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）是一种特征性较差的疾病，由于无法识别常见的生物标志物/疾病机制，因此难以诊断和治疗。这种疾病的发病率和患病率无法准确确定，因为无法做出明确的诊断。患者最初接受全身性类固醇治疗;然而，由于未知的机制，大部分初始应答者随着时间的推移变得难治。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，人工耳蜗植入物可以为AIED患者提供听力。我们已经确定了诱饵受体是一种新的生物标志物的自身免疫性内耳疾病（AIED）。这种分子诱饵受体作为一个陷阱，在没有随后的信号传导事件的情况下结合炎症蛋白，从而抑制炎症反应。我们已经观察到，与接受耳蜗植入手术的对照组相比，AIED患者暴露于自体外淋巴液的外周血单核细胞（PBMC）中的诱骗受体被最小程度地诱导（p<0.05）。此外，我们有初步证据表明，治疗前外周血诱饵受体水平可以预测AIED患者对类固醇治疗的临床反应，如听力改善所测量的（p<0.0001）。这使我们得出以下假设：AIED患者不能维持耳蜗的免疫豁免状态，因为他们不能表达诱饵受体以响应抗原刺激。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一种新标志物。这一假设将通过三个具体的目标进行测试：目标1：确定是否有利的反应，类固醇治疗推定AIED患者听力突然下降与增加诱饵受体表达的能力。目的2：确定关键炎症基因和/或HLA基因的单核苷酸多态性（SNPs）是否预测AIED中类固醇反应的结果。目标3：确定AIED患者外周血单个核细胞对外淋巴液应答时诱饵受体表达的失败是由于外淋巴液组成的差异，还是由于外周血单个核细胞对常见外淋巴液分子应答的改变。我们已经确定了自身免疫性内耳疾病（AIED）的潜在生物标志物，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将对类固醇反应，从而避免与预期不反应的患者的类固醇给药相关的过度风险，和（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.