Trends in Immunology
OpinionSpecial Issue: NeuroimmunologyRevisiting the Mechanisms of CNS Immune Privilege
Introduction
The CNS monitors and coordinates internal organ function and responds to changes in the environment. Being an essential system, it needs to be protected from endogenous and exogenous threats. Anatomically the CNS is protected by the CSF and the meninges that surround the brain and the spinal cord. The meninges comprise the pia mater, which intimately covers the parenchyma, a non-vascularized arachnoid mater, and a heavily vascularized dura mater that is attached to the skull. The subarachnoid space lies between the arachnoid and the dura mater and contains the CSF. The CNS is protected from the entry of pathogens, circulating immune cells, and factors within the blood by a physical blood–brain barrier (BBB) jointly maintained by tight junctions between brain endothelial cells, the basal lamina of these cells, and astrocyte endfeet processes (reviewed in 1, 2, 3, 4). Therefore, potentially damaging agents cannot readily gain access to the CNS. However, the meninges are more accessible to and populated by various immune cells (reviewed in 5, 6, 7). Although immune cells patrol the meninges 8, 9, the mechanism by which these cells and antigens from the CNS trigger immune responses has remained unclear.
Experiments in the mid-20th century gave rise to the concept of the brain as a site of immune privilege [10]. Several physiological characteristics of the CNS, in addition to the presence of the BBB, were thought to underlie the slow immune reactions in the brain. For example, there is an absence of professional antigen-presenting cells (APCs) in the brain parenchyma, low MHC class I and II expression, and the apparent absence of classical lymphatic drainage from the CNS, all of which limit the capacity for an immune response to CNS-derived antigens. Despite these physical barriers, interactions between the CNS and the immune system occur and are not limited to pathology but also extend to homeostatic functions. Since the initial studies from the beginning of the last century, substantial progress has been made in our understanding of neuroimmune interactions. It has been demonstrated that: (i) CNS-derived antigens induce an immune response in the deep cervical lymph nodes 11, 12; (ii) the immune response in the CNS has both beneficial and detrimental effects on brain function 13, 14, 15; and (iii) the CNS possesses a functional lymphatic system within the meninges that drains cellular and soluble constituents from the CSF into the deep cervical lymph nodes 16, 17, 18. We discuss these findings here and in this context examine the progression of our understanding of the concept of CNS immune privilege.
Section snippets
Immune Privilege of the CNS
Early studies of tumors 19, 20 or fetal tissue [21] transplanted into the brain parenchyma showed successful growth of heterologous tumors or development of embryonic tissue, suggesting that the brain might be an appropriate transplantation site for the study of embryonic and tumor development. The tolerance of these transplants compared with their rejection in the periphery suggested that the brain was immunologically unique. In the 1940s, Medawar performed seminal experiments where adult
Drainage from the CNS
In addition to blood, the CNS contains CSF and interstitial fluid (ISF). CSF is produced mainly in the ventricles of the brain by the epithelial cells of the choroid plexus and circulates from the lateral ventricles to the third and then the fourth ventricle, finally reaching the subarachnoid space in the meninges. The ISF circulates within the brain parenchyma. Drainage of the two fluids, although connected, supposedly occurs in different ways 25, 26.
In peripheral tissues, circulating ISF is
The Meningeal Lymphatic System
Recent findings have revealed the presence of a conventional and functional lymphatic system that is located in the meninges (in the dura mater) and enables fluid, macromolecules, and immune cells to drain from the CNS into the deep cervical lymph nodes 16, 17 (Figure 2). Dural lymphatics had been previously mentioned in the literature [18] but their role in CSF drainage remained unaddressed. Using both a newly established dissection of mouse meninges [16] and lymphatic cell reporter mice 16, 17
Potential Role of CNS Lymphatics in Health and Disease
Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, where immune cells specific to CNS antigens damage the CNS resulting in paralysis 64, 65, 66, 67, 68, 69, 70, 71, 72, 73. Autoimmune T cells traffic to the brain and cross the BBB and cause damage [74]; thus, preventing T cell migration to the CNS is a therapeutic target. Natalizumab, or Tysabri®, a monoclonal antibody that targets α4β1 integrin (VLA-4) on T cells and prevents their extravasation into the tissue, has
Concluding Remarks
The immune system functions in the CNS in a way that is unique compared with peripheral tissues. Our understanding of immune privilege continues to be refined as new discoveries are made. Originally thought to be immunologically pristine (Outstanding Questions), it is now accepted that immune cells are present in the meninges and provide immune surveillance of the CNS. Likewise, classical lymphatic vessels were discovered in the CNS meninges. The new findings provide a mechanism by which large
Acknowledgments
The authors thank Shirley Smith for editing the manuscript and Anita Impagliazzo for figure artwork. This work was primarily supported by a grant from the National Institute on Aging, National Institutes of Health (AG034113 award to J.K.).
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