NEGATIVE SELECTION OF AUTOREACTIVE ANTIBODIES

自身反应性抗体的阴性选择

• 批准号: 6284892
• 负责人: TIMOTHY L MANSER
• 金额: $ 23.85万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6284892
• 关键词: B cell receptor; B lymphocyte; antibody formation; antibody specificity; antinuclear autoantibody; apoptosis; autoimmunity; gene rearrangement; genetically modified animals; hybridomas; immunoglobulin genes; immunologic memory; laboratory mouse; lymph nodes; polymerase chain reaction

DESCRIPTION: (Adapted from the Investigator's abstract): The peripheral primary B cell compartment in mammals is characterized by expression of antigen receptors (BCRs) with "multi-reactivity" for both foreign and autoantigens. During the development of B cell memory the BCRS expressed by responding clonotypes are extensively altered by V gene somatic hypermutation. Hypermutation can create autoreactivity de novo, or enhance the autoreactivity intrinsic to precursor BCRS. We and others have proposed that a stringent self-tolerance process operates on B cells differentiating to the memory phenotype during foreign antigen driven immune responses. In the previous funding period we obtained evidence supporting this hypothesis. A B cell clonotype that dominates the memory compartment of the anti-arsonate immune response of A/J mice expresses BCRs with affinity for both arsonate and the self antigen DNA. In contrast, the hypermutated derivatives of these BCRs expressed by the memory compartment display increased affinity for arsonate and no affinity for DNA. However, if B cell apoptotic pathways are perturbed via enforced expression of Bcl-2 from a transgene, the BCRs expressed by members of this clonotype that enter the memory compartment display increased affinity for both arsonate and DNA. These data have led us to formulate the "specificity maturation" hypothesis-that during a foreign antigen driven immune response precursors to memory B cells undergoing hypermutation are subject to iterative cycles of both positive selection (for increased or unaltered affinity for the driving foreign antigen) and negative selection (for affinity for self antigens). The end result is a memory B cell compartment expressing BCRS with high specificity for the driving foreign antigen-a compartment that would efficiently recognize the foreign antigen and pose little risk for the development of autoimmunity. In the next proposed application period, we wish to test several tenets of this hypothesis as well as to begin to gain insight into the mechanism(s) that result in the generation of a memory B cell compartment with a high degree of specificity for the driving foreign antigen. Three interrelated questions will be addressed: 1) can B cells not subjected to central tolerance mechanisms and whose BCRs display "multi-reactivity," including autoreactivity, be recruited into the primary immune response and germinal center (GC) reaction, despite displaying a "self antigen regulated" phenotype?; 2) are members of such clones subsequently "purged" of their autoreactivity via somatic hypermutation or receptor editing prior to entry into the memory compartment?; and, 3) is the primary microenvironmental locale in which specificity maturation takes place the GC?

描述：（改编自研究者摘要）：外周原发性 哺乳动物中的B细胞区室的特征在于表达抗原 受体（BCR）对外来抗原和自身抗原具有"多反应性"。 在B细胞记忆的发育过程中，BCRS通过应答性表达， 克隆型被V基因体细胞超突变广泛改变。 超突变可以重新产生自身反应性，或增强自身反应性。 前体BCRS的固有特性。我们和其他人建议， 自身耐受过程作用于B细胞分化为记忆 在外源抗原驱动的免疫应答期间的表型。上一 在此期间，我们获得了支持这一假设的证据。A B细胞 克隆型，占主导地位的记忆隔室的抗纵火免疫 A/J小鼠的反应表达了对胂酸盐和 自身抗原DNA相反，这些BCR的高度突变衍生物 由记忆隔室表达的对纵火剂的亲和力增加， 对DNA没有亲和力然而，如果B细胞凋亡途径受到干扰， 从转基因中强制表达Bcl-2，由BCR成员表达的BCR 进入记忆舱的这种克隆型显示出增加的亲和力， 纵火物和DNA这些数据使我们制定了"特异性 成熟"假说-在外源抗原驱动的免疫应答期间 经历超突变的记忆B细胞的前体受到反复的 两个阳性选择循环（对于增加的或不变的对抗体的亲和力）， 驱动外来抗原）和阴性选择（对于自身亲和力 抗原）。最终结果是表达BCRS的记忆B细胞区室， 对驱动外来抗原的高度特异性--一个可以 有效地识别外来抗原，并且对免疫缺陷的风险很小。 自身免疫的发展。 在下一个拟议的应用期间，我们希望测试这一点的几个原则， 假设以及开始深入了解的机制， 导致产生具有高度的记忆性的记忆B细胞隔室， 驱动外源抗原的特异性。三个相互关联的问题 1）B细胞是否不受中枢耐受机制的影响， 其BCR显示"多反应性"，包括自身反应性， 进入初级免疫反应和生发中心（GC）反应，尽管 显示"自身抗原调节"表型？2)都是这种克隆体的成员 随后通过体细胞超突变"清除"其自身反应性， 在进入记忆舱之前进行受体编辑？（3）是 发生特异性成熟的主要微环境场所 GC？