Abstract:BackgroundLoss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced expression of pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium.MethodspIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunost… Show more
“…S10A; Table S2). pIgR is known for transport of IgA and IgM antibodies to mucosal surfaces, but not for pathogen clearance (43). In the context of the C3 importance in PPV23-elicited pathogen clearance, we hypothesized that IgM promotes pathogen capture by KCs via activating C3 on pneumococcal surface and thereby enabling C3opsonized bacteria to be recognized by C3 receptor(s) on KCs.…”
Section: Ppv23 Enables Kupffer Cells To Capture Pneumococci By Igm-in...mentioning
Certain vaccines are more effective than others against microbial infections, but the molecular mechanisms separating the two types of vaccines are largely undefined. Here, by comparing two vaccines of Streptococcus pneumoniae with identical antigens but different efficacies (pneumococcal conjugate vaccine – PCV13 and pneumococcal polysaccharide vaccine – PPV23), we reveal that superior vaccine protection against blood-borne bacteria is primarily achieved by activating pathogen capture of the sinusoidal endothelial cells (ECs) in the liver. Consistent with its superior protection in humans, PCV13 confers a more potent protection than PPV23 against pneumococcal infection in mice. In vivo real-time imaging and genetic mutagenesis revealed that PCV13 activates both liver ECs and resident macrophages Kupffer cells (KCs) to capture IgG-coated bacteria via IgG Fc gamma receptor (FcγR). In particular, the FcγRIIB-mediated capture by ECs is responsible for PCV13-induced superior protection. In contrast, PPV23 only activates KCs (but not ECs) to achieve a less effective pathogen capture and protection through complement receptor-mediated recognition of IgM- and C3-coated bacteria. These liver-based vaccine protection mechanisms are also found with the vaccines of Neisseria meningitidis and Klebsiella pneumoniae, another two important invasive human pathogens. Our findings have uncovered a novel EC- and FcγRIIB-mediated mechanism in the liver for more efficacious vaccine protection. These findings can serve as in vivo functional readouts to evaluate vaccine efficacy and guide the future vaccine development.One Sentence SummaryVaccine efficacy is defined by FcγRIIB-mediated capture of antibody-coated bacteria via liver sinusoidal endothelial cells.
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