Rationale: 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. Objectives: To assess the role of pulmonary Tfh- and germinal center-like lymphocytes in sarcoidosis. Methods: 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. Measurements and Main Results: 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. Conclusions: 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.

中文翻译：

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肺中滤泡辅助样 T 细胞突出了 B 细胞在结节病中的新作用。

基本原理：肺结节病通常被认为是 1 型 T 辅助细胞和巨噬细胞驱动的疾病。然而，小鼠模型最近表明，慢性发炎的肺组织也可以包含 T 滤泡辅助 (Tfh) 样细胞，并代表活跃的 T 细胞/B 细胞合作的位点。目的：评估肺 Tfh 和生发中心样淋巴细胞在结节病中的作用。方法：通过流式细胞术、免疫组织学、RNA 测序和体外 T 细胞/B 细胞协同试验分析来自结节病患者的 BAL 液、肺组织和外周血样本，用于生发中心样反应的表型和功能表征在发炎的组织中。测量和主要结果：我们鉴定了一个新的 Tfh 样细胞群，其特征是 B 辅助分子 CD40L 和 IL-21 在结节病患者的 BAL 中高表达。转录组分析进一步证实了 Tfh 样和组织驻留的表型。BAL T 细胞为 B 细胞分化为产生抗体的细胞提供了有力的帮助。在肺组织中，我们观察到大量的支气管周围浸润有紧密接触的 T 细胞和 B 细胞，以及许多 IgA+ 浆母细胞。大多数集群是非异位的；也就是说，它们不含滤泡树突状细胞。结节病患者血液中的 PD-1high CXCR5-CD40Lhigh ICOShigh Tfh 样细胞水平也升高，但经典 CXCR5+ Tfh 细胞水平不升高。结论：