Brain borders at the central stage of neuroimmunology

Abstract

The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.

Figure 1 ‖. Neuro-immune cross talk.

Cells of the central nervous system and immune systems communicate using numerous different signaling molecules. Cells of the immune system primary communicate via cytokine signaling on cytokine receptors but can also secrete and respond to molecules used by the central nervous system including neurotransmitters and neuropeptides. Conversely neurons in the central nervous typically communicate via neurotransmitters and neuropeptides but can also secrete and respond to cytokines via expression of cytokines themselves or cytokine receptors.

Figure 2 ‖. Anatomical sites for neuroimmune interactions at the brain borders.

The brain is surrounded by several distinct anatomical sites in which neuroimmune crosstalk can occur. The meninges represent a triple-layered membranous structure and surround the brain. Overlying the meninges, the skull contains bone marrow that is functionally connected to the meninges and underlying brain. The choroid plexus is situated within the ventricles of the brain. Numerous lymphatic efflux routes exist for the drainage of brain interstitial fluid via the cerebrospinal fluid. Perivascular spaces exist surrounding penetrating brain vasculature that contain cerebrospinal fluid and resident immune cells.

Figure 3 ‖. Meninges and neuroimmune interactions.

The meninges contain diverse immune populations that contribute to neuroimmune responses. Immune cells, including T cells, are situated in the dura mater and leptomeninges and produce cytokines that can signal onto neuronal cytokine receptors to alter firing patterns, alter neuronal connectivity, and control behavioral outcomes. Specialized vasculature in the meninges enables continuous T cell trafficking and interactions with resident antigen presenting cells. CSF continuously has access to the different meningeal layers, enabling T cell responses to brain derived antigens from the meninges allowing them to respond to brain perturbations. Recognition of these brain-derived antigens enables elimination of autoreactive B cells in the meninges to CNS-specific antigens. CSF efflux to the dura mater also enables it to be drained via a lymphatic network that exist in this layer to superficial and deep cervical lymph nodes for additional CNS immune surveillance and removal of CNS waste products.

Figure 4 ‖. Skull bone marrow and neuroimmune interactions.

A large pool of bone marrow is situated at the brain and spinal cord borders in the skull and vertebrae. Via channels that directly connect the bone marrow with the underlying dura mater these two layers are intimately connected. Under homeostasis, immune cells produced in the skull bone marrow, including B cells, monocytes, and neutrophils can utilize these channels to traffic into the dura mater. Under pathological conditions, these cells can further traffic to underlying leptomeninges and the brain and spinal cord parenchyma. These dural channels also allow CSF access to the skull and vertebrae bone marrow. Under homeostasis, CSF-derived ligands shape bone marrow cell phenotypes and under pathological conditions, including sterile injuries and infectious pathogens, inflammatory changes in the CSF alter hematopoiesis in the CNS-associated bone marrow to enhance immune cell production.