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展示技术，用于识别与人类副肿瘤性神经系统疾病 (PND) 相关的致病性抗原，因为 PND 会导致涉及自身免疫性脑炎的中枢神经系统疾病，从而使我处于快速新兴的神经免疫学领域。 PND 携带针对脑抗原的自身抗体，并且自身抗体谱的特异性可以预测临床症状和预后。我已经描述了与患者特异性相关的最大一组抗原。 PND，其中之一 KLHL11 是新颖的，最近发表，在目标 1 中，我将描述其他抗原并检验我的假设，即单个表位与 PND 患者自身免疫和脑炎有关。K99 将使我能够获得先进的结果。表位分析所需的生物信息学技能，导师实验室的优势 在目标 2 中，我通过一种方法测试细胞内 PND 抗原是否会导致自身免疫性脑炎。我将创建一个新的抗 KLHL11 PND 小鼠模型和一个互补的 KLHL11 敲除小鼠，以及删除免疫基因的现有小鼠。免疫组织化学 (IHC) 和单细胞测序可测试 PND 大脑中 T 细胞对非典型 MHC 途径的特异性靶向依赖性。顾问，以获得目标 2 和 3 中必要的免疫学先进知识，并帮助指导最初的 T 细胞研究。此外，UCSF 的使命，包括基础设施和研究环境，特别致力于促进基础免疫学家和临床免疫学家之间的直接互动。在目标 3 中，我计划在过渡到 R00 阶段时继续利用这种专业环境，并利用我之前在小鼠遗传学和细胞神经生物学方面的专业知识以及我的 K99 获得的分子免疫学知识。专业知识，利用 PND 抗原（目标 1 和 2）生成大脑中目标炎症的 3D 解剖图，我将测试大脑区域特异性 PND 脑炎是否由中枢神经系统 IHC 与大脑清除 T 细胞介导。在 PND 开始后的不同时间，将提供入侵 T 细胞及其与抗原表达细胞的关系的全面“3D”路线图，我提出的研究将全面了解决定机制。神经元抗原如何引发大脑自身免疫反应，并假设 T 细胞迁移路径对于解剖学上不同的自身免疫具有特异性，为识别不同 PND 病理学背后的神经元回路铺平道路，这是我作为独立研究者的目标。

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