Drainage of Brain Extracellular Fluid into Blood and Deep Cervical Lymph and its Immunological Significance

Abstract

Cerebral extracellular fluids drain from brain to blood across the arachnoid villi and to lymph along certain cranial nerves (primarily olfactory) and spinal nerve root ganglia. Quantification of the connection to lymph in rabbit, cat and sheep, using radiolabelled albumin as a marker of flow, indicates that a minimum of 14 to 47% of protein injected into different regions of brain or cerebrospinal fluid passes through lymph. The magnitude of the outflow to lymph is at variance with the general assumption that the absence of conventional lymphatics from the brain interrupts the afferent arm of the immune response to brain antigens. The immune response to antigens (albumin or myelin basic protein) introduced into the central nervous system (CNS) has been analysed using a rat model with normal brain barrier permeability. The micro-injection of antigen into brain or cerebrospinal fluid elicits a humoral immune response, with antibody production in cervical lymph nodes and spleen, and also affects cell-mediated immunity. Furthermore, antigen may be more immunogenic when administered into the CNS than into conventional extracerebral sites. Clearly, the afferent arm of the immune response to antigens, within the CNS, is intact. Modern studies suggest that the efferent arm is also intact with passage of activated lymphocytes into the brain. Results support a new view of CNS immunology which incorporates continuous and highly regulated communication between the brain and the immune system in both health and disease.

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…4 The evidence for permeability of the blood-brain barrier (BBB) under conditions of inflammation and tumor growth, such as in GBMs, the presence of lymphatic drainage, and the antigen-presenting ability of microglial cells reveals a more dynamic interaction of the central nervous system (CNS) with the systemic immune system. [13][14][15][16] Arming the immune system to mount a robust anti-tumor response is an attractive therapeutic approach, since the cytotoxic and memory responses of its effector cell populations can be specifically targeted to the tumor cells in the brain parenchyma.…”

Antigen Presentation After Stroke

“…These routes allow the drainage of interstitial fluid and solutes out of the brain parenchyma through the glymphatic system [24][25][26][27][28]. Brain fluid and macromolecules can eventually reach the cervical lymph nodes along extracranial nerves through the cribiform plate [29][30][31], and through the recently described lymphatic vessels in the dura matter of the mice [32,33]. Thus, APCs would capture neural antigens in the lymph nodes.…”

Experimental ‘hindbrain related’ syringomyelia: some mechanisms of spinal cord damage

“…This mechanisms allows auto reactive clones of lymphoid cells to act directly against CNS antigens. Lymphatic drainage of the CSF has been well documented in a number of mammalian species [4,5]. Then, by highly directionalised pathways, CSF drains to the olfactory bulbs and through arachnoid channels to connect with lymphatic vessels in the nasal mucosa and deep cervical lymph nodes.…”