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

中枢神经系统（CNS）损伤后免疫系统的抑制是神经系统疾病的常见特征，如中风、创伤性脑损伤（TBI）和胶质母细胞瘤（GBM）。这种免疫抑制导致死亡，并导致免疫调节疗法的失败。神经损伤后全身免疫抑制的潜在机制仍不清楚。在这项提案中，我们专注于胸腺，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CNS病毒感染、肿瘤、无菌性炎症、物理损伤和癫痫发作。所有损伤导致显著的胸腺退化，其在损伤清除后是可逆的。重要的是，胸腺退化没有发生后，外周侮辱。利用联体共生，我们发现胸腺退化是可转移的从胶质瘤轴承非肿瘤轴承的联体证明血清衍生的可溶性因子在介导胸腺退化的关键作用。具体地，分子量（MW）大于300 kDa的血清衍生分子被认为是免疫抑制性的。有趣的是，胸腺受到中枢神经系统的强烈支配，但这种神经支配在神经损伤和免疫抑制中的作用仍然未知。我们使用狂犬病毒神经示踪剂首次证明，胸腺受到外在神经元（胸腺外的细胞体）和内在神经元（胸腺内的细胞体）的严重神经支配。简而言之，神经损伤后的多方面免疫抑制改变了胸腺、骨髓和脾脏的免疫稳态。免疫器官的这些改变在多大程度上诱导短暂或持久的免疫缺陷仍有待研究。胸腺退化、血清中免疫抑制因子的存在、骨髓小生境内的变化以及持久的免疫缺陷共同解释了神经损伤后观察到的免疫缺陷，至少部分是这样。基于这些数据，我们假设，神经损伤后，大脑通过可溶性因子和神经支配抑制免疫系统全身和局部。这反过来又会改变免疫系统，影响长期免疫力。这一假设将在以下三个目标进行测试：目的1：确定神经损伤期间血清源性免疫抑制因子的分子特性;目的2：确定基线和神经损伤期间胸腺神经支配的功能;目的3：确定神经损伤后免疫抑制对免疫系统的短暂和长期功能后果。这些目标的成功完成将显著影响对神经损伤期间免疫系统的免疫抑制和神经控制的理解，并将帮助我们开发新的治疗方法，以对抗急性和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.