Pulmonary sarcoidosis is generally presumed to be a T helper-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.
Bronchoalveolar lavage (BAL) fluid, lung tissue, and peripheral blood samples from sarcoidosis patients 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 sarcoidosis patients. 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 non-ectopic, i.e., they did not contain follicular dendritic cells. Sarcoidosis patients 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.