Both central and peripheral nervous systems influence immune responses, and immune responses alter nervous system function. The concept of bidirectional interplay of immune and nervous systems has been supported by descriptive studies in experimental animals and humans for many decades, but understanding of mechanisms and functional significance has been improving only recently with the use of technical advances, including single-cell RNA sequencing, intravital multiphoton microscopy, optogenetics, and chemogenetics, among other modalities. Several general concepts supported by new studies have emerged:
• Immune cells can be activated or inhibited by neurons via the release of neurotransmitters and neuropeptides (which are themselves often functionally neurotransmitters) that bind to and act on receptors on immune cells.
• Immune cells can activate or inhibit neuronal functions through the secretion of cytokines and metabolites that bind to receptors on the neurons.
• The nervous system can modify immune responses by local interactions and by long-range reflex mechanisms involving the brain. Immune cells express receptors for several neuropeptides and other neural mediators, which may account for the ability of neural signals to induce or regulate immune responses.
• Lymph nodes, spleen, and mucosal immune tissues are innervated by the autonomic nervous system, mainly by sympathetic catecholamine-releasing neurons, but gut- and lung-associated lymphoid tissue also appear to have para sympathetic innervation.
• In several in vivo models, ablation of components of the brain tissue neuroimmune reflex circuits results in excessive, uncontrolled tissue inflammation. Conversely, stimulation of nerves (e.g., the vagus nerve) can inhibit the secretion of cytokines such as TNF and possibly ameliorate inflammatory diseases.
• Cholinergic and adrenergic signals in the spleen regulate antibody production.
• In the lung, microbes and other local stimuli induce production of neuropeptides that support activation of type 2 innate lymphoid cells and hence type 2 immunity, the basis of allergic diseases.
• The microbiome in the gut stimulates enteric nerves to release signals that induce differentiation of antiinflammatory and tissue-protective macrophages and signals that regulate the balance between proinflammatory Th17 cells and protective Treg cells. Thus, the microbiome uses neural circuits to maintain immune homeostasis in the gut, raising the possibility that abnormalities in this circuit contribute to intestinal inflammation.
• Immune reactions alter neurological and psychological functions. For example, neuronal development is regulated by the complement system and cytokines, and cytokines produced by immune cells may influence cognitive functions such as memory and social behavior. The central nervous system is not strictly an immune privileged site, and immune response to antigens in the brain and spinal cord occur through mechanisms dependent on CSF flow and meningeal lymphatics, as discussed bleow.
Immune Responses in the Brain
Adaptive immune responses to antigens within the brain provide protection against infection but may also mediate pathologic inflammatory disease. Historically, the CNS had been considered to be a site of immune privilege, where adaptive immune responses could not normally take place. This concept was originally based on rodent transplantation studies that showed foreign tissue placed within brain parenchyma was not rejected. A variety of anatomic features supported the idea of CNS immune privilege, including unique features of CNS blood vessels manifest as the blood-brain barrier that limit vascular permeability, actively transport small molecules out of the brain, and limit leukocyte trafficking into the brain. In addition, the brain parenchyma does not contain lymphatics or DCs with antigen-presenting functions, features that are required for initiation of T-cell responses in most other organs in the body. However, for several decades, there has been evidence contradicting stringent CNS immune privilege, including the demonstration that activated T cells do enter the brain and spinal cord, and patients treated with T-cell targeted immunosuppressive drugs are at increased risk for certain viral infections of the brain. More recently, there have been new findings showing that cerebral spinal fluid mixes with CNS interstitial fluid and drains into cervical lymph nodes. Evidence from animal studies indicate that this drainage serves as an immune surveillance function, bringing soluble antigens in the fluid that surrounds brain parenchyma to secondary lymphoid organs, where the antigens can be presented to T and B cells.
The meninges play a major role in promoting and regulating immune responses to brain antigens. The meninges include three layers of connective tissue, the pia adjacent to the brain and spinal cord, the dura adjacent to the skull and vertebrae, and the arachnoid beneath the dura mater; the CSF circulates in the sub arachnoid space between the arachnoid matter and the pia mat ter. Recent studies have revealed the presence of a wide variety of immune cell types in the meninges, most numerous near vessels in the dura, and including B cells, plasma cells, CD4+ and CD8+ T cells, FOXP3+ regulatory T cells, natural killer (NK) cells, NKT cells, monocytes, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, and ILC2s. These meningeal immune cells produce many cytokines, including IFNγ, IL-17, IL-4, and IL-1. In contrast to brain vessels, dural vascular sinuses that drain blood from cerebral veins have a phenotype supportive of leukocyte recruitment into the dural stroma.
Importantly for immune surveillance, brain interstitial fluid and CSF are continuously mixed together in the glial lymphatic (glymphatic) or periarterial drainage systems, and this fluid carries antigens from the brain into dural lymphatics that drain into cervical lymph nodes. Furthermore, CNS antigens in the CSF can be captured by dural dendritic cells, macrophages, and B cells, and can be presented T cells in that location. Although the dura may promote immune tolerance to self antigens in the brain, protective antimicrobial and pathological inflammatory and autoimmune responses may also occur in the meninges.
