Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion
Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion
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DOI：
10.1007/s00281-004-0182-2
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发表时间：
2005-03-01
期刊：
影响因子：
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通讯作者：
Herzenberg, LA
中科院分区：
文献类型：
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作者：
Baumgarth, N;Tung, JW;Herzenberg, LA
在完全没有外部抗原刺激的情况下，天然抗体的产生受到严格的控制。它们对病原体提供即时、早期和广泛的保护，使其成为体液免疫系统中至关重要的非多余组成部分。这些抗体主要是由被称为B-1细胞的长寿、自我补充的B细胞亚群产生的，如果不是唯一的话。我们认为，这些B-1细胞的独特发育模式依赖于自身抗原的积极选择，确保产生自然抗体，表达对入侵病原体的初始防御所需的进化上重要的特异性。对自身抗原反应性的阳性选择也可能导致产生有害的抗自身抗体。然而，B-1细胞已经进化出一种独特的反应模式，将自身免疫的风险降至最低。虽然这些细胞对宿主产生的天然信号(如细胞因子)和病原体编码的信号(如脂多糖和磷胆碱)做出快速而强烈的反应，但它们对受体介导的激活反应很差。此外，它们很少进入生发中心并经历亲和力成熟。因此，它们产生具有有害抗自身特异性的高亲和力抗体的潜力受到高度限制。B-1细胞的阳性选择发生在新生期，在此期间构成了长寿的自我更新的B-1群体。其中许多细胞(B-Ia)表达CD5，但较小的亚群(B-1b)不表达这种表面标志。重要的是，B-1a细胞不应与短暂的无能B-2细胞混淆，后者起源于成人的骨髓，在自身抗原识别后启动CD5表达和细胞程序性死亡。综上所述，我们认为B-1细胞产生天然抗体的机制反映了体液免疫系统，体液免疫系统在不同的发育机制下产生互补的曲线谱，共同作用以最大限度地灵活地应对入侵的病原体。B-2细胞可能存在于进化最高的一层(S)，它表达一种针对自我识别而明确选择的谱系，并针对外部抗原刺激产生高亲和力抗体反应。B-1细胞的功能是通过识别自身抗原来选择的，它属于可能是早期的细胞(S)，并内在地保持着对病原体相关的、而不是对抗原特异的信号做出反应的进化上重要的抗体特异性的产生。
Natural antibodies are produced at tightly regulated levels in the complete absence of external antigenic Stimulation. They provide immediate, early and broad protection against pathogens, making them a crucial non-redundant component of the humoral immune system. These antibodies are produced mainly, if not exclusively, by a Subset of long-lived, self-replenishing B cells termed B-1 cells. We argue here that the unique developmental pattern of these B-1 cells, which rests on positive selection by self antigens, ensures production of natural antibodies expressing evolutionarily important specificities that are required for the initial defense against invading pathogens. Positive selection for reactivity with self antigens could also result in the production of detrimental anti-self antibodies. However, B-1 cells have evolved a unique response pattern that minimizes the risk of autoimmunity. Although these cells respond rapidly and strongly to host-derived innate signals, such as cytokines, and to pathogen-encoded signals, such as lipopolysaccharide and phosphorylcholine, they respond very poorly to receptor-mediated activation. In addition, they rarely enter germinal centers and undergo affinity maturation. Thus, their potential for producing high-affinity antibodies with harmful anti-self specificity is highly restricted. The positive selection of B- 1 cells occurs during the neonatal period, during which the long-lived self-renewing B- 1 population is Constituted. Many of these cells (B-Ia) express CD5, although a smaller subset (B-1b) does not express this surface marker. Importantly, B-la cells should not be confused with short-lived anergic B-2 cells, which originate in the bone marrow in adults and initiate CD5 expression and programmed cell death following self-antigen recognition. In summary, we argue here that the mechanisms that enable natural antibody production by B-1 cells reflect the humoral immune system, which has evolved in layers whose distinct developmental mechanisms generate complementary repertoires that collectively operate to maximize flexibility in responses to invading pathogens. B-2 cells, present in what may be the most highly evolved layer(s), express a repertoire that is explicitly selected against self recognition and directed towards the generation of high-affinity antibody response to external antigenic stimuli. B-1 cells, whose repertoire is selected by recognition of self antigen, belong to what may be earlier layer(s) and inherently maintain production of evolutionarily important antibody specificities that respond to pathogen -related, rather then antigen-specific signals.