Loss of Intrinsic Control in Autoimmune T Helper Cells with Signaling Variants

具有信号变异的自身免疫 T 辅助细胞失去内在控制

基本信息

批准号：
8810642
负责人：
JEROEN ROOSE
金额：
$ 38.65万
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：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8810642
关键词：
Alleles Amino Acid Substitution Amino Acids Antibodies Antigen Presentation Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Biological CD4 Positive T Lymphocytes Cataloging Catalogs Catalytic Domain Cells Cellular Assay Complex Defect Development Dimerization Disease Ethylnitrosourea Event Gene Deletion Genes Genetic Genetic Polymorphism Genetic Variation Goals Health Helper-Inducer T-Lymphocyte Human Human Genetics IgE Immune Immune Cell Activation Immune System Diseases Inherited Insulin-Dependent Diabetes Mellitus Knowledge Lead Lymphocyte Lymphopenia Mission Modeling Molecular Mus Mutagenesis Mutant Strains Mice Mutation Myelogenous Myeloid Cells Nuclear Pathologic Pathology Patients Persons Phenotype Phosphotransferases Play Point Mutation Predisposition Process Production Proteins Proteinuria Publishing RNA Splicing Reporting Research Research Personnel Role Signal Pathway Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Structure Systemic Lupus Erythematosus T-Cell Activation T-Cell Development T-Lymphocyte Techniques Tissues Tyrosine United States National Institutes of Health Variant ZAP-70 Gene autoimmune arthritis base cytokine dimer genetic variant genome sequencing human FRAP1 protein immune activation in vivo insight interest mouse model novel novel strategies

项目摘要

DESCRIPTION (provided by applicant): B cells, CD4 T cells, and myeloid cells play a critical role in the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and can be engaged in a pathologic stimulatory network of autoantibody and cytokine production, tissue damage, and activation by released self-antigens. Our proposal is centered on CD4 T- and myeloid- cells in autoimmune diseases. New techniques have increased our understanding of the genetic basis of diseases like SLE and helped identify robust susceptibility loci, such as MHC. Recent whole genome sequencing has revealed a detailed catalog of the human genetic variation with a very high occurrence of ~12,000 gene variants per person. Much less robust is our knowledge of dysregulated signaling pathways in immune cells in SLE or other autoimmune diseases and how gene variants (non-synonymous SNPs) may underpin abnormal immune features. Here we combine molecular-, cellular-, and in vivo- approaches to understand the autoimmune features of CD4 T cells, how these T cells are entangled in a stimulatory loop with myeloid cells, and how subtle monoallelic, non-synonymous SNPs in patients can result in robust autoimmune phenotypes. In Preliminary Results, we present a novel mouse model, Rasgrp1Anaef, with a point mutation in the Ras activator Rasgrp1 that causes an autoimmune phenotype. Thorough characterization of T cell development demonstrates that Rasgrp1Anaef T cells develop effectively and Rasgrp1Anaef mice are not lymphopenic. Instead, CD44hiCXCR5+PD1+ CD4+ T cells aberrantly accumulate due to increased basal Rasgrp1Anaef- mTOR signaling, numbers of myeloid cell subsets increase, and mice show ANA (anti-nuclear antibodies) and proteinuria. Rasgrp1Anaef/WT heterozygous mice also demonstrate autoimmune pathology, thus one Rasgrp1WT allele cannot compensate for Rasgrp1Anaef. We present a recently published crystal structure of an autoinhibitory Rasgrp1 dimer and demonstrate that Rasgrp1Anaef can form a dimer with a Rasgrp1WT protein, presenting a mechanism of action for how monoallelic RasGRP1 variants, reported in patients with SLE, autoimmune (Type 1) diabetes, and Graves disease, can have a biological effect. Here we will investigate the immune character of the aberrantly accumulating Rasgrp1Anaef T cells (Aim 1), the intimate interaction between T-, B-, and myeloid cells and the role of Rasgrp1Anaef myeloid cells in the Rasgrp1Anaef autoimmune features (Aim 2), and how this Rasgrp1Anaef mouse model may serve as a paradigm for monoallelic, non-synonymous RasGRP1 SNP alleles (Aim 3). Results from the strongly related but independent aims will increase our understanding of how T cells and myeloid cells with seemingly innocent and subtle SNP variants can drive autoimmunity through a pathological stimulatory network, and how monoallelic genetic SNP events in RasGRP1 may cause autoimmune pathology.

描述（由申请人提供）：B细胞，CD4 T细胞和髓样细胞在自身免疫性疾病的发展中起着至关重要的作用，例如全身性红斑狼疮（SLE），并且可以参与自身抗体和细胞因子产生，组织损害，组织损害和激活的自身抗体的病理刺激网络。我们的建议集中在自身免疫性疾病中的CD4 T-和髓样细胞上。新技术增加了我们对SLE等疾病的遗传基础的理解，并有助于识别强大的敏感性基因座，例如MHC。最近的整个基因组测序揭示了人类遗传变异的详细目录，每人的出现〜12,000个基因变异。我们对SLE或其他自身免疫性疾病中免疫细胞中信号通路失调的知识差得多，以及基因变异（非同义SNP）如何支持异常免疫特征。在这里，我们结合了分子，细胞和体内方法，以了解CD4 T细胞的自身免疫特征，这些T细胞如何与髓样细胞纠缠在刺激性环中，以及患者的微妙单相平行，非同步性SNP如何导致强大的自身免疫性型型。在初步结果中，我们提出了一种新型的小鼠模型RasGRP1ANAEF，RAS激活剂RASGRP1中有一个点突变，会导致自身免疫表型。 T细胞发育的彻底表征表明Rasgrp1anaef T细胞有效发育，而Rasgrp1Anaef小鼠不是淋巴细胞减少症。取而代之的是，由于基础RasGRP1ANAEF-MTOR信号传导增加，髓样细胞亚群的数量增加，CD44HICXCR5+ PD1+ CD4+ T细胞异常积累，而小鼠显示ANA（抗核抗体）和蛋白尿。 rasgrp1anaef/wt杂合小鼠也证明了自身免疫性病理，因此一个RASGRP1WT等位基因无法补偿Rasgrp1anaef。我们提出了最近发表的自身抑制性RASGRP1二聚体的晶体结构，并证明RasGRP1ANAEF可以用RasGRP1WT蛋白形成二聚体，这对单平行性RASGRP1变体的作用机制呈现出了SLE，SLE，AutoMune（1型）糖尿病（1型）糖尿病（1型）糖尿病和GRAITES DISCAINTY和GRAVERSICATION和GRADES CALTIAL，GRAIMATIC CANTIAL，GRAIMATIC CANTIAL，OUTOMALIC RASGRP1变体的作用机制。 Here we will investigate the immune character of the aberrantly accumulating Rasgrp1Anaef T cells (Aim 1), the intimate interaction between T-, B-, and myeloid cells and the role of Rasgrp1Anaef myeloid cells in the Rasgrp1Anaef autoimmune features (Aim 2), and how this Rasgrp1Anaef mouse model may serve as a paradigm for monoallelic, non-synonymous RASGRP1 SNP等位基因（AIM 3）。来自密切相关但独立的目标的结果将提高我们对具有无辜和微妙的SNP变体的T细胞和髓样细胞如何通过病理刺激网络以及RASGRP1中的单相遗传SNP事件的自身免疫性如何引起自身免疫性。