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（由适用提供）：多发性硬化症（MS）是一种毁灭性的神经退行性疾病，其特征是慢性炎症和脱髓鞘。女性的MS事件是女性的2-3倍。然而，在怀孕晚期以及用妊娠水平的雌二醇（一种雌激素形式）治疗后，MS的继电器率降低，导致CNS病变降低。雌激素（E2）是免疫系统的潜在调节剂，也可以直接作用于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。我们的实验室令人信服地表明，在多发性硬化症（MS），实验性自身免疫性脑脊髓炎（EAE）的动物模型中，雌激素对临床和组织学疾病产生了明显的保护作用。雌激素的免疫调节特性包括衰减的促炎细胞（例如树突状细胞，巨噬细胞和脑源性T细胞）以及激活Breg和Treg细胞。我们的目标是确定导致CNS细胞保护的免疫介导的机制（例如神经元，少突胶质细胞和小胶质细胞，mg）。解解雌激素的神经保护作用和免疫调节作用对于可能的临床应用很重要。我们最近的发现表明，对E2介导的EAE的B细胞的要求，涉及通过ER？介导的Breg细胞和PD-1/PD-L负面共抑制途径的直接E2影响。长期活化的小胶质细胞可能导致MS进行性形式的神经元和轴突变性。由于该晶状体小胶质细胞激活的原因是不确定的，因此我们在此应用中提出，MG细胞代表了调节性B细胞和其他B细胞子集的一个主要目标，无论是通过IL-10分泌还是通过直接均值进行分泌或摘要中的Cell-Cell-Cell PD-1/PD-L（在摘要中），该建议将促进E2对B-Cell Subset and Controltation and Controlation and Contivation in Conee and ea ea ea ea ea and ea ea ea ea ea ea ea ea ea ea ea ea ea ea ea ea ea的含量和直接均值。