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

基本信息

批准号：
10599844
负责人：
Cuong Q Nguyen
金额：
$ 43.22万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599844
关键词：
Affect Alleles Animal Model Antigen Presentation Antigen-Presenting Cells Antigens Atrophic Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses B-Lymphocytes Binding Bladder Cell Death Cell surface Cells Chronic Clinical Clonal Expansion Complex Development Diagnosis Disease Disease Progression Disease susceptibility 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 Innate Immune Response Kidney Lacrimal gland structure Libraries Lung Lymphocyte MHC Class I Genes MHC Class II Genes Maps Medical Mononuclear Mus Organ Pathogenicity Patients Peptide Initiation Factors Peptides Play Postmenopause Process Reaction Receptor Activation Risk Role Salivary Salivary Glands Scanning Seminal Sialadenitis Sjogren&apos 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 Vagina Woman Xerostomia adaptive immune response alpha-beta T-Cell Receptor beta Chain Antigen T Cell Receptor chronic autoimmune disease design disorder risk effectiveness evaluation effector T cell eye dryness high risk human model immune self tolerance male men mouse model novel novel strategies prevent screening sexual dimorphism

项目摘要

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.

抽象的 Sjögren综合征（SJS）是一种自身免疫性疾病，其特征是唾液和泪腺功能障碍。尽管临床疾病通常会导致严重的口干和干眼睛，但可能是全身性的，会影响其他器官，例如肺，皮肤，肾脏，膀胱和阴道。像大多数自身免疫性疾病一样与男性相比，受影响> 10次的女性表现出性二态性，这表明很强性激素在疾病易感性和/或进展中的作用。 SJS的一个共同特征人类和动物模型是单核细胞浸润唾液和泪珠的凝聚进入称为淋巴细胞灶的簇。我们最近的研究确定腺体T辅助器（Th）1和对照和SJS患者的Th17细胞表达了常见的T细胞受体（TCR）β变量（TRBV）3-1和 TRBV20，而TCRα变量（TRAV）8-2由SJS患者的Th1细胞唯一表达。使用SJS B6.NOD-AEC1/2小鼠，我们已经表明，选择用于Trav8和Trbv16的唾液Th1细胞 Th1和Th17细胞，而雌性Th1细胞选择用于TRAV8，TRAV13D-2和TRBV23。其他研究通过确定人类和SJ的动物模型中的独特腺TCR来证明我们的发现。我们的开创性研究清楚地表明，效应T细胞与配置的TCR的克隆扩展是由唾液腺（SG）细胞抗原，并且自身免疫反应对SG细胞自身抗原证据免疫学自我耐受的丧失。因此，本应用程序的主要目标是测试 SJS TCR的特异性具有典型的SJS自身抗原并识别新型表位。此外，使用开创性方法，我们旨在通过致病性T细胞作为一种治疗来阻止自身抗原的抗原表现治疗这种使人衰弱的疾病。我们假设“腺体致病性T细胞具有寡克隆反应自身抗原的抗原表位的TCRαβ曲目，该阻滞自动抗原MHC复合物通过TCR激活将阻止SJ的发展。” 假设，我们将定义小鼠和人Th1的TCRαβ基因曲目的多样性， Th2和Th17细胞使用单细胞微型磨砂技术参与SJS（AIM 1）；确定具有规范SJS自动抗原的SJS TCR的特异性并识别识别靶标（AIM 2）；和检查自身抗原MHC复合物阻断致病性TCR激活的治疗作用使用基于理性结构的方法（AIM 3）。该项目的重要方面是它将对SG自身抗原在调节致病性T细胞及其的作用中的作用更广泛地理解 TCR曲目。此外，结果应确定产生和测试的方向适当的疗法来阻止抗原表现。干扰特定的抗原演示过程病原T细胞将通过为SJS开发个性化医疗提供一种新的方法基于特定的高风险HLA的患者，而不会产生一般的免疫缺陷。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GABA Administration Ameliorates Sjogren's Syndrome in Two Different Mouse Models.

DOI：
10.3390/biomedicines10010129
发表时间：
2022-01-07
期刊：
Biomedicines
影响因子：
4.7
作者：
Song M;Tian J;Middleton B;Nguyen CQ;Kaufman DL
通讯作者：
Kaufman DL

Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population.

DOI：
10.1371/journal.pone.0276700
发表时间：
2023
期刊：
PloS one
影响因子：
3.7
作者：
通讯作者：

A MZB Cell Activation Profile Present in the Lacrimal Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mice Defined by Global RNA Transcriptomic Analyses.

DOI：
10.3390/ijms23116106
发表时间：
2022-05-29
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Evidence of a Sjögren's disease-like phenotype following COVID-19 in mice and humans.

DOI：
10.1172/jci.insight.166540
发表时间：
2023-12-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Shen, Yiran;Voigt, Alexandria;Goranova, Laura;Abed, Mehdi;Kleiner, David E.;Maldonado, Jose O.;Beach, Margaret;Pelayo, Eileen;Chiorini, John A.;Craft, William F.;Ostrov, David A.;Ramiya, Vijay;Sukumaran, Sukesh;Brown, Ashley N.;Hanrahan, Kaley C.;Tuanyok, Apichai;Warner, Blake M.;Nguyen, Cuong Q.
通讯作者：
Nguyen, Cuong Q.

Upregulated Chemokine and Rho-GTPase Genes Define Immune Cell Emigration into Salivary Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mice.