Activation and Regulation of Rheumatoid Factor B cells

描述(由研究人员提供)：自身反应性B细胞是致病性自身抗体的来源，是刺激自身反应性T细胞的关键抗原前体细胞。因此，了解这些B细胞是如何发育的，在正常动物中是如何被调节的，以及在自身免疫过程中如何逃避自我耐受，这是至关重要的。这是我们实验室长期关注的主要问题。免疫球蛋白转基因(Ig-TG)小鼠系统在解决这些问题的努力中发挥了不可估量的作用。为了了解抗免疫球蛋白自身抗体(类风湿因子，RF)的调节，我们创建了一个名为AM14的Ig-TG模型。AM14只识别a同种异型的IgG2a(IgG2a“a”)，不识别IgG2a“b”。因此，我们使用同种异型小鼠来控制自身抗原的存在或缺失。在正常的AM14TG小鼠中，B细胞似乎没有克隆性。然而，随着时间的推移，只有当TGS被交叉到具有自身抗原的易于自身免疫的背景上时，AM14 RF B细胞才被诱导成为AFC。因此，AM14是一个模型系统，在该系统中可以很容易地观察和研究对相关自身抗原的耐受性丧失。此外，我们还意外地发现，在外PALS区域，在生发中心外增殖和分化的不寻常的B细胞群体中发生了体细胞的超突变和选择。 自发性自身免疫研究的一个主要局限是自身免疫的随机发生；即使在同一近交系的后代中，自身抗体的时间和性质也可能有很大的差异。最近，我们发现了一种在AM14系统中绕过这些问题的方法：我们发现，在自身免疫倾向的纯H-TG小鼠外周血中出现AM14 ID B细胞表明最近开始了增殖和分化--即自身免疫--在这些小鼠的脾里。连续跟踪H TG小鼠的队列可以揭示这些细胞第一次出现在PBL中的时间，从而揭示自身免疫的开始。从这一点出发，可以对小鼠进行分析、治疗或跟踪，以研究疾病的进一步演变。在这里，我们建议使用这个系统来：1)确定疾病的发生和早期传播所需的环境和遗传因素(自身反应性RF B细胞的扩张)；2)确定从最初的病灶增殖的自身反应性B细胞到慢性持续疾病的级联事件；3)在表型和分子水平上确定逃脱外周耐受的独特的B细胞系的身份。

DESCRIPTION (provided by investigator): Autoreactive B cells are the source of pathogenic autoantibodies and are critical APCs for the stimulation of autoreactive T cells. Hence, it is fundamentally important to understand how these B cells develop, are regulated in normal animals, and escape self-tolerance during autoimmunity. This has been the major long-term focus of our lab. Immunoglobulin transgenic (Ig-Tg) mouse systems have been invaluable in efforts to address these questions. To understand the regulation of anti-IgG autoantibodies (Rheumatoid Factors, RF), we have created an Ig-Tg model called AM14. AM14 recognizes only IgG2a of the a allotype (IgG2a"a") and not of IgG2a"b". Thus we have used allotype congenic mice to control the presence or absence of the autoAg. B cells appear clonally ignorant in normal AM14 Tg mice. However, AM14 RF B cells are induced over time to become AFC's only when the Tgs are crossed onto autoimmune-prone backgrounds that have the autoAg. Thus, AM14 is a model system in which the loss of tolerance to a relevant autoAg can be readily observed and studied. In addition we have found unexpectedly that somatic hypermutation and selection are occurring in unusual populations of B cells proliferating and differentiating outside of germinal centers, at the outer PALS area. A major limitation in the study of spontaneous autoimmunity is the stochastic onset of autoimmunity; the timing and nature of autoantibodies can vary widely even among littermates of the same inbred strain. Recently we have discovered a method to circumvent these problems in the AM14 system: we found that the appearance of AM14 Id+ B cells in the peripheral blood of autoimmune-prone H-only Tg mice indicates the recent onset of proliferation and differentiation-i.e. autoimmunity-in the spleens of these mice. Serially tracking cohorts of H Tg mice reveals when these cells appear in the PBL for the first time and thus, the onset of autoimmunity. From this point, the mice can be analyzed, treated, or followed to study the further evolution of disease. Here we propose to use this system to: 1) Determine the factors-environmental and genetic-that are required for the onset and early propagation of disease (expansion of autoreactive RF B cells); 2) Define the cascade of events that leads from an initial nidus proliferating autoreactive B cells to chronic, ongoing disease; 3) Determine the identities, at the phenotypic and molecular level, of the unique B lineage cells that that have escaped peripheral tolerance.