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Autoimmunity risk alleles compromising B cell anergy

损害 B 细胞无反应性的自身免疫风险等位基因

基本信息

批准号：
9121221
负责人：
John C Cambier
金额：
$ 45.51万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121221
关键词：
Acute Affect Alleles Antigen Receptors Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Cell Activation B-Lymphocytes Cells Chromatin Complement Constitution Development Disease Environmental Risk Factor Feedback Fingerprint Future Gene Deletion Gene Proteins Genes Genetic Genetic Models Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Glomerulonephritis Goals Hot Spot Human Immune Tolerance Immunoglobulin Class Switching Individual Infection Inherited Injury Inositol LYN gene Lead Life Style Lipids Lupus Maintenance Mediating Medical Modeling Molecular Monitor Mus PTEN gene PTPN22 gene PTPN6 gene Pathology Pathway interactions Patients Peripheral Phosphoric Monoester Hydrolases Phosphorylation Predisposition Prevention Production Protein Tyrosine Phosphatase Proteins Proto-Oncogene Proteins c-akt RNA Interference Receptor Signaling Regulation Regulatory Pathway Reporting Request for Applications Research Risk Role Signal Pathway Signal Transduction Site Specificity Systemic Lupus Erythematosus Testing Therapeutic Translating Tyrosine Phosphorylation Work anergy autoreactive B cell central tolerance disorder risk gene function genetic variant in vivo insight kinase inhibitor knock-down microbiome mimetics new therapeutic target personalized approach prevent protein function release of sequestered calcium ion into cytoplasm response risk variant

项目摘要

Autoimmunity is caused by conspiring effects of genetic predisposition and environmental factors such as injury, infection and microbiome constitution. While multiple genetic loci affect susceptibility, in most cases each in isolation has only a small effect, suggesting that disease develops only when multiple risk-conferring alleles that function in concert are inherited by a single individual. We hypothesize that such a situation exists in autoreactive B cells where multiple SLE risk alleles encode molecules that appear to function in signaling pathways that function normally to limit/terminate antigen receptor signaling. In this application we propose to test this hypothesis, analyzing the functional interplay of this set of genes/protein and their risk conferring alleles. Future development and implementation of “precision” medical approaches for treatment of autoimmunity will require an understanding of the mechanisms by which genetic variations conspire to increase disease risk, and research proposed here represents a critical first step to enable these efforts. A number of autoimmunity risk alleles encode molecules previously proposed to function as intermediaries in signaling pathways involved in regulation of B cell activation. As such they may be important in keeping autoreactive B cells from becoming activated and contributing to autoimmunity. In this application we request support to define the functions and functional interactions of proteins encoded by six genes, variants of which confer increased risk of autoimmunity. Previous reports indicate that B cell-targeted deletion of genes encoding SHIP-1, PTEN, SHP-1 or LYN, expression of PTPN22 (PEP-R619W), or increased expression of CSK, promote the development of autoimmunity. However the mechanism by which this occurs is unknown. We hypothesize that these proteins function as intermediaries in a bifurcating pathway in which final effectors are the inositol lipid phosphatases SHIP-1 and the tyrosine phosphatase SHP-1. Further, we suggest that both terminal effectors are required for maintenance of antigen unresponsiveness of anergic B cells. The studies will employ reductionist genetic models in which risk allele mimetic changes in expression/function of the proteins can be induced acutely in anergic B cells, and subsequent cell activation, proliferation, differentiation and autoantibody production monitored. Aim 1 will test the hypothesis that PTPN22, CSK and LYN act in linear pathways upstream of SHIP-1 and SHP-1, and that genetic variations that confer risk compromise anergy by undermining their regulatory function. Aim 2 will define the downstream consequences of acute introduction of risk allele mimetic conditions in terms of development of autoimmune disease, and will test candidate therapeutic kinase inhibitors. Aim 3 will translate findings, examining the role of SHIP-1 and SHP-1 phosphatases in maintenance anergy of human B cells. Proposed studies will provide important new insight regarding the in vivo lifestyle of autoreactive B cells whose anergy is compromised by autoimmunity risk alleles.

自身免疫是遗传易感性和环境因素共同作用的结果