Origins and clonal convergence of gastrointestinal IgE ⁺ B cells in human peanut allergy

Abstract

B cells in human food allergy have been studied predominantly in the blood. Little is known about IgE+ B cells or plasma cells in tissues exposed to dietary antigens. We characterized IgE+ clones in blood, stomach, duodenum, and esophagus of 19 peanut-allergic patients, using high-throughput DNA sequencing. IgE+ cells in allergic patients are enriched in stomach and duodenum, and have a plasma cell phenotype. Clonally related IgE+ and non-IgE–expressing cell frequencies in tissues suggest local isotype switching, including transitions between IgA and IgE isotypes. Highly similar antibody sequences specific for peanut allergen Ara h 2 are shared between patients, indicating that common immunoglobulin genetic rearrangements may contribute to pathogenesis. These data define the gastrointestinal tract as a reservoir of IgE+ B lineage cells in food allergy.

Exploring the Molecular Mechanisms Underlying the Protective Effects of Microbial SCFAs on Intestinal Tolerance and Food Allergy

“…The most characteristic form of food allergy is mediated by IgE-dependent pathways (42). Human IgE-triggered peanut allergy is associated with a high cell number of somatically mutated and clonally expanded gastrointestinal allergen-specific IgE + B cells suggesting a local isotype switching, which likely includes the transition between IgA and IgE antibody isotypes (43). Recent data suggest that some dietary components such as RA (an active derivative of dietary vitamin A) and dietary peptides, as well as microbial SCFAs may act together to promote intestinal homeostasis and suppress food allergy.…”

B cells and the microbiota: a missing connection in food allergy

“…77 New evidence for local regulation suggests that some IgE may originate in the gut. 78,79 Hoh et al show that subjects with peanut allergy have many clones of peanut-specific antibodies (IgE and other isotypes) in biopsy samples from the stomach and duodenum, while healthy subjects do not. 78 More distal regions of the gastrointestinal tract, like the ileum, were not analyzed in this study but would be interesting to examine in future studies.…”

“…78,79 Hoh et al show that subjects with peanut allergy have many clones of peanut-specific antibodies (IgE and other isotypes) in biopsy samples from the stomach and duodenum, while healthy subjects do not. 78 More distal regions of the gastrointestinal tract, like the ileum, were not analyzed in this study but would be interesting to examine in future studies. Analysis of clonal relationships between peanut-specific antibodies from the stomach and duodenum suggest that the majority of IgE clones are likely derived from antigen-experienced B cells that have undergone local class switching from IgG or IgA to IgE.…”

“…Analysis of clonal relationships between peanut-specific antibodies from the stomach and duodenum suggest that the majority of IgE clones are likely derived from antigen-experienced B cells that have undergone local class switching from IgG or IgA to IgE. 78,80 There are two pathways of CSR to IgE: either a direct switch to IgE or indirectly through IgA and IgG. [81][82][83] The indirect method of CSR to IgE results in much higher affinity IgE than the direct method, 83 as IgE + B cells are excluded from germinal centers and therefore do not undergo somatic hypermutation (SHM).…”

“…However, in humans, the gene for IgE is flanked by IgA1 and IgA2, which suggests that it may be possible to further class-switch IgE + B cells to a potentially tolerogenic IgA2 isotype. 78 Understanding the local regulation of CSR will be vital to manipulating and preventing aberrant IgE. Further studies are needed to examine the roles of IgE + memory B cells and PCs, as well as their sites of induction and accumulation in specific mucosal tissues.…”