Control of immediate hypersensitivity responses in parasitic and other diseases

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Control of allergic disease (and of parasitic helminth-associated pathology) is associated with the sequential induction of antigen-specific IgE and then antigen-specific IgG4. Although IL-10 appears to contribute to altering the antigen-specific IgE: IgG4 ratio, how this occurs remains largely unknown. Using in vitro cultures of human PBMCs and B cell subsets we have demonstrated that IL-10 acts indirectly through accessory cells to downregulate IL-4-induced production of IgE. In contrast, IL-10 can act directly on B cells to upregulate IL-4-induced production of IgG4, with its effects downstream of germline transcription (Lin et al, ImmunoHorizons 2019). The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy, but other data suggest parasitic infections may induce allergic responsiveness. To explore more fully the mechanisms underlying the allergy/helminth interface, a murine model of house dust mite (HDM)-induced allergic inflammation followed by Ascaris infections developed and used to demonstrate that allergic sensitization drives an eosinophil-rich pulmonary type-2 immunity (Th2 cells, M2-macrophages, ILC2s, IL-33, IL-4, IL-13 and mucus) that directly hinders Ascaris larval development and reduces markedly the parasite burden in the lungs. This effect is dependent on the presence of eosinophils, as eosinophil-deficient mice were unable to limit parasite development or numbers. In vivo administration of neutralizing antibodies to CD4 prior to HDM sensitization significantly reduced eosinophils in the lungs, resulting in the reversal of the HDM-induced Ascaris larval killing (Guimaraes-Gazzinelli et al, J. Clin Invest (in press). This effect is dependent on eosinophils triggered by innate immunity signaling on IL-13Ra1 in the lung, as allergen sensitized-IL-13Ra1 deficient mice were unable to limit parasite development or numbers. To explore further the role played by Th2 cells (and in particular the IL-13/IL-13R signaling axis) in mediating this eosinophil-dependent phenomenon, we show that in HDM-sensitized-IL-13Ra1 deficient mice, there was a dramatic suppression in the production of CCL11 (eotaxin-1) and CCL24 (eotaxin-2) levels, resulting in a significant reduction in lung tissue eosinophil frequency and numbers; as a consequence the mice failed to limit Ascaris larvae development. Moreover, in vivo administration of neutralizing antibodies to CD4 or the adoptive transfer of CD4+ T cells from IL-5-deficient mice to TCR-a knockout mice prior to HDM sensitization significantly impaired the HDM-specific type-2-immune response, diminishing markedly the HDM-specific antibody response, mucus production and the numbers of allergen-driven eosinophils in the lungs that in turn allowed normal larval development when compared to appropriate control mice. Taken together, our data suggest that HDM-induced inflammation drives an eosinophil-dependent helminth larval arrest/killing in the lung mediated by a pulmonary-resident IL-5 producing Th2 cells and IL-13/IL-13Ra1 signaling in the lung epithelia.