No abstract

Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAFlo B cells. Consistent with this, a majority of light and dark zone GC B cells were DAFlo and susceptible to complement-dependent phagocytosis, as compared with DAFhi GC B cells. We could also show that the DAFhi GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis.

Human hantavirus infections can cause hemorrhagic fever with renal syndrome (HFRS), major signs of the disease being thrombocytopenia and transient kidney dysfunction. By a comprehensive and longitudinal study of circulating B cells, we demonstrate that these two pathologies associate with distinct effects on the humoral immune system during HFRS. Low thrombocyte counts strongly associated with an abnormal frequency of plasmablasts in circulation, whereas kidney dysfunction was indicative of an accumulation of CD27 -B cells and plasmablasts. Finally, we provide evidence that high levels of extracellular ATP in circulation during HFRS correlates with shedding of surface CD27 on B cells via a metallomatrix proteinase-8-mediated mechanism. Since extracellular ATP is known to regulate kidney function, our study reveals a link between kidney dysfunction and the generation of CD27 -IgD -B cells, and a potential molecular target for treatment of the symptomatic phase of HFRS. Dobrava, Seol and Puumala (PUUV) strains, where PUUV is endemic to Scandinavia. To date, no efficacious treatment or vaccination regimen exists to protect against severe hantavirus infections.Well controlled human studies have shown that hantavirus infections cause aberrant activation of both innate and adaptive immunity (5)(6)(7)(8). A potent antiviral IgG-response is associated with protection from severe disease during both HPS and HFRS (9-12) and passive transfer of serum antibodies could reduce case fatality rate in a small cohort of HPS patients (13). These findings clearly demonstrate that activation of the humoral immune system and subsequent elicitation of antiviral antibodies play a central role in the control of viremia and/or pathogenesis during hantavirus infections.A recent study of HPS demonstrated that very high levels of plasmablasts (PBs) and CD27 -IgD -B cells were detected in circulation of patients (14). The rapid and extensive PB-response is similar to that reported during acute dengue virus infection and contrasts to the comparably moderate levels of PBs that are found in circulation during influenza infection or after influenza vaccination (15). An expansion of the CD27 -IgD -B cell subset has previously been shown for numerous inflammatory and infectious diseases, as well as during ageing and cancer (16-21), yet their functional role in humoral immunity remains undetermined. The CD27 -IgD -B cells resemble memory B cells, have isotype switched and hypermutated B cell receptors and therefore likely originate from T cell-dependent germinal center reactions in secondary lymphoid organs (16, 20). In systemic lupus erythematosus (SLE), an expanded population of CD27 -IgD -B cells was associated with the manifestation of nephritis in patients (16). This suggests that their detection in blood may be linked to reduced kidney function, but the cause for their expansion remains to be determined.During HFRS-causing hantavirus infections, reduced kidney function occurs independently of the induced thrombocytopenia (22, 23). We therefor...

Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the immunopathology driving tonsil hyperplasia and OSA remains unknown. Here we used multi-parametric flow cytometry to analyze the composition and phenotype of tonsillar innate lymphoid cells (ILCs), T cells, and B cells from pediatric patients with OSA, who had previous polysomnography. Unbiased clustering analysis was used to delineate and compare lymphocyte heterogeneity between two patient groups: children with small tonsils and moderate OSA (n = 6) or large tonsils and very severe OSA (n = 13). We detected disturbed ILC and B cell proportions in patients with large tonsils, characterized by an increase in the frequency of naïve CD27-CD21hi B cells and a relative reduction of ILCs. The enrichment of naïve B cells was not commensurate with elevated Ki67 expression, suggesting defective differentiation and/or migration rather than cellular proliferation to be the causative mechanism. Finally, yet importantly, we provide the flow cytometry data to be used as a resource for additional translational studies aimed at investigating the immunological mechanisms of pediatric tonsil hyperplasia and OSA.

It is now easy to perform multiome single-cell analysis, including both RNA and ATAC readouts from the same cell. This enables a closer linkage between the two types of modalities, but it remains an open question what more information can be extracted from this type of data. ATAC-seq is normally only used to assay transcription factor binding to open regions. By reanalyzing several large datasets, and generating an atlas of B cells, we show that telomere accessibility can better pinpoint processes related to cell cycle and chromatin condensation. We provide Telomemore, a tool that can extract telomeric reads, and give examples of new findings it enables. Our new findings will aid in the annotation and analysis of single-cell ATAC or multiome datasets.