The anatomy of mucosal immune responses
The anatomy of mucosal immune responses
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DOI：
10.1196/annals.1309.002
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Smith, KM
中科院分区：
文献类型：
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作者：
Garside, P;Millington, O;Smith, KM
目前尚不清楚如何以及在哪里导致对饲料抗原的无反应性。这种“口服耐受性”可能是必要的，以防止一系列免疫效应器机制需要中和粘膜病原体被误导到食物抗原或共生菌。显然，分析这种免疫同种作用在肠道中维持的地点、时间和方式是很重要的，但也有必要确定口服耐受的治疗应用是否需要类似的诱导和效应机制。这可能受到解剖学和微环境对抗原提呈细胞(APC)表型和/或激活状态的影响，APC提供口服递送的抗原。FED抗原通过肠腔内的绒毛上皮和Peyer‘s patches(PP)中的M细胞或粘膜固有层传递到PP的有组织淋巴组织和肠系膜淋巴结(MLN)。此外，有证据表明，粘膜注射的抗原也可以直接进入外周淋巴器官。这些地点中的每一个都包含不同的APC群体，并具有独特的局部微环境，这些微环境可能以不同的方式影响免疫反应。我们认为，大剂量喂养抗原可能会导致克隆无能、缺失或改变分化，因为它可以直接进入肠道相关淋巴组织(GALT)和外周淋巴器官的T细胞区的静止APC，在没有产生协同刺激的情况下出现。相反，低剂量的耐受抗原可能被GALT中的APC优先摄取和呈递，那里的局部环境可能有利于调节性T细胞的诱导。这与我们自己和其他人使用TCR TG T细胞过继转移的发现是一致的。这些研究表明，在喂食高剂量的蛋白质后，抗原特异性的CD4(+)T细胞在所有外周和肠道相关的淋巴器官中同时被激活，但当使用较低剂量的蛋白质时，这可能更限于局部组织。另一个层面的解剖学控制是在淋巴器官内施加的，在那里T细胞通过不同的解剖间隔迁移可以影响它们的分化。我们发现，与口服诱导的T细胞相比，口服耐受的T细胞在最初接触抗原时不能迁移到B细胞滤泡中。这会影响它们的分化，因为在随后用佐剂中的抗原攻击时，可以在毛囊中发现耐受的T细胞，但无法提供B细胞可以提供的B细胞帮助。我们假设，耐受T细胞最初的有缺陷的迁移阻止了它们从卵泡中的抗原特异性B细胞接收信号，并导致流产分化。因此，FED抗原呈递的粗略和精细解剖位置在粘膜免疫调节中可能是重要的。
It remains unclear how and where unresponsiveness to fed antigens is induced. This "oral tolerance" is probably necessary to prevent the array of immune effector mechanisms required to counteract pathogens of the mucosae from being misdirected against food antigens or commensal flora. It will obviously be important to dissect where, when, and how such immunological homoestasis is maintained in the gut, but it will also be necessary to determine whether similar inductive and effector mechanisms are required for the therapeutic applications of oral tolerance systemically. This may be influenced by anatomical and microenvironmental effects on the phenotype and/or activation state of the antigen-presenting cell (APC), which presents orally delivered antigen. Fed antigen passes from the intestinal lumen either via the villus epithelium and M cells in the Peyer's patches (PP) or the mucosal lamina propria to the organized lymphoid tissues of the PP and mesenteric lymph nodes (MLN). In addition, there is evidence that mucosally administered antigen also gains access directly to peripheral lymphoid organs. Each of these sites contains distinctive populations of APCs and has unique local microenvironments that may influence the immune response in different ways. We propose that feeding antigen in high doses may induce clonal anergy, deletion, or altered differentiation because it gains direct access to resting APCs in the T cell areas of both the gut-associated lymphoid tissues (GALT) and peripheral lymphoid organs, with presentation occurring in the absence of productive costimulation. By contrast, low doses of tolerizing antigen may be taken up and presented preferentially by APCs in the GALT, where the local environment may favor the induction of regulatory T cells. This is consistent with our own and others findings, using adoptive transfer of TcR tg T cells. These studies have shown that antigen-specific CD4(+) T cells are activated simultaneously in all peripheral and gut-associated lymphoid organs after feeding high doses of proteins, but that this may be more restricted to local tissues when lower doses are used. Another level of anatomical control is imposed within lymphoid organs, where migration of T cells through distinct anatomical compartments can affect their differentiation. We find that, in contrast to orally primed T cells, orally tolerized T cells are unable to migrate into B cell follicles during their initial exposure to antigen. This affects their differentiation as upon subsequent challenge with antigen in adjuvant, tolerized T cells can be found in follicles but are unable to provide the B cell help that primed T cells can deliver. We hypothesize that the initial defective migration of tolerized T cells prevents them from receiving signals from antigen-specific B cells in follicles and results in abortive differentiation. Thus, both gross and fine anatomical location of fed antigen presentation may be important in mucosal immunoregulation.