Type 2 memory B cells: The repository of allergic memory?

Abstract

Allergy is defined as an inappropriate immune response to a typically innocuous agent. Many allergic responses are IgE-mediated, wherein allergen-specific IgE antibodies bind mast cells and basophils to elicit degranulation upon allergen reexposure. Common allergens include proteins derived from foods (e.g., milks, peanuts), pollens (e.g., rye grass, birch), and insect-and arthropod-derived products (e.g., bee venom, house dust mite). Currently, disease-modifying treatments for allergies are limited, and a key obstacle to the development of novel therapies is an incomplete understanding of the etiology and maintenance of allergy, particularly how patients maintain sensitization for years between known exposures. Previous work has proposed that IgE memory resides within long-lived IgE antibody-secreting cells (ASC) or IgE memory B cells (MBC). A third explanation of IgE memory (Figure 1), investigated here by Ota, Hoehn, Fernandes-Braga and colleagues, supports that a subset of non-IgE B cells, specifically “type 2-marked” IgG MBC, are key for persistent sensitization, serving as a reservoir for allergic memory.¹

In pediatric patients with peanut-allergy, Ota et al. found a population of IgG MBC that had upregulated FCER2 (encoding CD23) and IL4R expression, marking them as type 2 cytokine-experienced cells. Consistent with a relationship to atopy, the frequency of CD23⁺ IgG MBC was highest in allergic patients with elevated peanut-specific IgE titers and correlated with total IgE titers. Moreover, in vitro stimulation of sorted IgG MBC from patients with high peanut-specific serum IgE revealed a greater incidence of peanut-specific antibodies in the supernatant of cultured CD23⁺ or IL-4R⁺ MBC compared to double negative counterparts (Figure 2). To further characterize the peanut-specific B cell compartment, the authors performed single cell analyses of B cells that bound Ara h 2 (one of two immunodominant allergens in peanut) or a control antigen, diphtheria toxin (DT). Ara h 2-binding B cells were enriched for IgG1 constant regions and expressed higher FCER2 compared to DT-binding counterparts.¹ Importantly, germline transcript of IGHE was detected in most Ara h 2-binding B cells, indicating that the IGHE locus was open and undergoing transcription, essential for IgE class switching upon antigen re-exposure. Ara h 2-binding IgG1 B cells were highly mutated, and monoclonal antibodies cloned from several of these cells were found to bind the same epitopes as previously identified IgE antibodies cross-reactive to peanut allergens.² Thus, these IgG1 B cells, expressing FCER2, IL4R, germline IGHE, and with convergent BCR repertoires, potentially act as repository of IgE ASC precursors, providing a possible explanation for the maintenance of allergen-specific IgE.

Similar type 2 cytokine-experienced MBC have been reported in the context of atopic dermatitis and allergies towards birch and rye grass pollens, peanut, and house dust mite, while infrequent for SARS-CoV-2 and DT.^{1, 3, 4} Of note, while type 2 MBC are infrequent in non-allergic individuals, even among allergen-specific MBC, they are present, indicating that type 2 MBC are not sufficient to drive allergic disease.^{3, 5} The presence of type 2 MBC may help explain the phenomenon that patients can develop allergic responses and anaphylaxis even years after allergen encounter, as they could be reactivated and become pathogenic IgE ASC, although this has yet to be directly shown.¹ This logic of a repository of IgE memory may also further account for the success of dupilumab—a blocking anti-IL-4Rα antibody that has demonstrated considerable efficacy in treating atopic dermatitis and food allergy, presumably by inhibiting IgE class switching and thus de novo IgE ASC differentiation.⁶ Further experiments characterizing the frequency of type 2 MBC in patients undergoing dupilumab treatment, and their association with serum IgE titers, would provide valuable clinical insights. It is also attractive to test biologics directly targeting IL-4R or CD23 in attenuating type 2 MBC formation or reactivation.

Given the prevalence of allergic disease, it is imperative to precisely resolve the underlying molecular mechanisms and establish what constitutes the repository of IgE memory. Based on current evidence, type 2 MBC provide an attractive target for the treatment of allergy due to their atopic specificity and ‘pre-pathogenic’ status, along with the potential to act as a biomarker of treatment efficacy.

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The authors declare no conflict of interest.