Food allergy is a potentially fatal disease affecting 8% of children and has become increasingly common in the past two decades. Despite the prevalence and severe nature of the disease, the mechanisms underlying sensitization remain to be further elucidated. The Collaborative Cross is a genetically diverse panel of inbred mice that were specifically developed to study the influence of genetics on complex diseases. Using this panel of mouse strains, we previously demonstrated CC027/GeniUnc mice, but not C3H/HeJ mice, develop peanut allergy after oral exposure to peanut in the absence of a Th2-skewing adjuvant. Here, we investigated factors associated with sensitization in CC027/GeniUnc mice following oral exposure to peanut, walnut, milk, or egg. CC027/GeniUnc mice mounted antigen-specific IgE responses to peanut, walnut and egg, but not milk, while C3H/HeJ mice were not sensitized to any antigen. Naïve CC027/GeniUnc mice had markedly lower total fecal IgA compared to C3H/HeJ, which was accompanied by stark differences in gut microbiome composition. Sensitized CC027/GeniUnc mice had significantly fewer CD3+ T cells but higher numbers of CXCR5+ B cells and T follicular helper cells in the mesenteric lymph nodes compared to C3H/HeJ mice, which is consistent with their relative immunoglobulin production. After oral challenge to the corresponding food, peanut- and walnut-sensitized CC027/GeniUnc mice experienced anaphylaxis, whereas mice exposed to milk and egg did not. Ara h 2 was detected in serum collected post-challenge from peanut-sensitized mice, indicating increased absorption of this allergen, while Bos d 5 and Gal d 2 were not detected in mice exposed to milk and egg, respectively. Machine learning on the change in gut microbiome composition as a result of food protein exposure identified a unique signature in CC027/GeniUnc mice that experienced anaphylaxis, including the depletion of Akkermansia. Overall, these results demonstrate several factors associated with enteral sensitization in CC027/GeniUnc mice, including diminished total fecal IgA, increased allergen absorption and altered gut microbiome composition. Furthermore, peanuts and tree nuts may have inherent properties distinct from milk and eggs that contribute to allergy.

Mast cells are an important cell type of the innate immune system that when activated, play a crucial role in generating protective innate host responses after bacterial and viral infection. Additionally, activated mast cells influence lymph node composition to regulate the induction of adaptive immune responses. The recognition that mast cells play a beneficial role in host responses to microbial infection and induction of adaptive immunity has provided the rationale to evaluate mast cell activators for use as antimicrobials or vaccine adjuvants. This review summarizes the role of mast cell activators in antimicrobial responses while also discussing the use of different classes of mast cell activators as potent vaccine adjuvants that enhance the induction of protective immune responses.

To the Editor, Peanut-specific allergen immunotherapy reduces peanut-specific serum IgE and T helper 2 (Th2) cell cytokines, IL-5 and IL-13, and increases peanut-specific serum IgG, IgG4, mucosal IgA, and T regulatory (Treg) cells 1,2 in hypersensitive individuals. However, it is not well understood how peanut-specific Th2 cells change after immunotherapy. This study aimed to evaluate potential mechanisms allergen-specific immunotherapy may use to reduce Th2 responses in peanut-hypersensitive mice.Utilizing a mouse nasal allergen-specific immunotherapy (NIT) model, we confirmed the beneficial effects of including the Toll-like receptor 9 ligand, CpG, as a Th1-enhancing adjuvant in peanut NIT 3,4 to reduce allergic disease severity. The comparison of CpGadjuvanted to unadjuvanted peanut-specific NIT was performed in IL-13-lineage-tracing mice to evaluate the contribution of CpG combined with peanut on peanut-specific Th2 cells in hypersensitive mice. This study tested the hypothesis that CpG-adjuvanted peanut NIT transitioned peanut-specific Th2 cells into peanut-specific Th1 and/or Treg cells.Peanut hypersensitivity was induced in C57BL/6J mice by gastric gavage with peanut extract (PN) and cholera toxin (CT) (Figure S1). LETTERS TO THE EDITOR | 2221with peanut immunotherapy generating non-Th2 cells, such as IL-10+ cells, to reduce allergic Th2-cell effects and desensitize or tolerize the host, it is possible that including potent Th1-enhancing adjuvants, such as CpG, to clinical peanut immunotherapy formulations will both generate new T cells and induce Th2-cell plasticity to, more effectively, reduce allergic disease severity compared to therapy with peanut allergens alone.Collectively, our study suggests CpG-adjuvanted PN NIT may generate new IL-10+ T cells and induce Th2-cell plasticity to enhance IFN-γ to reduce allergy severity. This information may provide insight toward developing improved peanut allergy immunotherapy formulations.

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