Control by Beta 7 integrins of the bacterial triggers of IBD

7.项目摘要/摘要 阻断淋巴细胞表面整合素(即Natalizumab(α4)，vedolizumab(α4β7))是FDA批准的 炎症性肠病(IBD)的治疗策略我们对他们的行动模式的理解是 它们对B细胞的影响还不完整，也很少受到重视。然而，单剂vedolizumab 在健康志愿者中，降低分泌性免疫球蛋白(Ig)A(SIgA)并减弱对 口服霍乱疫苗。探讨β7整合素在B细胞迁移、定位和功能中的作用 在炎症性肠病中，我们与肿瘤坏死因子高表达的小鼠(发生克罗恩样回肠炎的肿瘤坏死因子Δ)杂交。 以及β7缺陷(β7-/-)小鼠的IL 10-/-(倾向于结肠炎)。出乎意料的是，双突变(肿瘤坏死因子Δ是/β7-/-)小鼠 发生加速性回肠炎(发病更早，病情更严重)，而IL-10-/-β7-/-发展为致死性结肠炎。这 抗MAdCAM1(α4β7-Ligand)抗体可诱导细胞表型。加速型 表型不是由于缺乏产生维甲酸的αE(CD103)+树突状细胞，调节性T细胞 细胞、调节性B细胞衍生的细胞因子或防御素。然而，固有层明显减少。 (CD19+)B细胞，IgA+浆细胞定位不良，腔性IgA缺乏，以及微生物区系差异 合住兄弟姐妹的构成。此外，来自β7-/-小鼠的粪便微生物群移植诱导了小鼠结肠炎。 IL-10缺乏的小鼠，表明Ig缺陷可能允许结肠炎病原体的可传播性增殖。 因此，迫切需要了解整合素或其配体的持续阻断是否会 对粘膜免疫的影响。我们假设β7基因缺陷小鼠回肠炎和结肠炎的加速 是由B细胞迁移受损和不适宜的IgA转胞导致肠道免疫球蛋白介导的 病原体的缺失和增殖。为了验证这些假设，我们将检验：1.B细胞招募的作用 存活以维持管腔免疫球蛋白A。2.微生物区系组成的变化如何改变病程和严重程度 炎症性肠病？和3.进一步研究β7整合素(即αEβ7)在产生Ig A的浆细胞与 上皮细胞和最适的IgA转胞作用。这项研究具有重要意义，因为它开始解决B细胞的作用 以及它们独特的关键依赖于β7整合素到肠道，以及最佳的跨细胞免疫球蛋白A到 维持必需的免疫球蛋白A水平，在动态平衡期间控制微生物区系的某些致病因素 还有IBD。了解淋巴细胞整合素在微生物区系和宿主之间的作用 可能会让我们更好地理解当前的抗整合素疗法是如何起作用的，甚至会导致新的 采取干预措施，防止启动对引发IBD的微生物区系的失调免疫反应。

7. Project Summary/Abstract The blockade of lymphocyte surface integrins (i.e. natalizumab (α4), vedolizumab (α4β7)) is an FDA-approved strategy for the treatment of inflammatory bowel disease (IBD). Our understanding of their mode of action is incomplete and little emphasis has been placed on their effect on B cells. However, a single dose of vedolizumab in healthy volunteers lowers secretory immunoglobulin (Ig)A (SIgA) and weakens the immunization response to oral cholera vaccine. To address the role of β7 integrins for the migration, localization and function of B cells in IBD, we crossed tumor necrosis factor (TNF)-overproducing mice (TNFΔARE, which develop Crohn’s-like ileitis) and IL10-/- (colitic-prone) with β7-deficient (β7-/-) mice. Unexpectedly, double mutant (TNFΔARE/β7-/-) mice developed accelerated ileitis (earlier onset and worse severity), whereas IL-10-/-β7-/- develop lethal colitis. This phenotype could additionally be induced by an anti-MAdCAM-1(α4β7-ligand) antibody. The accelerated phenotypes were not due to a deficiency of retinoic acid-producing αE(CD103)+ dendritic cells, regulatory T cells, regulatory B cell-derived cytokines or defensins. There was, however, markedly decreased lamina propria (CD19+) B cells, poor localization of IgA+ plasma cells, luminal IgA deficiency, and differences in microbiota composition in co-housed siblings. Furthermore, fecal microbiota transplants from β7-/- mice induced colitis in IL-10-deficient mice, suggesting that an Ig deficit may allow transmissible proliferation of colitogenic pathobionts. Thus, there is a critical need to understand whether sustained blockade of integrins or their ligands may have implications for mucosal immunity. We hypothesize that the acceleration of ileitis and colitis in β7-deficient mice is mediated by impaired B cell migration and suboptimal IgA transcytosis leading to an intestinal immunoglobulin deficit and proliferation of pathobionts. To test these hypotheses, we will examine: 1. the role of B cell recruitment and survival to maintain luminal IgA. 2. How do changes in microbiota composition alter the course and severity of IBD? and 3. Further examine the role of β7 integrin (i.e., αEβ7) for docking of IgA-producing plasma cells with epithelium and optimal IgA transcytosis. This investigation is significant as it begins to address the role of B cells and their unique critical dependence on β7 integrins to home to the intestine and optimally transcytose IgA to maintain the required IgA levels that control certain pathogenic elements of the microbiota during homeostasis and IBD. Understanding the role of lymphocyte integrins at the interface between the microbiota and its host may lead to a better understanding of how do current anti-integrin therapeutics work and even lead to new interventions to prevent initiation of the dysregulated immune response to the microbiota that triggers IBD.