Identification of Biomarkers in Sjogren's Syndrome

描述（由申请人提供）：干燥综合征（SS）是一种自身免疫性疾病，其特征是外分泌腺中分泌腺泡细胞的进行性破坏。迄今为止用于晚期病例的治疗在逆转或预防疾病进展方面并不成功。由于缺乏可靠的生物标志物，目前无法在疾病的早期阶段做出阳性诊断。SS的诊断目前依赖于唇小唾液腺中淋巴细胞浸润或血清中抗Ro和La的自身抗体的出现。然而，疾病的严重程度，即由大唾液腺产生的唾液，通常与这些临床发现无关。在这种疾病的早期阶段，唾液腺形态可以基本上是正常的，并且Ro和La自身抗体可以不存在，但液体分泌经常受到损害。这些标记物对SS既不特别敏感也不特别特异。由于唾液中含有血清中发现的大多数相同蛋白质，因此唾液可用于诊断和监测局部和全身健康状况。唾液收集是简单、快速和非侵入性的。高通量蛋白质组学方法的最新进展使得鉴定人体体液中表达的蛋白质成为可能。重要的是要确定的蛋白质的子集，其表达被修改的唾液中的SS患者相对于正常受试者。需要鉴定新的抗体标志物。SS患者的唾液腺富含记忆B细胞，这些记忆B细胞可能在抗原驱动、趋化因子吸引和粘附分子保留的基础上归巢并在那里建立住所。使用这种疾病的发病机制的假设驱动模型，我们建议在血液和唾液中确定一组与早期SS相关的可靠生物标志物。具体而言：在目标1中，我们将确定与SS相关的唾液蛋白。在目标2中，我们将识别SS的自身抗体特征。在目标3中，我们将鉴定和验证用于诊断和评估SS的生物标志物。综上所述，这些研究的结果将解决我们对血液和唾液SS特异性生物标志物、唾液腺功能和疾病进展之间相关性的理解中的差距，并使我们能够更好地理解导致自身免疫记忆B细胞唾液浸润的致病过程，并开发一种实用的方法来测量临床中作为SS生物标志物的自身抗体。

DESCRIPTION (provided by applicant): Sjogren's syndrome (SS) is an autoimmune disease characterized by the progressive destruction of the secretory acinar cells in exocrine glands. Treatments used to date in advanced cases have not been successful in reversing or preventing disease progression. Due to the lack of reliable biomarkers, it is currently not possible to make a positive diagnosis in the early stages of the disease. The diagnosis of SS currently relies on either the appearance of lymphocytic infiltration in labial minor salivary glands or of autoantibodies against Ro and La in the serum. However, disease severity, i.e. saliva production by the major salivary glands, frequently does not correlate with these clinical findings. In the early stages of this disease, salivary gland morphology can be essentially normal and Ro and La autoantibodies can be absent, yet fluid secretion is often compromised. These markers are neither particularly sensitive nor specific for SS. Because saliva contains most of the same proteins found in serum, saliva can be used to diagnose and monitor local as well as systemic health status. Saliva collection is easy, rapid and non-invasive. Recent advances in high-throughput proteomics approaches have made it feasible to identify the proteins expressed in human fluids. It is important to identify that subset of proteins whose expression is modified in saliva of SS patients relative to normal subjects. There is a need to identify novel antibody markers. The salivary glands of SS patients are enriched for memory B-cells that have presumably homed and established residence there on the basis of antigenic drive, chemokine attraction and adhesion molecule retention. Using hypothesis-driven models of the pathogenesis of this disease, we propose to identify a dependable set of biomarkers in blood and saliva linked with early SS. Specifically: In Aim 1, we will identify salivary proteins associated with SS. In Aim 2, we will identify an autoantibody signature characteristic of SS. In Aim 3, we will identify and validate biomarkers for the diagnosis and evaluation of SS. Taken together, the results of these studies will address gaps in our understanding of the correlation between blood and saliva SS-specific biomarkers, salivary gland function, and disease progression, and will allow us to better understand the pathogenic processes resulting in the salivary infiltration by autoimmune memory B-cells and to develop a practical approach for the measurement of autoantibodies as SS biomarkers in the clinic.