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

描述(申请人提供)：多发性硬化症(MS)是一种毁灭性的神经退行性疾病，以慢性炎症和脱髓鞘为特征。多发性硬化症的发病率是女性的2-3倍。然而，多发性硬化症的复发率在妊娠晚期和孕期雌三醇(一种雌激素)治疗后都会降低，导致中枢神经系统病变的减少。雌激素(E2)是免疫系统的强大调节剂，也可能直接作用于中枢神经系统的细胞，包括小胶质细胞、星形胶质细胞、少突胶质细胞和神经元。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，我们的实验室已经令人信服地证明雌激素对临床和组织学疾病具有显著的保护作用。雌激素的免疫调节特性包括抑制前炎症细胞(如树突状细胞、巨噬细胞和脑源性T细胞)和激活Breg和Treg细胞。我们的目标是确定导致中枢神经系统细胞(如神经元、少突胶质细胞和小胶质细胞，MG)保护的免疫介导机制。了解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。我们最近的发现表明，在E2介导的EAE保护作用中，B细胞是必需的，这可能是因为E2通过ERα和PD-1/PD-L负向共抑制通路直接作用于Breg细胞。慢性激活的小胶质细胞很可能导致进行性多发性硬化症的神经元和轴突变性。由于这种慢性小胶质细胞激活的原因尚不清楚，我们在本应用中提出MG细胞是调节B细胞和其他B细胞亚群的一个主要靶点，无论是通过分泌IL-10还是通过直接途径(细胞-细胞PD-1/PD-L信号)。综上所述，这项建议将有助于提供关于B细胞亚群上的E2在调节MG激活和预防EAE方面的潜在作用的新信息。

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 ERα 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.