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Immune Privilege, CNS Autoimmunity, and Clostridium perfringens Epsilon Toxin

免疫特权、中枢神经系统自身免疫和产气荚膜梭菌 Epsilon 毒素

基本信息

批准号：
10754021
负责人：
TIMOTHY VARTANIAN
金额：
$ 67.97万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754021
关键词：
Active Immunization Animal Model Autoimmunity Binding Bioinformatics Biological Assay Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Stem CNS autoimmunity Candidate Disease Gene Catalogs Cell Separation Cell Surface Receptors Cells Cerebellum Clinical Clostridium perfringens Clostridium perfringens epsilon toxin Confocal Microscopy DNA Sequence Alteration Demyelinations Disease Endothelial Cells Endothelium Endotoxins Environmental Risk Factor Event Experimental Autoimmune Encephalomyelitis Experimental Models Flow Cytometry Frequencies Functional disorder Gene Deletion Gene Transfer Genes Genetic Risk Goals Human Immune Immunohistochemistry Individual Inflammatory Knockout Mice Lesion Leukocyte Trafficking Leukocytes Localized Lesion Location Lymphocyte Mediating Meningeal Messenger RNA Modeling Molecular Molecular Target Multiple Sclerosis Mus Mutant Strains Mice Myelin Neuroanatomy Neurologic Pathogenicity Pathology Pathway interactions Persons Pertussis Toxin Phenotype Prevalence Process Prosencephalon Proteins RNA Role Sampling Spinal Cord T-Lymphocyte Techniques Testing Time Tissues Toxin Transcriptional Regulation Wild Type Mouse Work adaptive immune response autoreactivity cellular targeting clinical phenotype clinically relevant diagnostic tool disability gain of function gene function gene induction gut microbiome high dimensionality immune cell infiltrate immunopathology innovation loss of function loss of function mutation migration multiple sclerosis patient neuropathology novel diagnostics postcapillary venule receptor single-cell RNA sequencing therapeutic evaluation therapeutic target transcriptome sequencing young adult

项目摘要

Why some people develop Multiple Sclerosis and others do not, despite similar genetic risk and quantities of circulating autoreactive lymphocytes, is not known. Our long-term goal is to identify environmental triggers of MS, define the molecular and cellular basis of their action, and in doing so, propose new diagnostic tools and therapeutic targets. The objectives of this proposal are to determine mechanistically how Clostridium perfringens epsilon toxin (ETX) and Bordetella pertussis toxin (PTX) overcome CNS immune privilege to trigger autoimmunity in the context of myelin autoreactive lymphocytes and to understand why ETX causes lesions to develop in the forebrain, cerebellum, brainstem, and spinal cord in contrast to PTX where lesions are more commonly localized to the spinal cord. The central hypothesis of this project is that ETX and PTX trigger CNS autoimmunity by inducing critical dysfunction at CNS barriers necessary for entry of pathogenic lymphocytes. The central hypothesis will be tested by pursuing two aims: 1) Determining the effect of cell specific deletion or introduction of the ETX receptor MAL (Myelin and Lymphocyte Protein) in active immunization models of experimental autoimmune encephalomyelitis (EAE), compare the neuroanatomical location, phenotype, and activation state of immune infiltrates between PTX- and ETX-induced EAE, and explore the effect of ETX on human lymphocytes, and 2) Determine the genes induced and suppressed in CNS-endothelial cells by ETX and PTX and define their function in overcoming CNS immune privilege through loss-of-function strategies. We will pursue these aims using an innovative combination of targeted genetic mutations to isolate cellular and molecular targets of ETX required to induce disease. We will use confocal microscopy, immunohistochemistry, high dimensional flow cytometry, and unbiased sampling of the entire CNS to compare the effects of ETX with PTX on immune phenotype, demyelination, and neuroanatomic localization of lesions. To determine toxin induced genes functioning to overcome CNS immune privilege, we will apply a combination of unbiased mRNA profiling techniques to CNS endothelial cells isolated from different neuroanatomic regions, advanced bioinformatics to define relevant gene modules, immunohistochemistry to validate localization of these induced proteins within individual post-capillary venules, and conditional loss-of-function mutations in endothelial cells to determine function. The rationale underlying this proposal is that completion will define the role by which a toxin, clinically associated with MS, functions in the multi-step process of autoimmunity, and will identify key molecular targets that can be tested therapeutically. This work will also help establish an experimental model that has greater clinical relevance to MS and more closely resembles MS neuropathology than experimental autoimmune encephalomyelitis models reliant on pertussis toxin.

为什么有些人会患多发性硬化症，而另一些人却不会，尽管有相似的遗传风险和数量