Induction of secretory immunity and memory at mucosal surfaces
Induction of secretory immunity and memory at mucosal surfaces
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DOI：
10.1016/j.vaccine.2006.12.001
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发表时间：
2007-07-26
期刊：
影响因子：
5.5
通讯作者：
Brandtzaeg, Per
中科院分区：
文献类型：
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作者：
Brandtzaeg, Per
粘液上皮包括广泛的脆弱屏障，其通过与适应性免疫密切合作的许多先天防御机制来加强。局部产生的分泌型伊加（SIgA）构成了人体最大的体液免疫系统。分泌性抗体通过在粘膜表面进行抗原排斥和通过上皮细胞内的病毒和内毒素中和而不引起组织损伤来起作用。因此，SIgA持续含有上皮屏障外的细菌，但也可以靶向病原体的入侵和有害抗原的渗透。对产毒素细菌如霍乱弧菌和肠毒素大肠杆菌的抗性似乎在很大程度上取决于SIgA，因此在未接种或免疫的条件下，对肠道病原体水平粪口传播的畜群保护作用对交叉反应性和记忆力都有很大的先天影响。与自然感染一样，活粘膜疫苗或非复制型疫苗和粘膜佐剂的适当组合不仅产生SIgA抗体，而且产生长期血清IgG和伊加应答。然而，记忆/效应细胞从粘膜诱导位点向分泌效应位点和全身免疫器官的迁移存在相当大的差异。此外，尽管免疫记忆是在粘膜引发后产生的，但这可能被保护肠道中诱导性淋巴组织的自限性反应所掩盖。靶向鼻咽相关淋巴组织的鼻内疫苗应用途径可能对某些感染更有利，但前提是在不使用可能到达中枢神经系统的毒性佐剂的情况下实现成功的刺激。粘膜接种后获得的保护程度从症状减轻到完全抑制再感染不等。在这种情况下，通常很难确定SIgA与血清抗体的相对重要性，但基因敲除小鼠的感染模型强烈支持SIgA在保护和交叉保护中发挥决定性作用的观点。然而，相对较少的粘膜疫苗已被批准用于人类使用，疫苗和佐剂设计，包括颗粒或活载体组合需要更多的基础工作。
Mucosal epithelia comprise an extensive vulnerable barrier which is reinforced by numerous innate defence mechanisms cooperating intimately with adaptive immunity. Local generation of secretory IgA (SIgA) constitutes the largest humoral immune system of the body. Secretory antibodies function both by performing antigen exclusion at mucosal surfaces and by virus and endotoxin neutralization within epithelial cells without causing tissue damage. SIgA is thus persistently containing commensal bacteria outside the epithelial barrier but can also target invasion of pathogens and penetration of harmful antigens. Resistance to toxin-producing bacteria such as Vibrio cholerae and enterotoxigenic Escherichia coli appears to depend largely on SIgA, and so does herd protection against horizontal faecal-oral spread of enteric pathogens under naive or immunized conditions-with a substantial innate impact both on cross-reactivity and memory. Like natural infections, live mucosal vaccines or adequate combinations of non-replicating vaccines and mucosal adjuvants, give rise not only to SIgA antibodies but also to longstanding serum IgG and IgA responses. However, there is considerably disparity with regard to migration of memory/effector cells from mucosal inductive sites to secretory effector sites and systemic immune organs. Also, although immunological memory is generated after mucosal priming, this may be masked by a self-limiting response protecting the inductive lymphoid tissue in the gut. The intranasal route of vaccine application targeting nasopharynx-associated lymphoid tissue may be more advantageous for certain infections, but only if successful stimulation is achieved without the use of toxic adjuvants that might reach the central nervous system. The degree of protection obtained after mucosal vaccination ranges from reduction of symptoms to complete inhibition of re-infection. In this scenario, it is often difficult to determine the relative importance of SIgA versus serum antibodies, but infection models in knockout mice strongly support the notion that SIgA exerts a decisive role in protection and cross-protection against a variety of infectious agents. Nevertheless, relatively few mucosal vaccines have been approved for human use, and more basic work is needed in vaccine and adjuvant design, including particulate or live-vectored combinations.