Follicular Helper-like T Cells in the Lung Highlight a Novel Role of B Cells in Sarcoidosis.
Follicular Helper-like T Cells in the Lung Highlight a Novel Role of B Cells in Sarcoidosis.
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DOI：
10.1164/rccm.202012-4423oc
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发表时间：
2021-12-15
影响因子：
24.7
通讯作者：
Hutloff A
中科院分区：
文献类型：
--
作者：
Bauer L;Müller LJ;Volkers SM;Heinrich F;Mashreghi MF;Ruppert C;Sander LE;Hutloff A
肺结节病通常被认为是一种t辅助细胞1型和巨噬细胞驱动的疾病。然而，小鼠模型最近显示，慢性炎症肺组织也可以包含T滤泡辅助细胞（Tfh）样细胞，并代表活跃的T细胞/ b细胞合作位点。探讨肺Tfh和生发中心样淋巴细胞在结节病中的作用。通过流式细胞术、免疫组织学、RNA测序和体外t细胞/ b细胞合作试验，对结节病患者的BAL液、肺组织和外周血样本进行分析，以确定炎症组织中生发中心样反应的表型和功能特征。我们发现了一种新的tfh样细胞群，其特征是在结节病患者的BAL中高表达B辅助分子CD40L和IL-21。转录组分析进一步证实了tfh样和组织驻留表型。BAL T细胞为B细胞分化为产生抗体的细胞提供了强有力的帮助。在肺组织中，我们观察到大量的支气管周围浸润，T细胞和B细胞密切接触，以及大量的IgA+质母细胞。大多数簇均为非异位；也就是说，它们不含滤泡树突状细胞。结节病患者血液中PD-1high CXCR5−CD40Lhigh icohigh Tfh样细胞水平升高，但经典CXCR5+ Tfh细胞水平不升高。炎症肺中活跃的t细胞/ b细胞合作和潜在致病性抗体的局部产生代表了结节病的一种新的病理机制，应该从诊断和治疗的角度考虑。
Pulmonary sarcoidosis is generally presumed to be a T-helper cell type 1– and macrophage-driven disease. However, mouse models have recently revealed that chronically inflamed lung tissue can also comprise T follicular helper (Tfh)-like cells and represents a site of active T-cell/B-cell cooperation. To assess the role of pulmonary Tfh- and germinal center–like lymphocytes in sarcoidosis. BAL fluid, lung tissue, and peripheral blood samples from patients with sarcoidosis were analyzed by flow cytometry, immunohistology, RNA sequencing, and in vitro T-cell/B-cell cooperation assays for phenotypic and functional characterization of germinal center–like reactions in inflamed tissue. We identified a novel population of Tfh-like cells characterized by high expression of the B helper molecules CD40L and IL-21 in BAL of patients with sarcoidosis. Transcriptome analysis further confirmed a phenotype that was both Tfh-like and tissue resident. BAL T cells provided potent help for B cells to differentiate into antibody-producing cells. In lung tissue, we observed large peribronchial infiltrates with T and B cells in close contact, and many IgA+ plasmablasts. Most clusters were nonectopic; that is, they did not contain follicular dendritic cells. Patients with sarcoidosis also showed elevated levels of PD-1high CXCR5− CD40Lhigh ICOShigh Tfh-like cells, but not classical CXCR5+ Tfh cells, in the blood. Active T-cell/B-cell cooperation and local production of potentially pathogenic antibodies in the inflamed lung represents a novel pathomechanism in sarcoidosis and should be considered from both diagnostic and therapeutic perspectives.