The amazing brain drain

The CNS has long been considered an immune-privileged site as tissues grafted into the CNS are not rejected as they are in other tissues (Medawar, 1948; Billingham and Boswell, 1953; Barker and Billingham, 1977). An avalanche of evidence now suggests that this privilege is not absolute, as robust immune responses can occur in the CNS during infections and autoimmune diseases such as multiple sclerosis (MS), as well as other neuroinflammatory diseases. One of the major thoughts as to why there is immune privilege is the lack of CNS parenchymal lymphatics, necessary to drain antigens into the lymph nodes. Lymphatic vessels (LVs) are critical for maintaining tissue homeostasis by recycling interstitial fluid (ISF), as well as participating in tissue immune responses by draining antigens into lymph nodes and regulating immune cell flux into and out of the tissues (Liao and Padera, 2013). Although there are no lymphatics within the brain parenchyma, there is a complex lymphatic system within the meninges that drains cerebrospinal fluid (CSF) from the meningeal coverings of the brain into the deep cervical lymph nodes (dcLNs). This meningeal lymphatic system was first described two centuries ago by Paolo Mascagni; however, it was largely ignored until the recent characterization of meningeal LVs (mLVs) in the rodent, primate, and human dura (Aspelund et al., 2015; Bucchieri et al., 2015; Louveau et al., 2015; Absinta et al., 2017). These studies, combined with the identification of the glymphatic system whereby the neural ISF is drained into the CSF along the veins, have allowed a deeper understanding of how ISF recycling is regulated in the CNS (Iliff et al., 2012; Asgari et al., 2016). The characterization of the meningeal lymphatics has thus enabled a reexamination of how immunity is regulated within the CNS and how this may be important for CNS infections, MS, and other neuroinflammatory diseases. Furthermore, the drainage of ISF molecules has become increasingly of interest especially in the context of Alzheimer’s disease (AD) where toxic buildup of amyloid β has been suggested to result from insufficient drainage. In this issue, Antila et al. first analyze the timing of mLV formation during mouse development and demonstrate that this occurs postnatally, in a spatially coordinated program. The very first mLVs are observed just before birth at the foramen magnum (FM), and starting from postnatal day (P) 0, they extend, following major arteries and venous sinuses until the complete formation of the mLV network at P24. The authors also describe the development of the meningeal lymphatic vascular network in the spinal cord, where it is initiated at P4 from the FM and is completed before P36. mLVs grow on both the dorsal and ventral sides of the spinal cord to develop a complex mLV network. The mLVs develop concomitantly at the cervical and lumbar levels of the spinal cord. This time course of mouse mLV development provides important physiological information for our understanding of how CNS immunity may be regulated differently during development and adulthood. It is of great interest to determine how the development in mouse correlates to human mLV development. One option is that the development in humans correlates with the same developmental stage as in mouse, and thus the human mLV initiation may occur at the end of the third trimester. Alternatively, mLV development may not be triggered by developmental stage but by environmental conditions at birth, such as oxygen content, so it is possible that human mLV development also initiates postnatally. It will also be interesting to determine how the development of the glymphatic and lymphatic systems are coordinated as these two systems appear to cooperate to drain neural ISF, first to the CSF and then to the dcLNs. The absence of an extended mLV network before birth brings up interesting questions regarding how brain homeostasis is regulated in embryonic periods. First, how is ISF recycled and debris cleared from the CNS before the establishment of the mLV network? There could be either an absence of clearance function or perhaps other mechanisms are in place before the development of the mLVs. Several other mechanisms of CSF drainage have been identified, including via arachnoid granulations and along the olfactory bulb to be drained by the nasal mucosal LVs. Understanding how these different drainage systems are coordinated is critical for understanding how CNS fluid balance is maintained during development and how this can be lost in children with hydrocephalus. Second, is CNS immunity regulated differently before and after the establishment of the mLV network? The lack of mLVs in em-