| Autor: |
Bauer L; Institute of Immunology and.; Chronic Immune Reactions and., Müller LJ; Chronic Immune Reactions and., Volkers SM; Department of Infectious Diseases and Respiratory Medicine, Charité University Medicine Berlin, Corporate Member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health, Berlin, Germany., Heinrich F; Therapeutic Gene Regulation, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany., Mashreghi MF; Therapeutic Gene Regulation, German Rheumatism Research Centre, A Leibniz Institute, Berlin, Germany., Ruppert C; Universities of Giessen and Marburg Lung Center, Giessen, Germany; and.; German Center for Lung Research (DZL)., Sander LE; Department of Infectious Diseases and Respiratory Medicine, Charité University Medicine Berlin, Corporate Member of Free University of Berlin, Humboldt University of Berlin, and Berlin Institute of Health, Berlin, Germany.; German Center for Lung Research (DZL)., Hutloff A; Institute of Immunology and.; Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany.; Chronic Immune Reactions and. |
| Abstrakt: |
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-1 high CXCR5 - CD40L high ICOS high 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. |
