Immune checkpoints in the CNS and HIV-associated neurocognitive disorder

中枢神经系统和艾滋病毒相关神经认知障碍中的免疫检查点

• 批准号: 10889463
• 负责人: Yunlong Liu
• 金额: $ 82.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10889463
• 关键词: Address; Affect; Alternative Splicing; Astrocytes; Bar Codes; Binding; Biological; Biological Markers; Biological Process; Biological Response Modifiers; Brain; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; CTLA4 gene; Cell Line; Cells; Central Nervous System; Cerebrospinal Fluid; Circulation; Clinical; DNA; Data; Detection; Enzyme-Linked Immunosorbent Assay; Exhibits; Frequencies; Gene Expression Profile; Genes; Growth Factor; HIV; HIV Seronegativity; HIV-associated neurocognitive disorder; Hippocampus; Homeostasis; Human; Image; Immune; Immunity; Immunoassay; Immunohistochemistry; Immunoprecipitation; Individual; Inflammatory; Interferon Type II; Interleukin-1 beta; Lead; Ligands; Macaca mulatta; Macrophage; Malignant Neoplasms; Measures; Membrane; Messenger RNA; Microglia; Neuroimmune system; Neurologic Symptoms; Neurons; Neuropathogenesis; Pathogenesis; Pathway interactions; Peripheral; Persons; Production; Protein Isoforms; Protein Secretion; Proteins; RNA Splicing; Regulation; Reporting; Repression; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; SIV; Sampling; Self Tolerance; Severities; Signal Transduction; T cell regulation; TNF gene; Tail; Techniques; Testing; Time; Tissue Sample; Tissues; Variant; Virus Diseases; antibody conjugate; brain cell; brain tissue; cancer cell; cell type; checkpoint receptors; chemokine; clinically relevant; cytokine; digital imaging; frontal lobe; immune cell infiltrate; immune checkpoint; in vivo; indexing; innovation; insight; melanoma; migration; monocyte; multiplex assay; neurocognitive disorder; neuroinflammation; peripheral blood; programmed cell death ligand 1; programmed cell death protein 1; receptor; single nucleus RNA-sequencing; spatial relationship; tumor

Abstract Immune checkpoints (ICPs) exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance through their ligand-receptor interactions. ICPs exist in both membrane-bound and soluble forms in vivo. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the peripheral blood and tissues have been well documented. Blockade of inhibitory mICPs such as CTLA-4, PD-1, and PD-L1 has become a revolutionary treatment for advanced stages of malignancies such as melanoma. However, the origin, regulation, and biological significance of both mICPs and soluble ICPs (sICPs) in the central nervous system (CNS) have not yet been systematically studied. We used a multiplex immunoassay to simultaneously quantify the concentrations of 16 sICPs in cerebrospinal fluid (CSF) samples from 33 HIV-negative individuals (HNIs) and 105 people living with HIV (PLWH), including 80 cases with HIV-associated neurocognitive disorder (HAND) and 25 cases without HAND. We found that 10 sICPs (sHVEM, sCD27, sGITR, sICOS, sLAG-3, sPD-1, sTIM-3, sBTLA, sCD28, & sCD40) were consistently detected in all CSF samples, and most of them were highly elevated in PLWH. Strikingly, CSF sHVEM was significantly increased in HAND when compared to PLWH without HAND. These 10 sICPs were also detectable in the CSF samples from rhesus macaques (RMs). Immunohistochemistry (IHC) analysis of brain tissues (frontal cortex and hippocampus) from RMs with and without simian immunodeficiency virus (SIV) infection showed that mHVEM was expressed at a basal level on neurons, but not on astrocytes or microglia, and mHVEM expression was highly increased in SIV-infected RMs (SIV/RMs). Furthermore, we have recently reported that PD-L1 expression in U87MG cells (a human astrocyte cell line) can be robustly induced by a mixture of IFN-γ/IL-1β/TNF-α, and induced PD-L1 controls production of MCP-1 (the most important chemokine that regulates migration of monocytes/macrophages) via PD-L1 intrinsic signaling. Thus, we hypothesize that both sICPs and mICPs are dysregulated in the CNS of PLWH, which are associated with HAND neuropathogenesis. We have two Specific Aims to test this central hypothesis: (1) To determine sICP profiles and biological functions in the CNS of PLWH and SIV/RMs, and (2) To characterize the cellular niches and spatial associations of ICP receptor/ligand-positive neural cells and infiltrating immune cells in the brain of PLWH and SIV/RMs. Our results will provide insights into the roles of ICPs in the CNS neuroimmune dysregulation and neuroinflammation of PLHIV with and without HAND. The CSF levels and profiles of sICPs such as sHVEM can potentially be used as a biomarker for HAND severity and progression.

抽象的 免疫检查点（ICP）对免疫防御，监视，执行抑制或刺激作用， 调节和通过配体 - 受体相互作用的自我耐受性。 ICP都存在于两个膜结合 并在体内形成可溶性。抑制性和刺激性膜结合的ICP（MICP）之间的不平衡 外周血和组织中的恶性细胞和免疫细胞已得到充分记录。封锁 抑制性MIC（例如CTLA-4，PD-1和PD-L1）已成为对先进的革命疗法 恶性肿瘤（例如黑色素瘤）的阶段。但是，两者的起源，调节和生物学性 中枢神经系统（CNS）中的MIC和固体ICP（SICP）尚未系统地。 Studiod。我们使用多重免疫测定简单地量化了16个SICP的浓度 来自33个HIV阴性个体（HNI）和105名HIV患者的脑脊液（CSF）样本 （PLWH），包括80例HIV相关神经认知障碍（手）和25例无手的病例。 我们发现10个SICP（SHVEM，SCD27，SGITR，SICOS，SLAG-3，SPD-1，STIM-3，SBTLA，SCD28，＆SCD40） 在所有CSF样品中都始终检测到，其中大多数在PLWH中都高度升高。令人惊讶的是， 与没有手的PLWH相比，CSF SHVEM的手显着增加。这10个SICP 也可以在恒河猕猴（RMS）的CSF样品中检测到。免疫组织化学（IHC）分析 带有和不含邻是否免疫缺陷病毒的RMS的脑组织（额叶皮层和海马） （SIV）感染表明，MHVEM在神经元上的基础水平表达，但在星形胶质细胞或 在SIV感染的RMS（SIV/RMS）中，小胶质细胞和MHVEM表达高度增加。此外，我们 最近报道说，U87mg细胞中的PD-L1表达（人星形细胞系）可以很强 由IFN-γ/IL-1β/TNF-α的混合物诱导，并诱导PD-L1控制MCP-1的产生（最多 重要的趋化因子通过PD-L1固有信号传导调节单核细胞/巨噬细胞的迁移）。那， 我们假设SICP和MIC在PLWH的中枢神经系统中均失调，这与 手神经病发生。我们有两个特定的目的来检验此中心假设：（1）确定SICP PLWH和SIV/RMS的中枢神经系统中的曲线和生物学功能，以及（2）表征细胞壁nir ICP受体/配体阳性神经细胞的空间关联以及脑中的免疫细胞浸润 PLWH和SIV/RMS。我们的结果将提供有关ICP在CNS Neuromune中角色的见解 PLHIV的功能障碍和神经炎症，没有手。 SICPS的CSF级别和轮廓 例如SHVEM可能被用作手部严重性和进展的生物标志物。