Immune-pathophysiology of lymphocytic foci in Sjogren's syndrome

描述(申请人提供)：干燥综合征(SjS)是一种自身免疫性疾病，其特征是外分泌功能丧失，主要是对唾液和泪腺的慢性免疫攻击，导致口干症(口腔干燥)和干眼症(眼睛干燥)。虽然一些其他组织可能会受累(例如，胃肠道、皮肤、肺、血管和肌肉系统、肾脏、膀胱和阴道)，但尤其令人感兴趣的是在近20%的SjS患者中发生的各种感觉神经病、外周神经病、颅脑和脊髓病。最近的研究表明，B细胞和自身抗体在外分泌腺功能障碍的发病中起着关键作用。虽然在没有B细胞淋巴瘤形成的情况下，SJS通常不被认为是一种致命的疾病，但随着疾病的进展，患者的生活质量越来越低。在人类和动物模型中，SjS自身免疫的一个特征是在唾液和泪腺中形成生发样中心，称为淋巴细胞灶(LF)。Lf和Lf评分虽然是临床疾病的重要诊断标准，但并不总是与疾病的严重程度相关，这表明对Lf内细胞的性质和功能普遍缺乏了解；然而，Lf必须包含有关最终导致外分泌腺功能障碍和最终破坏的自身免疫反应的重要信息。因此，本文提出的研究的基本目标是集中于确定唾液腺LF内形成的白细胞群体的性质，并确定这些细胞群体是否识别与SjS自身免疫有关的疾病机制。为了解决这些问题，提出了两个特定的目标：(1)定义和表征在SjS样疾病C57BL/6.NOD-4ecf Aec2小鼠模型中，IL-23分泌和CD4+TH17记忆T细胞群在SjS样疾病发展过程中渗入唾液腺的特征，以及(2)确定IL-27对C57BU6.NOD-.Aecf Aec2小鼠模型中CD4+TH17记忆T细胞群预防SjS发展的可能调节潜力。拟议的研究代表了首席研究员为将来从事SjS研究做准备的核心活动，而研究结果有望通过更好地确定Sjs相关表现的发展和发病的潜在因素，为未来的人类转译研究奠定基础。结果在SjS小鼠模型中确定和表征了LF的白细胞群体，以及在研究过程中开发的技术，将建立使用人类标本进行过渡性研究的可行性。本研究将进一步提供关于腺体内白细胞群体及其产物的动态相互作用的重要数据，从而导致与长期疾病状态相关的免疫病理生理表现和并发症。

DESCRIPTION (provided by applicant): Sjogren's syndrome (SjS) is an autoimmune disease characterized by loss of exocrine function as a result of a chronic immune attack primarily against the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). While a number of other tissues may become involved (e.g., the Gl tract, skin, the lungs, the vasculature and muscular systems, kidneys, bladder and vagina), of particular interest are the various sensory, peripheral, cranial and myelopathic neuropathies that develop in nearly 20% of SjS patients. Recent studies suggest that B cells and autoantibodies play a critical role in onset of exocrine glandular dysfunction. Although SjS is generally not considered a lethal disease in the absence of B cell lymphoma formation, patients have an increasingly diminished quality of life with disease progression. One feature of SjS autoimmunity in both humans and animal models is the formation of germinal-like centers in the salivary and lacrimal glands, referred to as lymphocytic foci (LF). LF and LF scores, while important diagnostic criteria for clinical disease, do not always correlate with disease severity, indicating a general lack of understanding about the nature and function of cells within LF; yet, LF must contain important information about the autoimmune response that ultimately results in exocrine glandular dysfunction and eventually destruction. Thus, the fundamental goal of the research proposed herein is to focus on defining the nature of the leukocyte populations forming within LF of the salivary glands and determine if these cell populations identify disease mechanisms involved in SjS autoimmunity. To address these issues, two specific aims are advanced: (1) Define and characterize the IL-23 secreting and CD4+ TH17 memory T cell populations infiltrating the salivary glands during development of SjS-like disease in the C57BL/6.NOD-4ecf Aec2 mouse model of SjS, and (2) Determine the possible regulatory potential of IL-27 on the CD4+ TH17 memory T cell populations for preventing development of SjS in the C57BU6.NOD-.Aecf Aec2 mouse model. The proposed research represents the core activity in preparing the principal investigator for a future career in SjS research, while the results are expected to establish the basis for future translational studies to humans by better defining factors underlying development and onset of SjS-associated manifestations. Results defining and characterizing leukocytic populations of LF in a mouse model of SjS, together with technologies developed during the conduct of the studies will establish the feasibility for transitional studies using human specimens. The present studies will further provide important data on the dynamic interactions of leukocytic populations and their products within the glands resulting in the immuno-pathophysiological manifestations and complications associated with long-term disease states.