Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA.
Sci Immunol. 2020 May 8;5(47). doi: 10.1126/sciimmunol.aay2754.
Immunoglobulin A (IgA) is the dominant antibody isotype in the gut and has been shown to regulate microbiota. Mucosal IgA is also widely believed to prevent food allergens from penetrating the gut lining. Even though recent work has elucidated how bacteria-reactive IgA is induced, little is known about how IgA to food antigens is regulated. Although IgA is presumed to be induced in a healthy gut at steady state via dietary exposure, our data do not support this premise. We found that daily food exposure only induced low-level, cross-reactive IgA in a minority of mice. In contrast, induction of significant levels of peanut-specific IgA strictly required a mucosal adjuvant. Although induction of peanut-specific IgA required T cells and CD40L, it was T follicular helper (T) cell, germinal center, and T follicular regulatory (T) cell-independent. In contrast, IgG1 and IgE production to peanut required T cells. These data suggest an alternative paradigm in which the cellular mechanism of IgA production to food antigens is distinct from IgE and IgG1. We developed an equivalent assay to study this process in stool samples from healthy, nonallergic humans, which revealed substantial levels of peanut-specific IgA that were stable over time. Similar to mice, patients with loss of CD40L function had impaired titers of gut peanut-specific IgA. This work challenges two widely believed but untested paradigms about antibody production to dietary antigens: (i) the steady state/tolerogenic response to food antigens includes IgA production and (ii) T cells drive food-specific gut IgA.
免疫球蛋白 A（IgA）是肠道中占主导地位的抗体同种型，已被证明可调节微生物群。黏膜 IgA 也被广泛认为可防止食物过敏原穿透肠壁。尽管最近的研究阐明了如何诱导针对细菌的 IgA，但对于如何调节针对食物抗原的 IgA 知之甚少。尽管假定在健康的肠道中通过饮食暴露在稳态下诱导 IgA，但我们的数据并不支持这一前提。我们发现，每日食物暴露仅在少数小鼠中诱导低水平的交叉反应性 IgA。相比之下，显著水平的花生特异性 IgA 的诱导严格需要黏膜佐剂。尽管花生特异性 IgA 的诱导需要 T 细胞和 CD40L，但它是 T 滤泡辅助（Tfh）细胞、生发中心和 T 滤泡调节（Tfr）细胞独立的。相比之下，花生特异性 IgG1 和 IgE 的产生需要 T 细胞。这些数据表明了一种替代范式，其中针对食物抗原的 IgA 产生的细胞机制与 IgE 和 IgG1 不同。我们开发了一种等效的测定法来研究来自健康非过敏人群的粪便样本中的此过程，结果显示存在大量稳定的花生特异性 IgA。与小鼠类似，CD40L 功能丧失的患者肠道花生特异性 IgA 的滴度受损。这项工作挑战了关于饮食抗原产生抗体的两个广泛存在但未经测试的范式：（i）针对食物抗原的稳态/耐受反应包括 IgA 产生；（ii）T 细胞驱动食物特异性肠道 IgA。
