Maintenance of B Cell Anergy

携带对自体抗原特异性的受体的淋巴细胞必须被沉默，以防止免疫应答。 自身免疫的发展。使用免疫球蛋白转基因小鼠的研究，其中所有B细胞都是 自身反应性表明细胞与低亲合力抗原的相互作用可导致无反应性沉默， 细胞存活一段时间（t1/2~ 5天）并保留其结合抗原的能力，但 对免疫原性刺激无反应。尽管自身免疫似乎是由 这些无反应性B细胞的无意中重新唤醒，无反应性在维持免疫系统中的重要性， 正常动物的耐受性尚不清楚。此外，尚不清楚抗原无应答性是如何影响免疫缺陷病毒的抗原无应答性的。 无反应性细胞被维持，什么“信号”可能恢复它们的反应性，导致自身免疫。 我们最近定义了一组细胞表面标志物，似乎是唯一表达在无反应性细胞表面。 B细胞，并可用于计数和分离具有正常多样性B细胞的小鼠中的无反应性B细胞 保留曲目。对这一群体的研究，称为An 1（无反应性1）室，表明在正常情况下， 动物30-50%的新产生的B细胞注定成为无反应性的。为了理解 它们在自身免疫中的作用，我们在目标1中提出了抑制性信号通路的阐明， An 1细胞的抗原无反应性。目标2中提出的研究解决了细菌 感染以促使细胞从An 1群体中离开并恢复它们对抗原的应答性。 最后，在目标3中，我们提出了在淋巴结中发现的An 1样细胞群体的表征， 探索它们对抗原的反应性以及它们作为以下结果出现的可能性： 通过体细胞突变获得的自身反应性。 拟议的研究将采用B细胞无反应性的转基因模型以及衍生的An 1群体。 从正常的老鼠。这些将与生物化学和分子遗传学方法结合使用， 定义调节信号通路，并分析“危险”、生存和T辅助信号对 无反应性细胞功能。 拟议的研究应该通过定义自身免疫的起源来促进我们对自身免疫起源的理解。 免疫耐受性被感染因子和使免疫耐受性丧失的突变破坏的情况。 维持无反应性的关键分子调节机制。

Lymphocytes bearing receptors specific for autologous antigens must be silenced in order to prevent the development of autoimmunity. Studies using immunoglobulin transgenic mice in which all B cells are autoreactive indicate that cell interactions with low avidity antigens can lead to silencing by anergy, a condition wherein the cell survives for a period of time (t1/2~5days) and retains its ability to bind antigen, but is unresponsive to immunogenic stimulation. Although it seems likely that autoimmunity is be caused by the inadvertent reawakening of these anergic B cells, the importance of anergy in maintaining immunologic tolerance in normal animals is unknown. Furthermore it is unclear how the antigen unresponsiveness of anergic cells is maintained and what "signals" might restore their responsiveness leading to autoimmunity. We have recently defined a set of cell surface markers that appear to be uniquely expressed on anergic B cells, and can be used to enumerate and isolate anergic B cells in mice with a normal diverse B cell repertoire. Studies of this population, referred to as the An1 (anergic 1) compartment, indicate that in normal animals 30-50% of newly produced B cells are destined to become anergic. Towards an understanding of their role in autoimmunity, we propose in Aim 1 the elucidation of inhibitory signaling circuitry that maintains the antigen unresponsiveness of An1 cells. Studies proposed in aim 2 address the ability of bacterial infection to prompt departure of cells from the An1 population and restore their responsiveness to antigen. Finally in Aim 3 we propose the characterization of a population of An1-like cells found in lymph nodes, exploring their responsiveness to antigen and the possibility that they arise as a consequence of autoreactivity acquired by somatic mutation. The proposed studies will employ transgenic models of B cell anergy as well as An1 populations derived from normal mice. These will be used in conjunction with biochemical and molecular genetic approaches to define regulatory signaling circuitry, and analysis of the effect of "danger", survival and T helper signals on anergic cell function. The proposed studies should advance our understanding of the genesis of autoimmunity by defining circumstances in which immunologic tolerance is broken by infectious agents and by mutations that disable molecular regulatory mechanisms critical for maintenance of anergy.