{
  "abstract": "Introduction Therapeutic delivery to the CNS remains one of the greatest limitations in stroke care. Emerging evidence suggests this limitation may be fundamentally incorrect. The term ‘immune privilege’ has been widely accepted throughout the last century to describe the functional advantage of specific organs such as the central nervous system (CNS) to be self-contained and limit immune reactions as a protective mechanism of vital structures. However, emerging evidence suggests that this paradigm is incomplete. The blood-brain barrier (BBB), blood- cerebrospinal fluid (CSF) barrier, and glymphatic system together formulate a dynamic and integrated view of circulation between the parenchyma and meninges which maintain separation between the CNS and the peripheral immune system. Recent discoveries, including meningeal lymphatics and arachnoid cuff exits (ACE points), suggest that the CNS is not immunologically isolated but instead participates in bidirectional immune communication. These findings have significant implications for secondary injury following ischemic stroke and introduce potential therapeutic access points previously thought to be inaccessible.Methods This review synthesizes emerging evidence to define a new bidirectional concept of immune interaction between the brain and the periphery, with emphasis on the role of the meninges and calvarial bone marrow as active participants and reservoirs for immune surveillance.Results Collectively, these findings demonstrate that the skull bone marrow houses immune cell populations capable of responding to local CNS inflammation and supplying adjacent meningeal compartments independent of systemic circulation. Structural and functional connectivity between calvarial marrow and the meninges supports a model of regionally specialized immune response with bidirectional crosstalk. Additionally, ACE points represent anatomical discontinuities that permit cellular and molecular exchange between the dura and subarachnoid space, providing a pathway for immune trafficking in neuroinflammatory states. Mast cell-mediated signaling at the meningeal border zone, including modulation of Mrgprb2 and Sema3a pathways, regulates immune cell recruitment and has been shown to influence stroke outcomes in murine models. Importantly, these mechanisms establish a foundation for therapeutic targeting. Pharmacologic inhibition of immune signaling pathways reduced skull marrow-derived neutrophil recruitment and improved neurologic outcomes following stroke. Furthermore, engineered nanoparticle delivery via calvarial immune cells demonstrated successful targeted therapy by leveraging these migratory pathways, bypassing traditional BBB constraints.Conclusion These findings redefine the traditional view of CNS immune privilege and position the meningeal-calvarial interface as a dynamic immunologic and therapeutic gateway. The biological plausibility of immune-mediated transport and localized immune modulation introduces novel opportunities for targeted intervention in stroke and other neuroinflammatory conditions. Continued investigation into these pathways represents actionable targets for the development of neurointerventional strategies that utilize endogenous immune trafficking to attenuate secondary injury and improve neurologic outcomes.Disclosures A. Hirshman: None. S. Wolfe: None. A. Aguillard: None. Z. Xiang: None.",
  "authors": [
    {
      "affiliations": [
        "Student, Wake Forest School of Medicine, Winston Salem, NC, NC"
      ],
      "name": "A Hirshman"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Wake Forest School of Medicine, Winston Salem, NC"
      ],
      "name": "S Wolfe"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Wake Forest School of Medicine, Winston Salem, NC"
      ],
      "name": "A Aguillard"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Wake Forest School of Medicine, Winston Salem, NC"
      ],
      "name": "Z Xiang"
    }
  ],
  "title": "P-014 Reframing CNS immune privilege: meningeal-calvarial immune crosstalk as a therapeutic gateway for stroke intervention",
  "uid": "ef940081-1c14-5b1a-be7c-d169d3ad8e09"
}