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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.

摘要干燥综合征(SjS)是一种以唾液和泪腺功能障碍为特征的自身免疫性疾病。虽然这种临床疾病通常会导致严重的口干和眼干，但它可能是全身性的，影响其他器官，如肺、皮肤、肾脏、膀胱和阴道。像大多数自身免疫性疾病一样，SjS 表现出性别两面性，女性受到影响的频率是男性的10倍，这表明性激素在疾病易感性和/或进展中的作用。SjS的一个共同特征是人类和动物模型是单个核细胞渗入唾液和泪腺，它们聚集在那里形成称为淋巴细胞灶的簇状细胞。我们最近的研究发现，腺样T辅助细胞(Th)1和正常人和干燥综合征患者的Th17细胞表达共同T细胞受体(TcR)β变量(TRBV)3-1和而TCRTRAV变异体(TCRTh1 Variable，TRAV)8-2仅在系统性红斑狼疮患者α细胞中表达。使用SjS B6.NOD-Aec1/2小鼠，我们已经证明在TRAV8和TRBV16中选择雄性小鼠的唾液Th1细胞 Th1和Th17细胞，而女性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识别独特的腺体TCR来证明我们的发现。我们的开创性研究清楚地表明，带有保守的TCRs的效应性T细胞的克隆性增殖是由唾液腺(SG)细胞抗原，而对SG细胞自身抗原的自身免疫反应证明了一种特异性丧失免疫自我耐受性。因此，此应用程序的主要目标是测试 SjS TCRs与典型SjS自身抗原的特异性和识别新的表位。此外，使用开创性的方法，我们的目标是通过致病T细胞来阻断自身抗原的抗原递呈作为一种治疗来治疗这种令人衰弱的疾病。我们假设“腺性致病T细胞具有寡克隆针对自身抗原的保守抗原表位反应的TCRαβ谱系和阻断自身抗原-MHC复合体激活TCR将阻止SJS的发展。为了测试这一点假设，我们将定义小鼠和人类Th1的TCRαβ基因谱系的多样性， Th2和Th17细胞参与SjS的单细胞微雕技术(目标1)；确定 SjS TCR与典型SjS自身抗原的特异性和识别识别目标(目标2)；以及自身抗原-MHC复合体阻断致病性TCR激活的疗效观察使用基于合理结构的方法(目标3)。这个项目的重要方面是它将更广泛地了解SG自身抗原在调节致病T细胞和它们的 TCR曲目。此外，结果应该为生成和测试阻断抗原提呈的适当治疗。干扰特定的抗原提呈过程致病T细胞将为SjS的个性化治疗提供一种新的途径患者基于特定的高危HLA而不会产生全身性免疫缺陷。

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.