Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States.
Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany.
Front Immunol. 2022 Jul 5;13:881655. doi: 10.3389/fimmu.2022.881655. eCollection 2022.
Mast cells and basophils have long been implicated in the pathogenesis of IgE-mediated hypersensitivity reactions. They express the high-affinity IgE receptor, FcϵRI, on their surface. Antigen-induced crosslinking of IgE antibodies bound to that receptor triggers a signaling cascade that results in activation, leading to the release of an array of preformed vasoactive mediators and rapidly synthesized lipids, as well as the production of inflammatory cytokines. In addition to bearing activating receptors like FcεRI, these effector cells of allergy express inhibitory ones including FcγR2b, an IgG Fc receptor with a cytosolic inhibitory motif that activates protein tyrosine phosphatases that suppress IgE-mediated activation. We and others have shown that food allergen-specific IgG antibodies strongly induced during the course of oral immunotherapy (OIT), signal FcγR2b to suppress IgE-mediated mast cell and basophil activation triggered by food allergen challenge. However, the potential inhibitory effects of IgA antibodies, which are also produced in response to OIT and are present at high levels at mucosal sites, including the intestine where food allergens are encountered, have not been well studied. Here we uncover an inhibitory function for IgA. We observe that IgA binds mouse bone marrow-derived mast cells (BMMCs) and peritoneal mast cells. Binding to BMMCs is dependent on calcium and sialic acid. We also found that IgA antibodies inhibit IgE-mediated mast cell degranulation in an allergen-specific fashion. Antigen-specific IgA inhibits IgE-mediated mast cell activation early in the signaling cascade, suppressing the phosphorylation of Syk, the proximal protein kinase mediating FcεRI signaling, and suppresses mast cell production of cytokines. Furthermore, using basophils from a peanut allergic donor we found that IgA binds to basophils and that activation by exposure to peanuts is effectively suppressed by IgA. We conclude that IgA serves as a regulator of mast cell and basophil degranulation, suggesting a physiologic role for IgA in the maintenance of immune homeostasis at mucosal sites.
肥大细胞和嗜碱性粒细胞长期以来一直被认为与 IgE 介导的过敏反应的发病机制有关。它们在表面表达高亲和力 IgE 受体 FcεRI。抗原诱导与该受体结合的 IgE 抗体交联触发信号级联反应，导致激活，导致一系列预先形成的血管活性介质和快速合成的脂质释放，以及炎症细胞因子的产生。除了携带激活受体如 FcεRI 之外，这些过敏效应细胞还表达抑制性受体，包括 FcγR2b，这是一种 IgG Fc 受体，具有细胞质抑制基序，可激活蛋白酪氨酸磷酸酶，从而抑制 IgE 介导的激活。我们和其他人已经表明，在口服免疫疗法 (OIT) 过程中强烈诱导的食物过敏原特异性 IgG 抗体信号通过 FcγR2b 抑制食物过敏原挑战引发的 IgE 介导的肥大细胞和嗜碱性粒细胞激活。然而，针对 OIT 产生的并且在包括肠道等粘膜部位存在高水平的 IgA 抗体的潜在抑制作用尚未得到很好的研究。在这里，我们揭示了 IgA 的抑制功能。我们观察到 IgA 结合小鼠骨髓来源的肥大细胞 (BMMC) 和腹腔肥大细胞。与 BMMC 的结合依赖于钙和唾液酸。我们还发现 IgA 抗体以过敏原特异性方式抑制 IgE 介导的肥大细胞脱颗粒。抗原特异性 IgA 在信号级联的早期抑制 IgE 介导的肥大细胞激活，抑制介导 FcεRI 信号的近端蛋白激酶 Syk 的磷酸化，并抑制肥大细胞细胞因子的产生。此外，使用花生过敏供体的嗜碱性粒细胞，我们发现 IgA 结合嗜碱性粒细胞，并且暴露于花生可有效抑制 IgA 的激活。我们得出结论，IgA 作为肥大细胞和嗜碱性粒细胞脱颗粒的调节剂，表明 IgA 在维持粘膜部位的免疫稳态方面具有生理作用。
