The regulation of myeloid cell development and mobilization during autoimmune dem

描述（由申请人提供）：血源性骨髓细胞（巨噬细胞和树突状细胞）是多发性硬化症（MS）患者和实验性自身免疫性脑脊髓炎（EAE）动物炎症浸润的主要组成部分。它们与导致这些疾病残疾的脱髓鞘和轴突丧失有关。然而，在自身免疫性脱髓鞘疾病中，髓系细胞是如何在外周和中枢神经系统中受到调节的，我们所知相对较少。我们发现髓系祖细胞在EAE恶化前从骨髓中以加速的速度被动员。新输出的Ly6ChiCD11b+单核细胞在临床前阶段浸润中枢神经系统，产生CD11c+MHC分类DC，在症状期构成神经炎症细胞的显著百分比。在目的1中，我们将研究EAE期间骨髓样细胞扩张和动员的细胞因子途径和分子机制。我们的假设是，髓鞘特异性T细胞诱导的GM-CSF和MIP-1a刺激骨髓基质细胞产生G-CSF和CXCL1/2。这些因子反过来激活驻留的中性粒细胞分泌蛋白酶，降解趋化因子和粘附分子，这些分子对于髓内壁龛中造血前体细胞的隔离至关重要。阻断这一途径中的任何步骤（例如，通过中和G-CSF或通过使蛋白酶失活）都将阻止髓细胞释放，并最终耗尽在复发期间提供中枢神经系统浸润细胞来源的外周单核细胞池。在Aim 2中，我们将研究刺激Ly6ChiCD11b+单核细胞在中枢神经系统内分化为CD11c+MHC iii类DC的因素。我们认为，中枢神经系统浸润单核细胞通过与髓磷脂特异性T细胞的直接相互作用而获得髓系树突状细胞的特征。将评估候选可溶性因子（如GM-CSF和TNF）和细胞表面分子（如RANKL、CD40L和Lymphotoxin-¿）的作用。我们的研究可能为自身免疫过程中驱动致病性骨髓细胞动员和发育的途径提供见解。该研究结果有望为髓细胞失调相关的MS提供新的治疗靶点和生物标志物。

DESCRIPTION (provided by applicant): Blood borne myeloid cells (macrophages and dendritic cells) comprise a major component of the inflammatory infiltrates in patients with multiple sclerosis (MS) and animals with experimental autoimmune encephalomyelitis (EAE). They have been implicated in the demyelination and axonal loss that cause disability in these disorders. However, relatively little is known about how myeloid cells are regulated in the periphery and CNS during autoimmune demyelinating disease. We have found that myeloid progenitor cells are mobilized from the bone marrow at an accelerated rate immediately prior to EAE exacerbations. Newly exported Ly6ChiCD11b+ monocytes infiltrate the CNS during the preclinical stage and give rise to the CD11c+MHC ClassIIhi DC that constitute a significant percent of neuroinflammatory cells during the symptomatic stage. In Aim 1 we will investigate the cytokine pathways and molecular mechanisms underlying the expansion and mobilization of bone marrow myeloid cells during EAE. Our working hypothesis is that GM-CSF and MIP-1a, induced by myelin-specific T cells, stimulate bone marrow stromal cells to produce G-CSF and CXCL1/2. These factors, in turn, activate resident neutrophils to secrete proteases that degrade chemokines and adhesion molecules critical for the sequestration of hematopoietic precursor cells in intramedullary niches. Interruption of any step in this pathway (ex, by neutralizing G-CSF or by inactivating proteases) will prevent myeloid cell release and ultimately exhaust the peripheral monocyte pools that provide a source of CNS infiltrating cells during relapses. In Aim 2 we will investigate the factors that stimulate Ly6ChiCD11b+ monocytes to differentiate into CD11c+MHC Class IIhi DC within the CNS. We propose that CNS infiltrating monocytes acquire characteristics of myeloid dendritic cells consequent to direct interactions with myelin- specific T cells. The roles of candidate soluble factors (such as GM-CSF and TNF) and cell surface molecules (such as RANKL, CD40L and Lymphotoxin-¿) will be assessed. Our studies are likely to provide insights into the pathways driving the mobilization and development of pathogenic myeloid cells during autoimmunity. The results are expected to suggest novel therapeutic targets and biomarkers in MS related to myeloid cell dysregulation. PUBLIC HEALTH RELEVANCE: Although recent advancements in the immunotherapy of multiple sclerosis (MS) have focused on the T cell component of the autoimmune response, myeloid cells (including macrophages and dendritic cells) compose the majority of CNS-infiltrating cells in MS and its model, experimental autoimmune encephalomyelitis (EAE), and mediate direct damage to neurons and glia. The purpose of this proposal is to elucidate the cytokine pathways and molecular mechanisms that underlie the mobilization of myeloid cells from the bone marrow and that drive their differentiation into pathogenic effector cells during autoimmune demyelinating disease. It is anticipated that our results will lead to the discovery of novel biomarkers and therapeutic targets related to myeloid cell dysregulation in MS.