Organ-specific autoimmunity resulting from two genetic defects in tolerance

由两种耐受性遗传缺陷引起的器官特异性自身免疫

基本信息

批准号：
10341142
负责人：
Anthony L Defranco
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341142
关键词：
Ablation Age Alleles Animal Model Animals Arrestins Atypical lymphocyte Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Avidity B-Lymphocytes CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Patient Cell surface Cells Clone Cells Complementary DNA Defect Dendritic Cells Disease Disease Outcome Disease susceptibility Dissection Epitopes Event Excision Exhibits Eye Frequencies Generations Genetic Genetic Predisposition to Disease Goals Human Immune Tolerance Immunologics Individual Inflammation Lead Life Mediating Modeling Monozygotic twins Mus Mutant Strains Mice Mutation Myelin P2 Protein Nature Onset of illness Organ Organ Model Pathogenicity Pathway interactions Peptide/MHC Complex Phenotype Predisposition Prevalence Property Protein Tyrosine Kinase Proteins Receptor Signaling Regulatory T-Lymphocyte Resistance Retina Rod Outer Segments Role Signal Transduction Specificity T-Lymphocyte Testing Thymus Gland Tissues Twin Studies Uveitis Work adaptive immune response anergy autoimmune pathogenesis autoimmune uveitis central tolerance draining lymph node effector T cell experimental study immune checkpoint blockade insight interstitial retinol-binding protein lupus-like macrophage mouse model non-genetic novel novel therapeutics prevent receptor systemic autoimmunity thymocyte

项目摘要

Project Summary A diversity of tolerance mechanisms work together to prevent autoimmune disease in most individuals by limiting the activity of self-reactive lymphocytes. How genetically determined defects in particular tolerance pathways may interact to lead to autoimmune disease is not well understood. The goal of this project is to provide insights into the basis of multigenic autoimmune susceptibility by modeling it in mice using two genetic defects with especially well understood immunologic mechanisms, namely a complete deficiency in Lyn and partial deficiency in Aire. Aire controls the expression of a large number of tissue-restricted self antigens in the thymus and therefore promotes central tolerance of T cells. Lyn is a protein tyrosine kinase that restrains the activities of dendritic cells, macrophages, and B cells due to its importance in mediating the signaling of inhibitory receptors on the surface of these cells. Remarkably, mice containing both a hypomorphic allele of Aire, which by itself leads to little autoimmunity on the autoimmune resistant C57BL/6 background, and a deficiency in Lyn spontaneously develop a highly destructive autoimmune attack on their retinas. This disease occurs in 50% of Lyn-/- AireGW/+ mice, all of which have severe disease by 8 weeks of age, whereas the other 50% are protected. The disease prevalence in the double mutant mice is strikingly similar to results of identical twin studies in humans with autoimmune diseases. Moreover, this new animal model of spontaneous organ- specific autoimmune disease has several features that are especially favorable for mechanistic dissection and may make it possible to provide new conceptual insights into the nature of autoimmune disease susceptibility and initiation. The proposed studies will determine the epitope specificity and avidity of the CD4 T cells that break tolerance and initiate autoimmune attack. How reduced self-antigen expression in the thymus enables the pathogenic potential of these T cells will be determined. In addition, for mice that do not develop uveitis, there is a small expansion of retinal autoantigen-specific CD4 T cells in the eye-draining lymph nodes. The immunological mechanisms that prevent these T cells from initiating autoimmune attack in 50% of animals will be determined. We shall determine whether tolerance in the protected animals is primarily due to anergy of effector T cells, to dominant suppression by retina-specific Treg, or to a tissue-specific checkpoint. In these protected mice, we shall determine whether immunological perturbations can unleash disease in otherwise protected animals, a situation that may be relevant to the organ-specific autoimmunity seen in some cancer patients treated with checkpoint blockade. These studies will provide novel and valuable insights into the question of how genetic defects in two different immune tolerance pathways can interact to result in genetic susceptibility to autoimmune disease and in understanding how autoimmune disease in initiated in some but not all individuals with the same degree of genetic susceptibility.

项目摘要多种耐受机制共同起作用，以预防大多数个体的自身免疫性疾病通过限制自反应性淋巴细胞的活性。遗传确定的缺陷如何特别耐受性途径可能相互作用以导致自身免疫性疾病。这个项目的目标是通过使用两个遗传在小鼠中对多基因自身免疫性敏感性进行洞察力，以实现多基因自身免疫性敏感性具有尤其了解免疫机制的缺陷，即Lyn和 AIRE的部分缺陷。 Aire控制大量组织限制的自抗原的表达胸腺，因此促进了T细胞的中心耐受性。 Lyn是一种蛋白质酪氨酸激酶，可限制树突状细胞，巨噬细胞和B细胞的活性在介导的信号传导中的重要性这些细胞表面上的抑制受体。值得注意的是，同时含有肌远高位等位基因的小鼠 AIRE本身会导致自身免疫性自身免疫性耐受性C57BL/6背景，并且林恩（Lyn）的缺乏自发地对其视网膜产生了高度破坏性的自身免疫性攻击。这种疾病发生在50％的lyn - / - airegw/+小鼠中 50％受到保护。双突变小鼠中的疾病患病率与同一结果的结果非常相似对自身免疫性疾病的人类的双胞胎研究。此外，这种自发器官的新动物模型特定的自身免疫性疾病具有多种特征，这些功能特别有利于机械剖析和可能使对自身免疫性疾病易感性本质的新概念见解成为可能和启动。拟议的研究将确定CD4 T细胞的表位特异性和亲和力破坏公差并启动自身免疫攻击。胸腺中自我抗原表达如何减少这些T细胞的致病潜力将被确定。此外，对于不发展葡萄膜炎的小鼠，视网膜自身抗原特异性CD4 T细胞在淋巴淋巴结中存在少量膨胀。这防止这些T细胞引发自身免疫攻击的免疫机制将在50％的动物中可以确定。我们将确定受保护动物的耐受性是否主要是由于效应T细胞，由视网膜特异性Treg或组织特异性检查点主要抑制。在这些受保护的小鼠，我们将确定免疫扰动是否可以释放受保护的动物，这种情况可能与某些癌症中的器官特异性自身免疫有关接受检查点封锁治疗的患者。这些研究将为您提供新颖而有价值的见解问题的问题如何在两个不同的免疫耐受性途径中相互作用以导致遗传对自身免疫性疾病的敏感性以及了解某些人的自身免疫性疾病是如何启动的并非所有具有相同遗传易感性的人。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thymic tolerance as a key brake on autoimmunity.

DOI：
10.1038/s41590-018-0128-9
发表时间：
2018-07
期刊：
Nature immunology
影响因子：
30.5
作者：
Cheng M;Anderson MS
通讯作者：
Anderson MS

Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.

DOI：
10.1073/pnas.2311487121
发表时间：
2024-01-30
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Yin, Mianmian;Smith, Jennifer A.;Chou, Marissa;Chan, Jackie;Jittayasothorn, Yingyos;Gould, Douglas B.;Caspi, Rachel R.;Anderson, Mark S.;Defranco, Anthony L.
通讯作者：
Defranco, Anthony L.