B-cell receptor physical properties affect relative IgG1 and IgE responses in mouse egg allergy

Abstract

Mutated and unmutated IgE and IgG play different and partly opposing roles in allergy development, but the mechanisms controlling their relative production are incompletely understood. Here, we analyzed the IgE-response in murine food allergy. Deep sequencing of the complementary-determining region (CDR) repertoires indicated that an ongoing unmutated extrafollicular IgE response coexists with a germinal center response, even after long-lasting allergen challenges. Despite overall IgG1-dominance, a significant proportion of clonotypes contained several-fold more IgE than IgG1. Clonotypes with differential bias to either IgE or IgG1 showed distinct hypermutation and clonal expansion. Hypermutation rates were associated with different physiochemical binding properties of individual B-cell receptors (BCR). Increasing BCR signaling strength inhibited class switching from IgG1 to IgE in vitro, preferentially constraining IgE formation. These data indicate that antigen-binding properties of individual BCRs determine differential IgE hypermutation and IgE versus IgG1 production on the level of single B-cell clones.

Interleukin-10-alveolar macrophage cell membrane-coated nanoparticles alleviate airway inflammation and regulate Th17/regulatory T cell balance in a mouse model

“…IgE, murine IgG1, and human IgG4 are produced by Th2-type cytokines, and IL-10 can induce a switch toward IgG4 and IgE inhibition, as shown in human studies (35). Elevated IgG4 levels have been associated with controlled allergic diseases in human studies (36). Although studies have found that class switch recombination to IgE occurs in the nasal tissues and bronchial mucosa (37,38), the class switch always occurs in mature B cells in the germinal centers of the spleen, nodes, and Peyer's patches (39).…”

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

“…46 Sequential switching via IgG1 in mice was proposed 37 and has since been shown to be the main mechanism by which such IgE arises, 129 although, a recent study challenges this notion. 130 46 IgE responses also ensue via the extrafollicular route for long periods in parallel with GC responses, 131 and unmutated clones are found among IgE + B-lineage cells of atopic individuals. 39 Therefore, during type 2 immune responses such as allergies, IgE + ASC can arise via the extrafollicular route, but mainly form from the differentiation of GC or post-GC mBC populations; whether GC or post-GC mBC are the dominant source is unclear.…”

“…Which is the dominant formation route of IgE ASC is a current question. It may be possible to visualize this with in vivo microscopy in dual fluorescent IgE and ASC reporter mouse strains, and literally see whether GC 137 or the recently defined subcapsular sinus proliferative foci 141 are the sites of IgE + ASC differentiation, but sequencing studies also provide insight into IgE + ASC relationships to precursors 39,131 …”

“… 130 Interestingly, GC B cells express IL‐13Rα1, 46 and BCL6‐driven IL‐13 deletion reduces IgE antibody affinity to nonreaginic thresholds, indicating the capacity of GC B cells to respond to IL‐13 may influence IgE affinity. 46 IgE responses also ensue via the extrafollicular route for long periods in parallel with GC responses, 131 and unmutated clones are found among IgE + B‐lineage cells of atopic individuals. 39 Therefore, during type 2 immune responses such as allergies, IgE + ASC can arise via the extrafollicular route, but mainly form from the differentiation of GC or post‐GC mBC populations; whether GC or post‐GC mBC are the dominant source is unclear.…”

“… 137 , 138 Still, as IgE + ASC with heavily mutated BCR may arise in chronic allergen exposure models, 139 it would be warranted to study IgE + B cell persistence in GC throughout such a response. This is especially important as IgE + and IgG1 + B‐lineage cells display overlap in clonality, but certain clones can be preferentially expanded among IgE + B‐lineage cells, which also tend to have lower SHM burdens than contemporaneously isolated IgG + B‐lineage cells, 37 , 39 , 40 , 43 , 129 , 131 , 137 suggesting that there are overlapping, yet distinct processes regulating IgE and IgG production. ASC can arise from differentiation directly from a GC B cell, or via the reactivation of mBC near the subcapsular sinus.…”