University of Chicago Autoimmunity Center of Excellence

描述（由申请人提供）：芝加哥大学自身免疫卓越中心（UCACE）的中心主题是自身免疫性疾病的耐受性和适应性免疫。UCACE有两个首要目标。首先是确定适应性自身免疫是如何在特定终末器官受累的自身免疫性疾病中进化和原位繁殖的。我们将重点讨论狼疮肾炎（LuN），这是系统性红斑狼疮（SLE）最常见的严重表现。肾衰竭的进展与小管间质炎症（TII）相关，并且与TII相关的免疫过程是肾脏固有的。这些过程并没有完全反映在外周血中，SLE的小鼠模型不能模仿人类狼疮TII的原位适应性免疫反应。因此，动物模型不能代替人体的初步研究。在ACE的最后一个周期中，我们开发了新的方法来研究人体组织的原位免疫。我们现在可以克隆原位表达的抗体，表达这些抗体并描述它们结合的抗原。然而，原位识别抗原并不足以了解这些B细胞是如何被原位选择的。正如在合作和试点项目中所描述的，我们已经开发出新的计算工具来识别同源细胞：细胞相互作用和人类炎症中细胞组织的整体模式。在合作项目中，我们将把这些研究扩展到其他疾病状态，以建立原位耐受性在自身免疫中失败的特异性和全局机制。

DESCRIPTION (provided by applicant): The central theme of the University of Chicago Autoimmune Center of Excellence (UCACE) is tolerance and adaptive immunity in autoimmune diseases. The UCACE has two over-riding goals. The first is to determine how adaptive autoimmunity evolves and is propagated in situ in autoimmune diseases with specific end organ involvement. We will focus on lupus nephritis (LuN) which is the most common severe manifestation of systemic lupus erythematosus (SLE). Progression to renal failure correlates with tubulointerstitial inflammation (TII) and that the immunological processes associated with TII are intrinsic to the kidney. These processes are not fully reflected in the peripheral blood an murine models of SLE do not mimic the in situ adaptive immune responses of human lupus TII. Therefore, animal models cannot substitute for primary studies in humans. During the last cycle of the ACE, we developed novel methods to study in situ immunity in human tissue. We can now clone in situ expressed antibodies, express these antibodies and characterize the antigens they bind. However, identifying the antigens recognized in situ is not sufficient to understand how those B cells are being selected in situ. As described in the Collaborative and Pilot Projects, we have developed novel computational tools to identify both cognate cell:cell interactions and global patterns of cellular organization in human inflammation. In the Collaborative Project, we will extend these studies to other disease states to establish specific and global mechanisms by which in situ tolerance fails in autoimmunity. The second goal to be pursued by the UCACE is complementary to the first. While the first addresses how autoimmunity is propagated in situ, the second examines the consequences of a loss of tolerance, and autoimmunity, in the development of protective immunity to infection. Surprisingly, SLE patients mount more effective humoral immune responses to influenza vaccination than normal controls. In the Primary Project, we will determine if enhanced protective immunity is a consequence of the broader immunoglobulin repertoire associated with SLE and/or if the cytokine milieu of SLE enables better protective immunity. RELEVANCE: The focus of the University of Chicago Autoimmunity is on lupus. Lupus is a severe body-wide autoimmune disease with severe consequences and for which we have few effective therapies. Furthermore, many of these treatments are very toxic. One goal of the UCACE is to better understand lupus which will enable the development of more effective and less toxic therapies. Principal Project: Exploring the mechanistic basis for altered peripheral B cell selection in SLE Project Leader (PL): Wilson, Patrick C. DESCRIPTION (as provided by applicant): 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. RELEVANCE: We have found that lupus patients make higher affinity antibodies to influenza upon vaccination. This finding suggests that SLE may have resulted from a selective advantage allowing higher affinity antibody responses to pathogens. Understanding the mechanism by which higher affinity and self-reactive antibodies are produced by patients is important for understanding the underlying causes of SLE.