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共同特征，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然很大程度上未知。在这个提议中，我们关注胸腺，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，包括中枢神经系统的病毒感染、肿瘤、无菌炎症、物理损伤和癫痫活动。所有的损伤都导致胸腺退化，这种退化在损伤清除后是可逆的。重要的是，胸腺退化并没有在外周损伤后发生。通过异种共生，我们发现胸腺复旧可以从患有胶质瘤的异种转移到非肿瘤的异种，这表明血清衍生的可溶性因子在介导胸腺复旧中起着至关重要的作用。具体来说，分子量（MW）大于300 kDa的血清衍生分子被认为具有免疫抑制作用。有趣的是，胸腺受中枢神经系统的大量支配，但这种神经支配在神经损伤和免疫抑制中的作用尚不清楚。我们首次使用狂犬病毒神经示踪剂证明胸腺受外源性神经元（胸腺外的细胞体）和内源性神经元（胸腺内的细胞体）的大量神经支配。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引起短暂或长期的免疫缺陷仍未得到充分研究。胸腺退化、血清中免疫抑制因子的存在、骨髓生态位的改变以及长期的免疫缺陷，至少在一定程度上解释了神经损伤后观察到的免疫缺陷。基于这些数据，我们假设在神经损伤后，大脑通过可溶性因子和神经支配抑制了全身和局部的免疫系统。这反过来又改变了免疫库并影响长期免疫。这一假设将在以下三个目标中得到验证：目的1：确定神经损伤期间血清来源的免疫抑制因子的分子特性；目的2：确定基线和神经损伤时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影响。这些目标的成功完成将显著影响对神经损伤期间免疫抑制和免疫系统神经控制的理解，并将帮助我们开发新的治疗方法，以对抗急性和慢性神经损伤患者的免疫抑制。

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.