Estrogen-Induced Regulatory B Cells Protect Against EAE & Limit CNS Inflammation

雌激素诱导的调节性 B 细胞可预防 EAE

• 批准号: 8851694
• 负责人: Halina Offner
• 金额: $ 33.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851694
• 关键词: Aftercare; Animal Model; Antigen-Presenting Cells; Antigens; Astrocytes; Autoantigens; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Blood - brain barrier anatomy; CD19 gene; Cells; Chronic; Clinical; Coupled; Demyelinations; Dendritic Cells; Development; Disease; Dose; Estriol; Estrogen Receptors; Estrogens; Exhibits; Experimental Autoimmune Encephalomyelitis; Female; Genes; Goals; Gonadal Steroid Hormones; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunosuppression; Incidence; Individual; Inflammation; Inflammatory; Interleukin-10; Laboratories; Lead; Lesion; Link; Mediating; Mediator of activation protein; Microglia; Monitor; Multiple Sclerosis; Mus; Myelin Proteins; Myelogenous; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurons; Oligodendroglia; Outcome; Pathway interactions; Pattern; Peripheral; Pregnancy; Process; Production; Property; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Relapse; Reporter; Role; Severities; Signal Transduction; Source; T-Cell Activation; T-Lymphocyte; Therapeutic Effect; Time; Transitional Cell; Up-Regulation; Woman; Work; axonal degeneration; base; clinical application; clinical effect; hormone therapy; immunoregulation; insight; interest; macrophage; migration; neurotoxic; protective effect; receptor; receptor binding; reconstitution; repaired; treatment effect

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a devastating neurodegenerative disease, characterized by chronic inflammation and demyelination. The incidence of MS is 2-3 times higher in women. However, the relapse rate of MS decreases during late pregnancy and also after treatment with pregnancy levels of estriol (a form of estrogen), leading to a decrease in CNS lesions. Estrogen (E2) is a potent regulator of the immune system and may also act directly on cells of the CNS, including microglia, astrocytes, oligodendrocytes and neurons. Our laboratory has convincingly demonstrated that estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Immunoregulatory properties of estrogen include dampening proinflammatory cells (e.g. dendritic cells, macrophages and encephalitogenic T cells) and activating Breg and Treg cells. Our goal is to determine the immune-mediated mechanisms that lead to protection of CNS cells (e.g. neurons, oligodendrocytes and microglia, MG). Deciphering the neuroprotective and immunoregulatory effects of estrogen is important for its possible clinical application. Our recent findings demonstrate a requirement for B-cells in E2-mediated protection against EAE involving direct E2 effects on Breg cells mediated through ER¿ and the PD-1/PD-L negative co-inhibitory pathway. It is likely that chronically activated microglia cause the neuronal and axonal degeneration that occurs in progressive forms of MS. Since the cause of this chronic microglial activation is uncertain, we propose in this application that MG cells represent one major target for regulatory B-cells and other B-cell subsets, whether by secretion of IL-10 or via direct means (cell-cell PD-1/PD-L signaling). In summary, this proposal will contribute new information regarding the potential role of E2 on B-cell subsets in regulating MG activation and protection against EAE.

描述（由申请人提供）：多发性硬化症（MS）是一种破坏性神经退行性疾病，其特征在于慢性炎症和脱髓鞘。MS的发病率在女性中高出2-3倍。然而，MS的复发率在妊娠晚期以及用妊娠水平的雌三醇（一种雌激素）治疗后降低，导致CNS病变减少。雌激素（E2）是免疫系统的有效调节剂，并且还可以直接作用于CNS的细胞，包括小胶质细胞、星形胶质细胞、少突胶质细胞和神经元。我们的实验室已经令人信服地证明，雌激素在多发性硬化症（MS），实验性自身免疫性脑脊髓炎（EAE）的动物模型的临床和组织学疾病发挥显着的保护作用。雌激素的免疫调节特性包括抑制促炎细胞（例如树突细胞、巨噬细胞和致脑炎性T细胞）和激活布雷格和Treg细胞。我们的目标是确定免疫介导的机制，导致保护中枢神经系统细胞（如神经元，少突胶质细胞和小胶质细胞，MG）。解读雌激素的神经保护和免疫调节作用对其可能的临床应用具有重要意义。我们最近的研究结果表明，在E2介导的EAE保护中需要B细胞，E2通过ER和PD-1/PD-L阴性共抑制途径介导对布雷格细胞的直接作用。可能的是，慢性活化的小胶质细胞引起在MS的进行性形式中发生的神经元和轴突变性。由于这种慢性小胶质细胞活化的原因是不确定的，我们在本申请中提出MG细胞代表调节性B细胞和其他B细胞亚群的一个主要靶标，无论是通过分泌IL-10还是通过直接手段（细胞-细胞PD-1/PD-L信号传导）。总之，这项建议将有助于新的信息E2对B细胞亚群的潜在作用，在调节MG激活和保护EAE。