Baumgarth Nicole, Tung James W, Herzenberg Leonore A
Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA.
Springer Semin Immunopathol. 2005 Mar;26(4):347-62. doi: 10.1007/s00281-004-0182-2. Epub 2005 Jan 5.
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-1a) express CD5, although a smaller subset (B-1b) does not express this surface marker. Importantly, B-1a 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.
天然抗体在完全没有外部抗原刺激的情况下以严格调控的水平产生。它们为抵御病原体提供即时、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冗余组成部分。这些抗体主要（如果不是唯一的话）由一类称为B-1细胞的长寿、自我更新的B细胞亚群产生。我们在此认为，这些B-1细胞独特的发育模式依赖于自身抗原的阳性选择，确保产生表达进化上重要特异性的天然抗体，这些特异性是抵御入侵病原体初始防御所必需的。与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。尽管这些细胞对宿主来源的先天信号（如细胞因子）和病原体编码的信号（如脂多糖和磷酸胆碱）迅速而强烈地做出反应，但它们对受体介导的激活反应非常差。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儿期，在此期间形成了长寿的自我更新B-1细胞群体。这些细胞中的许多（B-1a）表达CD5，尽管较小的亚群（B-1b）不表达这种表面标志物。重要的是，B-1a细胞不应与短暂无反应性的B-2细胞混淆，B-2细胞起源于成年个体的骨髓，在识别自身抗原后启动CD5表达和程序性细胞死亡。总之，我们在此认为，使B-1细胞产生天然抗体的机制反映了体液免疫系统，该系统是分层进化的，其独特的发育机制产生互补的抗体库，共同作用以最大限度地提高对入侵病原体反应的灵活性。存在于可能是进化程度最高的层中的B-2细胞，表达一种明确针对自身识别进行选择的抗体库，并针对外部抗原刺激产生高亲和力抗体反应。其抗体库通过识别自身抗原而选择的B-1细胞，属于可能更早的层，并固有地维持对病原体相关而非抗原特异性信号做出反应的进化上重要的抗体特异性的产生。
