te Lei, Scott Drutman, Matthew D. Hellmann, Margaret K. Callahan, Matthew Adamow, Phillip Wong, Jedd D. Wolchok, Geetha Rao, Cindy S. Ma, Yuka Nakajima, Tomonori Yaguchi, Kenji Chamoto, Samuel C. Williams, Jean-Francois Emile, Flore Rozenberg, Michael S. Glickman, Franck Rapaport, Gaspard Kerner, Garrett Allington, Ilhan Tezcan, Deniz Cagdas, Ferda O. Hosnut, Figen Dogu, Aydan Ikinciogullari, V. Koneti Rao, Leena Kainulainen, Vivien Bziat, Jacinta Bustamante, Silvia Vilarinho, Richard P. Lifton, Bertrand Boisson, Laurent Abel, Dusan Bogunovic, Nico Marr, Luigi D. Notarangelo, Stuart G. Tangye, Tasuku Honjo, Philippe Gros, Stphanie Boisson-Dupuis, Jean-Laurent Casanova
Issue&Volume: 2021-06-28
Abstract: The pathophysiology of adverse events following programmed cell death protein 1 (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, similarly 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, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4CD8 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 interleukin (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.
DOI: 10.1038/s41591-021-01388-5
Source: https://www.nature.com/articles/s41591-021-01388-5
Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex