Molecular understanding of self immunity in the brain

大脑自我免疫的分子理解

• 批准号: 10224356
• 负责人: Caleigh Mandel-Brehm
• 金额: $ 10.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224356
• 关键词: 3-Dimensional; Adult; Affect; Anatomy; Antigens; Area; Autoantibodies; Autoimmune; Autoimmune Responses; Autoimmune encephalitis; Autoimmunity; Bacteriophages; Bioinformatics; Brain; Brain Stem; Brain region; CD8-Positive T-Lymphocytes; CD8B1 gene; CNS autoimmunity; Cells; Cellular Neurobiology; Central Nervous System Diseases; Cerebellum; Child; Childhood; Clinical; Cues; Cytotoxic T-Lymphocytes; Data; Dependence; Disease; Disease Progression; Encephalitis; Environment; Epitopes; Excision; Follow-Up Studies; Gene Deletion; Genes; Goals; Histocompatibility Antigens Class I; Human; I-antigen; Immune; Immunity; Immunohistochemistry; Immunologist; Immunology; Immunoprecipitation; Inflammation; Infrastructure; Interferon Type II; Invaded; Knockout Mice; Knowledge; Link; MHC Class I Genes; Malignant Neoplasms; Maps; Mediating; Mentors; Mission; Molecular; Molecular Immunology; Mus; Nervous System Paraneoplastic Syndromes; Neurobiology; Neurologist; Neurons; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phage Display; Phage ImmunoPrecipitation Sequencing; Phase; Prognosis; Proteins; Publishing; Recombinants; Refractory; Research; Research Personnel; Resolution; Role; Route; Signal Transduction; Specificity; Symptoms; Syndrome; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tumor-infiltrating immune cells; Up-Regulation; Ursidae Family; Workplace; antigen detection; antigen test; antigen-specific T cells; brain cell; cancer immunotherapy; cell motility; cell type; clinical predictors; diagnostic biomarker; glymphatic system; lens; mouse genetics; mouse model; neoplastic cell; nervous system disorder; neuroimmunology; neuroinflammation; neuronal circuitry; novel; novel marker; programs; recruit; relating to nervous system; response; side effect; single cell sequencing; skills; tumor

I recently developed a programmable phage display for identifying pathogenic antigens related to human paraneoplastic neurological disorders (PNDs). This workplace me in the rapidly emerging area of neuro- immunology, as PNDs are debilitating central nervous system disorders that involve autoimmune encephalitis. Patients with PND harbor autoantibodies against brain antigens, and specificity in the autoantibody profile predicts clinical symptoms and prognosis. I have characterized the largest set of antigens that are linked specifically to patient PNDs, one of which, KLHL11, was novel and published recently. In Aim 1, I will characterize the additional antigens and test my hypothesis that a single epitope is causal to PND patient autoimmunity and encephalitis. The K99 will allow me to acquire the advanced bioinformatics skills necessary for epitope analysis, strengths of the mentor's lab. In Aim 2, I test whether intracellular PND antigens cause autoimmune encephalitis through a non-canonical MHC-I class-dependent pathway, an unexpected mechanism with implications for treatment. I will create a new mouse model for anti-KLHL11 PND and a complementary KLHL11 knockout mouse. Together with existing mice deleted in immunity genes, I will use immunohistochemistry (IHC) and single cell sequencing to test dependence in specific targeting of T-cells in the brain of PND on the non-canonical MHC pathway. The K99 will allow me, with classes and advisors, to acquire the necessary advanced knowledge in immunology built into Aims 2 and 3 and help guide the initial T cell studies. Further, the UCSF mission, including infrastructure and research environment, is geared particularly towards facilitating direct interactions between basic and clinical immunologists and neurologists. I plan to continue to exploit this specialized environment as I transition to the R00 phase in this aim. In Aim 3, I bring to bear my previous expertise in mouse genetics and cellular neurobiology, and my K99 acquired molecular immunology expertise, to leverage PND antigens (Aims 1 and 2) to generate 3D anatomical maps of targeted inflammation in the brain. I will test whether brain region-specific PND encephalitis is mediated by the CNS lymphatic system. IHC with brain clearing for T cells, at different times after initiation of PND, will provide a comprehensive “3D” roadmap of the invading T cells and their relationship to antigen-expressing cells. My proposed studies will result in a comprehensive picture of the mechanisms determining how neuronal antigens elicit a brain autoimmune response, and assuming T cell migration routes are specific for anatomically distinct auto immunities, pave the way for identifying neuronal circuitries underlying the distinct PND pathologies, my goal as an independent investigator.

我最近开发了一种可编程噬菌体显示，用于识别与人副塑性神经系统疾病（PNDS）相关的致病抗原。由于PND正在使涉及自身免疫性脑炎的中枢神经系统疾病使我处于神经免疫免疫学的快速新兴领域。 PND港口自身抗体的患者针对脑抗原，自身抗体谱的特异性预测了临床符号和预后。我表征了与患者PND相关的最大抗原集，其中之一是KLHL11，最近出版了。在AIM 1中，我将表征额外的抗原，并检验我的假设，即单个发作是PND患者自身免疫性和脑炎的因果。 K99将使我能够获得表位分析所需的先进生物信息学技能，即精神实验室的优势。在AIM 2中，我测试了细胞内PND抗原是否通过非典型的MHC-I类依赖性途径引起自身免疫性脑炎，这是一种意外的机制，对治疗有影响。我将为抗KLHL11 PND创建一个新的鼠标模型和一个完整的KLHL11敲除鼠标。与免疫基因中删除的现有小鼠一起，我将使用免疫组织化学（IHC）和单细胞测序来测试PND大脑中T细胞对非经典MHC途径的特定靶向的依赖性。 K99将允许我在课堂和顾问中获得AIMS 2和3中所必需的免疫学高级知识，并帮助指导最初的T细胞研究。此外，包括基础设施和研究环境在内的UCSF任务特别旨在支持基本和临床免疫学家和神经病学家之间的直接相互作用。我计划在此目标中过渡到R00阶段时继续利用这种专业环境。在AIM 3中，我带来了我以前在小鼠遗传学和细胞神经生物学方面的专业知识，而我的K99获得了分子免疫学专业知识，以利用PND抗原（AIMS 1和2）来产生大脑中靶向炎症的3D解剖图。我将测试大脑区域特异性PND脑炎是否由CNS淋巴系统介导。在PND启动后的不同时间，IHC带有大脑清除T细胞的IHC将为入侵的T细胞提供全面的“ 3D”路线图及其与表达抗原的细胞的关系。我提出的研究将为确定神经元抗原如何引起脑自身免疫反应的机制提供全面的了解，并假设T细胞迁移途径特有解剖学上不同的自身免疫性，铺平了为识别独立PND病理学的神经元电路的方法，这是我作为独立研究员的靶标的。

项目成果

ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD.

• DOI: 10.1002/ana.26380
• 发表时间: 2022-08
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Mandel-Brehm, Caleigh;Benson, Leslie A.;Tran, Baouyen;Kung, Andrew F.;Mann, Sabrina A.;Vazquez, Sara E.;Retallack, Hanna;Sample, Hannah A.;Zorn, Kelsey C.;Khan, Lillian M.;Kerr, Lauren M.;McAlpine, Patrick L.;Zhang, Lichao;McCarthy, Frank;Elias, Joshua E.;Katwa, Umakanth;Astley, Christina M.;Tomko, Stuart;Dalmau, Josep;Seeley, William W.;Pleasure, Samuel J.;Wilson, Michael R.;Gorman, Mark P.;DeRisi, Joseph L.
• 通讯作者: DeRisi, Joseph L.

Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.

• DOI: 10.1172/jci.insight.174976
• 发表时间: 2023-12-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Rackaityte, Elze;Proekt, Irina;Miller, Haleigh S.;Ramesh, Akshaya;Brooks, Jeremy F.;Kung, Andrew F.;Mandel-Brehm, Caleigh;Yu, David;Zamecnik, Colin R.;Bair, Rebecca;Vazquez, Sara E.;Sunshine, Sara;Abram, Clare L.;Lowell, Clifford A.;Rizzuto, Gabrielle;Wilson, Michael R.;Zikherman, Julie;Anderson, Mark S.;Derisi, Joseph L.
• 通讯作者: Derisi, Joseph L.

Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes.

• DOI: 10.4049/jimmunol.2100225
• 发表时间: 2021-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Mandel-Brehm C;Fichtner ML;Jiang R;Winton VJ;Vazquez SE;Pham MC;Hoehn KB;Kelleher NL;Nowak RJ;Kleinstein SH;Wilson MR;DeRisi JL;O'Connor KC
• 通讯作者: O'Connor KC