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

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。

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.