Nervous system control and regulation of the immune system following neurological insults

中枢神经系统(CNS)受损后的免疫系统抑制是中风、创伤性脑损伤(TBI)和胶质母细胞瘤(GBM)等各种神经系统疾病的共同特征。这种免疫抑制会导致死亡，并导致免疫调节疗法的失败。神经系统损伤后全身性免疫抑制的潜在机制在很大程度上仍不清楚。在这项建议中，我们将重点放在胸腺上，胸腺是负责儿童和成人T细胞发育的主要免疫器官。我们测试了各种神经损伤后的胸腺功能，包括中枢神经系统的病毒感染、肿瘤、无菌炎症、身体损伤和癫痫活动。所有的侮辱都导致显著的胸腺退化，这种退化在损伤清除后是可逆的。重要的是，胸腺退化没有发生在外周侮辱之后。利用异生现象，我们发现胸腺退化可以从带胶质瘤的副生物转移到非带瘤的副生物身上，这表明血清来源的可溶性因子在调节胸腺退化中起着至关重要的作用。具体地说，分子量(MW)大于300 kDa的血清衍生分子被认为是免疫抑制。有趣的是，胸腺受到中枢神经系统的严重支配，但这种神经支配在神经损伤和免疫抑制中的作用仍不清楚。我们首次使用狂犬病病毒神经示踪剂证明，胸腺受到外部神经元(胸腺外的细胞体)和内在神经元(胸腺内的细胞体)的高度神经支配。简而言之，神经损伤后的多方面免疫抑制改变了胸腺、骨髓和脾的免疫动态平衡。免疫器官中的这些变化在多大程度上导致短暂或长期的免疫缺陷仍未得到研究。胸腺退化，血清中免疫抑制因子的存在，骨髓内的变化，以及长期的免疫缺陷，至少部分地共同解释了神经损伤后观察到的免疫缺陷。基于这些数据，我们假设，在神经学上的侮辱之后，大脑通过可溶性因子和神经支配从系统和局部两方面抑制免疫系统。这反过来会改变免疫系统，影响长期免疫力。这一假设将在以下三个目标中得到验证：目的1：确定神经损伤时血清衍生免疫抑制因子的分子同一性；目标2：确定在基线和神经损伤期间胸腺神经支配的功能；目标3：确定免疫抑制对神经损伤后免疫系统的短暂和长期的功能影响。这些目标的成功实现将对理解神经损伤期间免疫系统的免疫抑制和神经控制产生重大影响，并将帮助我们开发新的疗法来对抗大量急慢性神经创伤患者的免疫抑制。

Suppression of the immune system following damage to the central nervous system (CNS) is a common feature of neurological diseases as diverse as stroke, traumatic brain injury (TBI), and glioblastoma (GBM). This immunosuppression causes mortality and leads to the failure of immune-modulating therapies. The underlying mechanisms of systemic immunosuppression following neurological insults remain largely unknown. In this proposal, we focus on the thymus, the primary immune organ responsible for T cell development in children and adults. We tested thymic function following various neurological insults, including viral infections of the CNS, tumors, sterile inflammation, physical injury, and seizure activity. All insults resulted in significant thymic involution that was reversible upon clearance of the injury. Importantly, thymic involution did not occur following peripheral insults. Using parabiosis, we found that thymic involution was transferable from glioma- bearing to non-tumor-bearing parabionts demonstrating the crucial role of serum-derived soluble factors in mediating thymic involution. Specifically, serum-derived molecules with molecular weights (MW) larger than 300 kDa were deemed immunosuppressive. Interestingly, the thymus is heavily innervated by the CNS, yet the role of this innervation during neurological injuries and immunosuppression remains unknown. We demonstrated, for the first time, that the thymus is heavily innervated by both extrinsic neurons (cell bodies outside of the thymus), and intrinsic neurons (cell bodies within the thymus) using rabies virus neurotracers. In short, the multifaceted immunosuppression following neurological insults alters immune homeostasis in the thymus, bone marrow, and the spleen. The extents to which these alterations in the immune organs induce transient or long-lasting immunological defects remain understudied. Thymic involution, presence of immunosuppressive factors in serum, changes within the bone marrow niche, and long-lasting immunological defects together account, at least in part, for immune deficiencies observed following neurologic injuries. Based on these data, we hypothesized that following neurological insults the brain suppresses the immune system both systemically and locally through soluble factors and innervation. This in turn alters the immune repertoire and affects long-term immunity. This hypothesis will be tested in the following three aims: Aim1: To determine the molecular identity of serum-derived immunosuppressive factors during neurological insults; Aim 2: To determine the function of thymic innervation at baseline and during neurological insults; Aim 3: To determine transient and long-lasting functional consequences of immunosuppression on the immune system following neurological injuries. Successful completion of these aims will significantly impact understanding of immunosuppression and nervous control of the immune system during neurological injuries and will help us develop new therapeutics to combat immunosuppression in a large cohort of patients with acute and chronic neurological traumas.