Primordially conserved principles governing mucosal immune responses to microbiota

在整个进化过程中，特异性免疫球蛋白（IG）同种型已经变得专门化， MB稳态。在哺乳动物中，分泌型IgA（sIgA）在MB调节中起主要作用。我们有 证明了sIgT在鱼类中充当sIgA的功能类似物。因此， sIgA和sIgT强烈支持使用鱼作为研究粘膜损伤的替代脊椎动物模型。 免疫力 虽然目前的教条表明sIgA是调节MB体内平衡的主要同种型，但它具有 最近显示，sIgM识别并覆盖人体大部分管腔MB， 协助sIgA将高度多样化的MB锚定到人肠道中的粘液上。有趣的是，sIgM不会覆盖肠道 MB，从而排除了进一步研究sIgA和sIgM在小鼠中的特异性贡献。 在该实验系统中维持MB稳态。重要的是，我们已经证明，与人类一样， sIgM靶向肠道MB的很大一部分。因此，鱼类提供了一种独特的易处理的脊椎动物模型来解决 IgM在调节肠道MB中的作用。使用这个系统，我们提供了第一个演示，不同的 免疫球蛋白（IgT和IgM）主要识别非哺乳动物物种中的不同肠道细菌分类群。这 这一发现使我们假设sIgT和sIgM在识别中的独特和互补作用， 调节和控制肠道MB。 最近在哺乳动物中的一些研究表明，血清中MB特异性IgA和IgG在哺乳动物中起重要作用。 在MB诱导的脓毒症消退中的作用。然而，血清IgM参与这些系统性 反应和诱导这种反应的微生物类群的性质仍然不清楚。在这里，我们表明， 鱼血清含有非常高水平的MB特异性IgM，而IgT的水平可以忽略不计。这些数据让我们 假设血清IgM在识别和控制系统性 易位的微生态MB。此外，在结肠炎诱导的生态失调后，我们主要发现吞噬性IgT + B 在肠道中具有内化的生态失调MB的细胞，而吞噬性IgM + B细胞在脾脏中占优势。这些 结果使我们假设IgT+和IgM + B细胞在免疫系统中发挥不同但互补的作用。 控制微生态MB。 为了验证上述假设，我们将使用我们新开发的缺乏IgT，IgM的鱼类模型 或两者，与我们的新型DSS诱导的结肠炎鱼模型组合。我们预测我们对鱼类的研究 为该领域提供了独特的系统发育维度。 因此，本提案的目标是：目标1。sIgT和sIgM在维持免疫功能中的特异性作用 MB稳态; AIM 2. MB分类群识别以及sIgT和sIgM在MB诱导的脓毒症中的保护作用;目的 3. IgT+和IgM + B细胞在识别和控制微生态MB中的作用

Throughout evolutionary time, specific immunoglobulin (Ig) isotypes have become specialized in the maintenance of MB homeostasis. In mammals, secretory IgA (sIgA), plays the predominant role in MB regulation. We have demonstrated that sIgT acts as the functional analog of sIgA in fish. Thus, the primordially conserved functions of sIgA and sIgT strongly support the use of fish as an alternative vertebrate model for the study of mucosal immunity. While the current dogma indicates that sIgA is the predominant isotype regulating MB homeostasis, it has recently been shown that sIgM recognizes and coats a large percentage of the luminal MB in humans and may assist sIgA in anchoring a highly diverse MB to mucus in the human gut. Intriguingly, sIgM does not coat gut MB in mice, thus precluding further investigation of the specific contributions of sIgA and sIgM in the maintenance of MB homeostasis in this experimental system. Critically, we have shown that as in humans, fish sIgM targets a significant portion of the gut MB. Thus, fish provide a unique tractable vertebrate model to address the role of IgM in the regulation of gut MB. Using this system, we provide the first demonstration that distinct immunoglobulins (IgT and IgM) primarily recognize different gut bacterial taxa in a non-mammalian species. This finding leads us to hypothesize unique and complementary roles for sIgT and sIgM in the recognition, regulation and control of gut MB. Several recent studies in mammals suggest that MB-specific IgA and IgG in the serum play an important role in the resolution of MB-induced sepsis. However, the involvement of serum IgM in these systemic responses, and the nature of the microbial taxa inducing such responses, are still ill-defined. Here, we show that fish serum contains very high levels of MB-specific-IgM, whereas those of IgT are negligible. These data lead us to hypothesize that serum IgM plays a critical role in the recognition and control of systemically translocated dysbiotic MB. Moreover, following colitis-induced dysbiosis, we primarily find phagocytic IgT+ B cells with internalized dysbiotic MB in the gut, while phagocytic IgM+ B cells predominate in the spleen. These results lead us to hypothesize that IgT+ and IgM+ B cells play distinct but complementary roles in the control of dysbiotic MB. To test the above mentioned hypotheses, we will use our newly developed fish models that lack IgT, IgM or both, in combination with our novel DSS-induced colitis fish model. We predict that our studies with fish will provide a unique phylogenetic dimension to the field. Thus, the aims of this proposal are: AIM 1. Specific contributions of sIgT and sIgM in the maintenance of MB homeostasis; AIM 2. MB taxa recognition and protective roles of sIgT and sIgM in MB-induced sepsis; AIM 3. Contributions of IgT+ and IgM+ B cells in the recognition and control of dysbiotic MB.