Exploring the mechanistic basis for altered peripheral B cell selection in SLE

在芝加哥大学ACE的前一个资助期的令人惊讶的发现中，我们发现系统性狼疮 SLE患者产生更高亲和力和更强中和性的抗流感病毒抗体， 抗体（手稿在准备中）。我们还在MRL-lpr/lpr小鼠中证明了这种趋势 SLE模型这些发现表明了我们认为是核心的两个主要假设之一 了解SLE的病因。首先，有一种可能性， 亲和性抗体通常也具有较高的狼疮风险。所有人都可能产生自身抗体 不时的回应。然而，在任何情况下都倾向于产生高亲和力抗体的个体， 免疫应答可能产生更高亲和力，因此有时会产生病理性自身抗体， 表位扩散将导致SLE。第二种可能性是自身免疫可以提高抗体水平， 应答因此，更高的亲和力和伴随的自身免疫性被一起选择，增加了 SLE。这是自身免疫性库，或与自身免疫相关的其他特征，如 炎症，使更有效的抗体反应。在这次更新申请中，我们建议测试 各种假说揭示了SLE患者更有效的体液免疫机制， 对流感和其他疫苗的反应。我们还注意到，与对照受试者不同， 有些自身反应性，来自SLE患者的那些仅对自身抗原反应，而不是多反应性的。 这些发现表明，在SLE患者中，外周血中对多反应性的选择， 免疫反应是完整的，支持狼疮病理模型，其中高亲和力自身抗体是 在自身抗原特异性反应中产生。在具体目标1中，我们将进行实验来探索这一点 假说.在具体目标2和3中，我们将探索产生高亲和力的机制基础， 相反，在SLE患者和对照组（Aim 2）或SLE小鼠模型中， 自身免疫（目的3）。这些实验将提供深入了解为什么自身免疫可能维持在 普通民众。

In surprising findings from the previous funding period of the UChicago ACE we found that systemic lupus erythematous (SLE) patients generated higher-affinity and more potently neutralizing anti-influenza antibodies (manuscript in preparation). We have also demonstrated this tendency in the Mrl-lpr/lpr mouse model of SLE. These findings suggest one of two primary hypotheses that we believe are of central importance to understanding the cause of SLE. First, there is the possibility that people who make higher affinity antibodies in general are also at a higher risk for lupus. All people likely make autoantibody responses from time to time. However, individuals that are prone to make high affinity antibodies during any immune response may make higher affinity and therefore pathological autoantibodies on occasion that with epitope spreading will result in SLE. The second possibility is that autoimmunity may improve antibody responses. Thus higher-affinity and concomitantly autoimmunity are selected together, increasing the risk for SLE. That is the autoimmune repertoire, or other features associated with autoimmunity such as inflammation, enables more effective antibody responses. In this renewal application, we propose to test various hypotheses to reveal the mechanisms by which SLE patients mount more effective humoral immune responses to influenza and other vaccines. We also noted that unlike control subject antibodies that were somewhat autoreactive, those from SLE patients were uniquely reactive to self-antigens without being polyreactive. These findings suggest that in SLE patients, selection against polyreactivity during peripheral immune responses is intact, supporting a model for lupus pathology in which high-affinity autoantibodies are generated in self-antigen specific responses. In Specific Aim 1 we will perform experiments to explore this hypothesis. In Specific Aims 2 and 3 we will explore the mechanistic basis for generating high affinity, and conversely, autoimmune-prone responses in SLE patients and controls (Aim 2) or in mouse models of autoimmunity (Aim 3). These experiments will provide insight into why autoimmunity might be maintained in the general population.