Control of immediate hypersensitivity responses in parasitic and other diseases

控制变态反应性疾病(和寄生虫相关的病理)与依次诱导抗原特异性的IgE和抗原特异性的IgG4有关。尽管IL-10似乎有助于改变抗原特异性的IgE/IgG4比率，但这是如何发生的在很大程度上仍不清楚。利用体外培养的人PBMCs和B细胞亚群，我们证明了IL-10通过辅助细胞间接作用于下调IL-4诱导的IgE的产生。相比之下，IL-10可以直接作用于B细胞，上调IL-4诱导的IgG4的产生，其影响位于生殖系转录的下游(Lin等人，《免疫地平线2019》)。 卫生学假说表明，寄生虫感染调节宿主免疫反应，减少特应性，但其他数据表明，寄生虫感染可能会诱导过敏反应。为了更全面地探讨过敏/蠕虫界面的潜在机制，我们开发了一种由屋尘螨(HDM)诱导的过敏性炎症继而发生蛔虫感染的小鼠模型，并用于证明过敏致敏作用驱动富含嗜酸粒细胞的肺2型免疫(Th2细胞、M2-巨噬细胞、ILC2s、IL-33、IL-4、IL-13和粘液)，从而直接阻碍蛔虫幼虫的发育，显著减少肺部的寄生虫负担。这种效应依赖于嗜酸性粒细胞的存在，因为嗜酸性粒细胞缺陷小鼠无法限制寄生虫的发展或数量。在HDM致敏之前，体内注射CD4中和抗体可显著减少肺部的嗜酸性粒细胞，从而逆转HDM诱导的蛔虫幼虫杀灭(Guimaraes-Gazzinelli等，J.Clin Invest(印刷中))。 这种效应依赖于肺中IL-13Ra1的先天免疫信号触发的嗜酸性粒细胞，因为过敏原致敏的IL-13Ra1缺陷小鼠无法限制寄生虫的发展或数量。为了进一步探讨Th2细胞(尤其是IL-13/IL-13R信号轴)在介导这种嗜酸性粒细胞依赖现象中所起的作用，我们发现在HDM致敏的IL-13Ra1缺陷小鼠中，CCL11(嗜酸性粒细胞趋化因子-1)和CCL24(嗜酸性粒细胞趋化因子-2)水平受到显著抑制，导致肺组织嗜酸性粒细胞频率和数量显著减少；结果，小鼠未能限制蛔虫幼虫的发育。此外，在HDM致敏之前，体内注射中和抗体或将IL-5缺陷小鼠的CD4+T细胞过继转移到TCR-a基因敲除小鼠可显著削弱HDM特异性的2型免疫反应，显著降低HDM特异性抗体反应、粘液产生和肺中过敏原驱动的嗜酸性粒细胞的数量，与适当的对照小鼠相比，这反过来又允许正常的幼虫发育。综上所述，我们的数据表明，HDM诱导的炎症通过肺内常驻的产生IL-5的Th2细胞和肺上皮细胞中的IL-13/IL-13Ra1信号介导，在肺内驱动嗜酸性粒细胞依赖的蠕虫幼虫的停止/杀死。

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.