Mapping the T cell receptor/antigen complex and identifying the genetic-based treatment in Sjogren’s syndrome

绘制 T 细胞受体/抗原复合物图谱并确定干燥综合征的遗传治疗方法

• 批准号: 10371171
• 负责人: Cuong Q Nguyen
• 金额: $ 47.4万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371171
• 关键词: Affect; Alleles; Animal Model; Antigen Presentation; Antigens; Atrophic; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; B-Cell Antigen Receptor; B-Lymphocytes; Bladder; Cell Death; Cell surface; Cells; Chronic; Clinical; Clonal Expansion; Complex; Development; Diagnosis; Disease; Disease susceptibility; Effectiveness; Epithelial Cells; Epitopes; Etiology; Eye; Female; Foundations; Frequencies; Functional disorder; General Population; Genes; Genetic; Gonadal Steroid Hormones; HLA Antigens; Helper-Inducer T-Lymphocyte; Human; Hybridomas; Immune; In Vitro; Incidence; Infiltration; Inflammatory; Kidney; Lacrimal gland structure; Libraries; Lung; Lymphocyte; MHC Class I Genes; MHC Class II Genes; Maps; Medical; Mononuclear; Mus; Organ; Pathogenicity; Patients; Peptides; Play; Postmenopause; Process; Receptor Activation; Risk; Role; Salivary; Salivary Glands; Scanning; Seminal; Sialadenitis; Sjogren' s Syndrome; Skin; Specificity; Structure; Symptoms; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Th1 Cells; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Vagina; Woman; Xerostomia; adaptive immune response; alpha-beta T-Cell Receptor; base; chronic autoimmune disease; design; disorder risk; effector T cell; eye dryness; high risk; human model; immune self tolerance; male; men; mouse model; novel; novel strategies; prevent; screening; sexual dimorphism

ABSTRACT Sjögren's syndrome (SjS) is an autoimmune disease characterized by salivary and lacrimal gland dysfunction. Although the clinical disease usually results in severe dry mouth and dry eyes, it can be systemic, affecting other organs such as the lungs, skin, kidneys, bladder, and vagina. Like most autoimmune diseases, SjS shows a sexual dimorphism with women affected >10-times more frequently than men, suggesting a strong role for sex hormones in disease susceptibility and/or progression. One common feature of SjS in both humans and animal models is mononuclear cells infiltrating salivary and lacrimal glands where they aggregate into clusters referred to as lymphocytic foci. Our recent study has identified that glandular T helper (Th)1 and Th17 cells of control and SjS patients expressed common T cell receptor (TCR)β variables (TRBV)3-1 and TRBV20, whereas TCRα variable (TRAV)8-2 was uniquely expressed by Th1 cells of SjS patients. Using SjS B6.NOD-Aec1/2 mice, we have shown that salivary Th1 cells of male mice selected for TRAV8 and TRBV16 in Th1 and Th17 cells, whereas female Th1 cells selected for TRAV8, TRAV13D-2, and TRBV23. Other studies attest our findings by identifying unique glandular TCRs in the humans and animal models of SjS. Our seminal studies clearly imply that the clonal expansion of the effector T cells with the conserved TCRs is driven by salivary gland (SG) cell antigens, and that autoimmune responses to SG cell autoantigens evidence a specific loss of immunological self-tolerance. Therefore, the primary objectives of this application are to test the specificity of the SjS TCRs with canonical SjS autoantigens and identify novel epitopes. Furthermore, using a pioneering approach, we aim to block antigen presentation of autoantigens by pathogenic T cells as a therapy to treat this debilitating disease. We hypothesize that “glandular pathogenic T cells possess oligoclonal TCRαβ repertoires that react against conserved antigenic epitopes of autoantigens and that blocking TCR activation by autoantigen-MHC complexes will prevent the development of SjS.” To test this hypothesis, we will define the diversity of the TCRαβ gene repertoires for both mouse and human Th1, Th2, and Th17 cells involved in SjS using single-cell microengraving technology (Aim 1); determine the specificity of SjS TCRs with canonical SjS autoantigens and identify targets for recognition (Aim 2); and examine the therapeutic effects of blocking pathogenic TCR activation by autoantigen-MHC complexes using a rational structure-based approach (Aim 3). The significant aspect of this project is that it will provide a broader understanding of the role SG autoantigens play in modulating pathogenic T cells and their TCR repertoires. Additionally, results should establish the direction forward for generating and testing an appropriate therapy for blocking antigen presentation. Interfering with specific antigen presentation processes and pathogenic T cells will provide a novel approach by developing a personalized medical treatment for SjS patients based on specific high risk HLAs without generating general immune deficiency.

摘要 干燥综合征是一种以唾液腺和泪腺功能障碍为特征的自身免疫性疾病。 虽然临床疾病通常导致严重的口干和眼干，但它可以是全身性的，影响 其他器官，如肺、皮肤、肾脏、膀胱和阴道。与大多数自身免疫性疾病一样，SjS 显示出性别二型性，女性比男性多受10倍以上的影响，这表明 性激素在疾病易感性和/或进展中的作用。SjS的一个共同特征是， 在人类和动物模型中，单核细胞浸润唾液腺和泪腺， 形成称为淋巴细胞灶的簇。我们最近的研究已经确定，腺性T辅助细胞（Th）1和 对照组和SjS患者的Th17细胞表达共同T细胞受体（TCR）β变量（TRBV）3 - 1， TCR α可变区（TRAV）8 - 2仅由SjS患者的Th1细胞表达。使用SjS B6. NOD-Aec 1/2小鼠，我们已经表明，在N0D-Aec 1/2小鼠中，选择TRAV 8和TRBV 16的雄性小鼠的唾液Th1细胞在N0D-Aec 1/2小鼠中表达。 Th1和Th17细胞，而雌性Th1细胞选择TRAV8、TRAV13D-2和TRBV23。其他研究 通过在SjS的人类和动物模型中鉴定独特的腺体TCR来证实我们的发现。我们的种子 研究清楚地表明，具有保守TCR的效应T细胞的克隆扩增是由 唾液腺（SG）细胞抗原，以及对SG细胞自身抗原的自身免疫应答证明了一种特异性的 免疫自身耐受性丧失。因此，本申请的主要目的是测试 SjSTCR与典型SjS自身抗原的特异性，并鉴定新的表位。此外，使用A 开创性的方法，我们的目标是阻断病原性T细胞对自身抗原的抗原呈递作为一种治疗方法， 来治疗这种使人衰弱的疾病我们假设"腺性致病性T细胞具有寡克隆 TCR α β谱系，其与自身抗原的保守抗原表位反应并阻断自身抗原的保守抗原表位， TCR被自身抗原-MHC复合物激活将阻止SjS的发展。为了验证这一 假设，我们将定义小鼠和人Th1的TCR α β基因库的多样性， 使用单细胞显微雕刻技术（Aim 1）确定SjS中涉及的Th2和Th17细胞; SjS TCR与典型SjS自身抗原的特异性，并鉴定用于识别的靶标（目标2）;以及 检测通过自身抗原-MHC复合物阻断致病性TCR活化的治疗效果 使用基于理性结构的方法（目标3）。该项目的重要方面是，它将 提供了对SG自身抗原在调节致病性T细胞及其 TCR库。此外，研究结果应确定生成和测试 用于阻断抗原呈递的适当疗法。干扰特异性抗原呈递过程 而致病性T细胞将通过开发针对SjS的个性化药物治疗提供新的方法 患者基于特定的高风险HLA，而不产生全身免疫缺陷。