AID biology

B淋巴细胞是一种免疫系统细胞，通过其细胞表面称为抗体的特殊受体识别和处置病原体，如病毒和细菌。免疫系统如何通过抗体分子识别和消除病原体，在很大程度上取决于针对B细胞抗体基因的两个遗传过程：体细胞高突变和类开关重组。第一种机制在抗体基因的N端部分引入随机点突变。在免疫反应过程中，与细胞选择有关的突变增加了抗体与病原体的结合亲和力。第二种机制(通过基因重组)改变抗体基因的C末端部分，这反过来决定了免疫系统用来消除有问题的病原体的策略。体细胞的超突变和开关重组都是由一种新发现的酶：AID进行的。 AID在免疫反应中的重要性在AID缺乏的人和动物中得到强调，这些人和动物对感染高度敏感，并表现出肠道菌群依赖性的肠道绒毛增生。相反，复杂的疾病，如自身免疫，长期以来一直与依赖艾滋病的超突变有关。此外，不及时、异位或升高的AID表达会导致B细胞和T细胞的易位和恶性转化。这些考虑强调了了解调控AID表达和活性的分子途径的必要性。为了探索AID在动物模型中的调控，我们培育了AID报告小鼠。通过融合AID基因的绿色和黄色荧光分子(从水母Aequorea Victoria中分离出来)，我们能够在各种免疫学设置中可视化AID表达的B细胞。最近发表在《实验医学杂志》上的这项研究表明，AID的表达仅限于B淋巴细胞群，该B淋巴细胞群在被称为生发中心的特殊微环境中与滤泡树突状细胞和激活的CD4T细胞相互作用。 手稿中报告的其他主要发现包括： I)当细胞离开生发中心微环境时，艾滋病很容易被关闭。 Ii)在T细胞非依赖性免疫反应中，大量的前浆细胞(在免疫反应中分泌抗体分子)在终末分化之前表达AID。 3)肠道固有层中活化的B细胞也可表达AID。 IV)AID不存在于未成熟的骨髓B细胞中，但在逆转录病毒感染后可被诱导表达。 目前，我们正在将我们的艾滋病报告系统与自身免疫的小鼠模型相结合。这些小鼠被称为MRL/LPR，表现出系统性自身免疫、与T细胞增殖相关的淋巴结病和免疫复合体肾炎，所有这些都是人类系统性红斑狼疮和关节炎的特征。因此，我们研究的一个主要目标是更好地描述AID在具有临床相关性的自身免疫性疾病发展中的作用。

B lymphocytes are the immune system cells that recognize and dispose pathogens such as viruses and bacteria though special receptors on their cell surface known as antibodies. How the immune system recognizes and eliminates pathogens via antibody molecules depends to a great extent on two genetic processes targeting B cell antibody genes: somatic hypermutation and class switch recombination. The first mechanism introduces random point mutations at the N terminal portion of the antibody gene. Mutations coupled to cell selection during the immune response increase the binding affinity of the antibody for the pathogen. The second mechanism changes (via gene recombination) the C terminal portion of the antibody gene, which in turns dictates the strategy used by the immune system to eliminate the pathogen in question. Both somatic hypermutation and switch recombination are carried out by a newly discovered enzyme: AID. The importance of AID in the immune response is highlighted in AID deficient humans and animals, which are highly susceptible to infection and exhibit gut flora-dependent hyperplasia of intestinal villi. Conversely, complex diseases such as autoimmunity have long been associated with AID-dependent hypermutation. Moreover, untimely, ectopic, or elevated AID expression results in translocations and malignant transformation of B cells and T cells. These considerations emphasize the need to understand the molecular pathways that regulate AID expression and activity. To explore AID regulation in an animal model we generated AID reporter mice. By fusing to the AID gene green and yellow fluorescent molecules (isolated from the jellyfish Aequorea victoria), we were able to visualize AID expressing B cells during a variety of immunological settings. The study, which was recently published in the Journal of Experimental Medicine, showed that AID expression is restricted to a B lymphocyte population that interacts with follicular dendritic cells and activated CD4 T cells in a specialized microenvironment known as the germinal center. The other major findings reported in the manuscript include: i) AID is readily shut down as cells exit the germinal center microenviroment. ii) During T cell independent immune responses, a large number of pre-plasma cells (which secrete antibody molecules during the immune response) express AID prior to terminal differentiation. iii) Activated B cells in the gut lamina propria can also express AID. iv) AID is not present in immature bone marrow B cells but its expression can be induced upon retroviral infection. Currently, we are combining our AID reporter system to a mouse model of autoimmunity. The mice, known as MRL/lpr, show systemic autoimmunity, lymphadenopathy associated with T cell proliferation, and immune complex glomerulonephritis, all of which are characteristic of systemic lupus erythematosus and arthritis in humans. Thus a primary goal for our studies is to better delineate the role of AID in the development of autoimmune diseases with clinical relevance.