Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

Alessia Corrado,Deepak Tomar,Christopher Tipton,Christopher D Scharer,Matthew C Woodruff,Swetha Garimalla,Sanjeev Gumber,Chris Fucile,John M Delgaudio ,Iñaki Sanz ,Joshua M Levy ,Sarah K Wise ,Merin Kuruvilla ,Alexander F Rosenberg ,Hao Wu,Richard P Ramonell,Greg Gibson,Kelly R Magliocca,Jeremy M Boss,F Eun-Hyung Lee

doi:10.1038/s41385-021-00410-w

Alessia Corrado, Deepak Tomar + Show 18 more

Open Access

https://doi.org/10.1038/s41385-021-00410-w

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Abstract

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.

Highlights

IgE antibodies play a key role in the pathogenesis of severe allergic disease and of late, have been implicated in other airway diseases unrelated to atopy
nasal polyps (NP) samples were enriched for IgD−CD27− double negative B cells, an EF population we previously described in patients with active systemic lupus erythemathosus (SLE)[16]
In summary, this study demonstrates that local IgD+ B cells are a major source of NP IgE antibody secreting cells (ASC) through an EF differentiation pathway compared to other potential sources such as IgG and IgA memory cells

Summary

Introduction

IgE antibodies play a key role in the pathogenesis of severe allergic disease and of late, have been implicated in other airway diseases unrelated to atopy. IgE is produced by IgE antibody secreting cells (ASC) that arise from terminally differentiated B cells in the presence of Th2 cytokines IL-4 and IL-13. IgE has the lowest abundance in the serum and the shortest half-life[1] suggesting that ongoing IgE secretion is necessary to maintain tissue or serum levels in disease. Mucosal and not serum IgE levels correlate with disease severity in allergic patients[2] illustrating that local ASC in tissues are responsible for disease pathogenesis. NB cells can undergo extrafollicular (EF) reactions outside the GC and directly differentiate into ASC as described initially in mice models of Ehrlichia muris, Salmonella enterica serovar Typhimurium, and Borrelia burgdorferi[5,6,7,8,9,10,11,12,13,14,15] and more recently in humans in autoimmunity and primary viral infections such as SARS-CoV-216–19

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