A Decoy Receptor as a Novel Biomarker for Autoimmune Inner Ear Disease

描述（由申请人提供）：自身免疫性内耳疾病（AIED）是一种特征不明确的疾病，由于无法识别疾病的共同生物标志物/机制，难以诊断和治疗。由于无法做出明确的诊断，这种疾病的发病率和流行率无法准确确定。患者最初接受全身性类固醇治疗；然而，由于未知的机制，很大比例的初始应答者随着时间的推移变得难治性。幸运的是，对于那些疾病进展和随后的听力损失无法预防的患者，人工耳蜗可以为耳聋的AIED患者提供听力。我们已经确定了一个诱饵受体作为自身免疫性内耳疾病（AIED）的一种新的生物标志物。这种分子诱饵受体作为一个陷阱，在没有后续信号事件的情况下结合炎症蛋白，从而抑制炎症反应。我们观察到，与接受人工耳蜗手术的对照组相比，AIED患者暴露于自体淋巴周围的外周血单个核细胞（PBMC）诱导这种诱饵受体的程度最低（p<0.05）。此外，我们有初步证据表明，通过听力改善测量，外周血预处理诱饵受体水平可以预测AIED患者对类固醇治疗的临床反应（p<0.0001）。这导致我们提出以下假设：AIED患者不能维持耳蜗的免疫特权状态，因为他们无法表达诱饵受体来响应抗原刺激。这导致免疫介导的内耳炎症，导致进行性感音神经性听力损失。我们进一步假设这种诱饵受体是AIED患者类固醇反应性听力损失的新标志物。这一假设将通过三个特定目的进行验证：目的1：确定患有听力突然下降的AIED患者对类固醇治疗的有利反应是否与诱饵受体表达增加的能力相关。目的2：确定关键炎症基因和/或HLA基因的单核苷酸多态性（snp）是否预测AIED中类固醇反应的结果。目的3：确定AIED患者PBMC中诱饵受体表达对淋巴周围反应的失败是由于淋巴周围成分的差异，还是由于PBMC对常见淋巴周围分子的反应改变。我们已经确定了一个潜在的自身免疫性内耳疾病（AIED）的生物标志物，可以预测类固醇反应。预测类固醇反应的能力将：(1)有助于开发AIED的诊断测试，(2)更好地预测哪些患者会对类固醇有反应，从而避免对那些预计不会有反应的患者使用类固醇带来的过度风险，(3)为开发新疗法提供理论依据。

DESCRIPTION (provided by applicant): Autoimmune Inner Ear Disease (AIED) is a poorly characterized disease that is difficult to diagnose and treat because of the inability to identify a common biomarker/mechanism of disease. Incidence and prevalence of this disorder cannot be accurately determined, because of the inability to make a definitive diagnosis. Patients are initially treated with systemic steroids; however, a large percentage of initial responders become refractory over time, due an unknown mechanism. Fortunately, for those patients whose disease progression and subsequent hearing loss cannot be prevented, a cochlear implant can provide hearing to the deafened AIED patient. We have identified a decoy receptor to be a novel biomarker for Autoimmune Inner Ear Disease (AIED). This molecular decoy receptor serves as a trap to bind inflammatory proteins without the subsequent signaling events, thus suppressing an inflammatory response. We have observed that this decoy receptor is minimally induced in peripheral blood mononuclear cells (PBMC) exposed to autologous perilymph in patients with AIED, as compared to controls undergoing cochlear implant surgery (p<0.05). Furthermore, we have preliminary evidence that pretreatment decoy receptor levels in the peripheral blood can predict the clinical response to steroid therapy in AIED patients, as measured by audiometric improvement (p<0.0001). This has led us to the following hypothesis: Patients with AIED do not maintain the immunoprivileged status of the cochlea because they are unable to express the decoy receptor in response to antigenic stimuli. This leads to immune mediated inner ear inflammation resulting in progressive sensorineural hearing loss. We further hypothesize that this decoy receptor is a novel marker of steroid responsive hearing loss in patients with AIED. This hypothesis will be tested through three specific aims: Aim 1: Determine if a favorable response to steroid therapy in presumptive AIED patients with sudden declines in hearing correlates with the ability to increase decoy receptor expression. Aim 2: Determine if single nucleotide polymorphisms (SNPs) of key inflammatory genes and/or HLA genes predict the outcome of steroid response in AIED. Aim 3: Determine if the failure of decoy receptor expression in PBMC from AIED patients in response to perilymph is due to differences in perilymph composition, or a result of altered PBMC responses to common perilymph molecules. We have identified a potential biologic marker for Autoimmune Inner Ear Disease (AIED) that can predict steroid response. The ability to predict steroid response would: (1) aid in development of a diagnostic test for AIED, (2) better predict which patients would respond to steroids thereby avoiding undue risk associated with administration of steroids for those who are expected not to respond, and (3) provide a rationale for development of novel therapies.