IgG memory B cells expressing IL4R and FCER2 are associated with atopic diseases

Abstract

Background Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell‐produced IL‐4 and IL‐13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. Methods Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non‐atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. Results We identified a novel population of IgG memory B cells characterized by the expression of IL‐4/IL‐13 regulated genes FCER2/CD23, IL4R, IL13RA1, and IGHE, denoting a history of differentiation during type 2 immune responses. CD23+IL4R+IgG+ memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23+IL4R+IgG+ memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE+ cells than B cells from non‐atopic subjects. Conclusions These findings suggest that CD23+IL4R+ IgG+ memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production.

The origins and longevity of IgE responses as indicated by serological and cellular studies in mice and humans

“…Recent discoveries have uncovered the unique biology of IgE responses. These include that a population of high IL‐4‐producing, low IL‐21‐producing TFH13 cells mediates reaginic IgE production, 46 that expression of the IgE BCR provides an intrinsic predisposition toward ASC differentiation 151–153 and potentially apoptosis 151,153,181,192 and that mouse and human IgG class‐switched, post‐GC mBC are the likely reservoir of IgE + ASC forming cells in re‐exposure contexts 43–45 . A more contentious finding is the persistence of IgE + ASC in bone marrow 139 .…”

“…The transcriptional maturity of IgE + ASC in bone marrow 137,138 2017 IgG1 + B cells shown to hold IgE memory for recall responses in mice 43 2018 Transcriptome of human IgE plasmablasts published, confirming SHM 38 2019 General acceptance that IgE memory resides primarily among non-IgE mBC in humans 147,201 2019 Discovery of TFH13 cells and regulation of IgE affinity by IL-13 46 2021 Neuritin discovered to suppress IgE responses 49 2023 Type 2 memory B cells identified 44,45,144 although accurate determination of incidence is challenging and varies by geographic location, milk and egg allergies tend to predominate in infants, 57,61 although in countries with high consumption of fish, fish allergies can be quite prevalent in infants and children as well. 62 The majority of milk and egg allergies resolve by age 12.…”

“…Similarly, in individuals with hyper IgE syndrome, IgE and IgG antibodies can bind to distinctive epitopes on allergens 42 . Despite this, the memory of an IgE response resides primarily in the IgG class‐switched mBC pool 43–45 . The identification of high IL‐4‐producing, IL‐13‐producing T follicular helper (TFH)13 cells may suggest a unique T‐helper cell that biases responses toward reaginic IgE production 46 .…”

Memory B cells with extraordinary longevity upon smallpox vaccination: Implications for type 1 hypersensitivities

“…These MBCs may be responsible for the replenishment of the allergen‐specific IgE pool during a lifetime upon exposure to even minute amounts that do not trigger an allergic response (Figure 2). This notion is supported by the correlation of CD23 + IL4R + IgG + MBCs transcribing IGHE and the production of pathogenic IgE 5 . Moreover, chronic exposure may allow extensive somatic hypermutations in the germinal center as indicated by high mutation levels of MBC2 6 …”

“…This notion is supported by the correlation of CD23 + IL4R + IgG + MBCs transcribing IGHE and the production of pathogenic IgE. 5 F I G U R E 2 B5 + IgG + B cells, isolated from the spleen of smallpox-vaccinated individuals, were phenotyped by transcriptomics and metabolomics (top left side). Those cells showed upregulated NOTCH and CD21 expression in the spleen while a comparable population in the peripheral blood were characterized by reduced -intermediate -CD21 expression.…”