Autoantibody Signatures as Biomarkers of Interstitial Cystitis.

描述（由申请人提供）：间质性膀胱炎（IC）是一种使人衰弱的慢性膀胱综合征。目前，尚无有效的IC生物标志物。然而，炎症与IC相关已得到充分证实。尽管自身免疫被认为是IC的潜在原因，但IC的某些方面表明，它可能在启动或维持这种疾病中明显的慢性炎症反应中发挥作用。例如，在IC患者的血清中检测到的自身抗体比对照组更大，IC中自身抗体识别的抗原的多样性表明，膀胱上皮细胞的变性可能刺激了自身抗体的产生。因此，IC中炎症/自身免疫的存在可能允许使用机体自身免疫反应作为识别IC生物标志物的手段。显然，了解这些潜在的自身抗原可能有助于更好地理解IC的病理生物学，并促进自身抗体标记作为潜在诊断生物标志物的开发或使用。虽然自身抗体有很多潜在的优势，但它的致命弱点是它的敏感性。自身免疫性疾病的经验表明，通常只有15-20%的患者对任何给定抗原表现出反应。然而，蛋白质组学可能是成功的关键，因为它能够提供多种途径。通过将对几种抗原的反应连接在一起，测试的敏感性和特异性大大提高。最近，我们描述了“反向捕获”自身抗体微阵列的开发和使用，这是一个使用高密度单克隆抗体捕获阵列固定500种特定抗原的平台。这些抗原靶点是参与信号转导、细胞周期调节、基因转录、细胞凋亡、细胞生长、受体、膜蛋白以及粘附和迁移分子的蛋白质。用固定抗原作为“诱饵”，我们可以测定实验组和对照组对固定抗原的自身抗体反应性。我们相信这个平台可能非常适合集成电路的研究。因此，我们对这个应用的研究目标是：1)验证IC患者血清自身抗体库可用于自身抗体谱分析的假设，2)确定“反向捕获”自身抗体微阵列识别自身抗体特征作为IC生物标志物的可行性、稳健性和可重复性。间质性膀胱炎（IC）是一种衰弱的慢性膀胱综合征，以尿急、尿频和盆腔/膀胱疼痛为特征。IC研究的当前需求是识别IC生物标志物，因为目前还没有经过验证的IC生物标志物。IC生物标志物的识别很重要，因为它们可能被用来创建IC诊断的临床工具，并为IC患者开发靶向治疗。虽然IC的病因目前尚不清楚，但有一个可能的原因值得注意：炎症。尽管自身免疫作为IC的潜在原因存在争议，但已发表的证据表明，它可能在启动或维持这种疾病中所见的慢性炎症反应中发挥作用。因此，IC中炎症/自身免疫的存在可能允许研究人员使用人体自身免疫反应作为识别IC生物标志物的手段。在本应用中，我们的目标是通过使用IC个体患者的抗体来识别IC生物标志物。

DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is a debilitating, chronic bladder syndrome. Currently, there are no validated biomarkers for IC. It is well established, however, that inflammation is associated with IC. Although autoimmunity is debated as a potential cause, certain aspects of IC suggest that it may play a role in initiating or sustaining the chronic inflammatory response evident in this disease. For example, autoantibodies have been detected in the sera of IC patients to a greater extent than in controls, and the variety of antigens recognized by autoantibodies in IC suggests that the degeneration of bladder epithelial cells that occurs may stimulate the production of autoantibodies. Thus, the presence of inflammation/autoimmunity in IC may allow the use of the body's own immune response as a means of identifying biomarkers of IC. Clearly, knowledge of these potential autoantigens might better enable a greater understanding of the pathobiology of IC, and facilitate the development or use of autoantibody signatures as potential diagnostic biomarkers. With all of the potential advantages, the Achilles heel of autoantibodies is their sensitivity. Lessons from autoimmune diseases show that typically only 15-20% of patients demonstrate a response to any given antigen. However, proteomics may hold the key to success because of its ability to provide the means to multiplex. By linking the responses to several antigens together, the sensitivity and specificity of the test increases considerably. Recently, we described the development and use of a "reverse capture" autoantibody microarray, a platform that immobilizes 500 specific antigens using a high-density monoclonal antibody capture array. These antigen targets are proteins that are involved in signal transduction, cell-cycle regulation, gene transcription, apoptosis, cell growth, receptors, membrane proteins, as well as adhesion and migration molecules. Using the immobilized antigens as "baits," we can determine the autoantibody reactivity between test and controls to the immobilized antigens. We believe this platform may be well suited for the study of IC. Thus, the objectives of our research for this application are: 1) to test the hypothesis that the serum autoantibody repertoire from patients with IC can be exploited for autoantibody profiling, and 2) to determine the feasibility, robustness, and reproducibility of the "reverse capture" autoantibody microarray to identify autoantibody signatures as biomarkers of IC. Interstitial Cystitis (IC) is a debilitating, chronic bladder syndrome characterized by urinary urgency, frequency, and pelvic/bladder pain. A current need in IC research is the identification of IC biomarkers, as there are presently no validated biomarkers for IC. The identification of IC biomarkers is important because they could potentially be used to create clinical tools for the diagnosis of IC and for the development of targeted treatments for IC patients. While the cause of IC is currently unknown, one possible contributor to this condition is worth noting: inflammation. Although autoimmunity is debated as a potential cause of IC, there is published evidence that suggests it may play a role in initiating or sustaining the chronic inflammatory response seen in this disease. Thus, the presence of inflammation/autoimmunity in IC may allow researchers to use the body's own immune response as a means of identifying biomarkers of IC. In this application, our goal is to identify biomarkers of IC by using antibodies from individual patients with IC.