Section Summary

The immune system is broadly divided into innate and adaptive responses. Innate responses are rapid, non-specific, and stereotyped, meaning that they occur in more or less the same pattern and intensity each time a pathogen or antigen is encountered. Adaptive responses are specific to the antigen encountered, ramp up slowly, and build long-term memory for specific pathogens. The immune system uses a diverse army of signaling molecules called cytokines and chemokines to communicate among its distinct cell types, as well as with the nervous and endocrine systems. The brain was once thought to be completely separate from the immune system, but we now know that it has its own resident immune cells- microglia- and likely is more exposed to peripheral immune cells than originally thought.

In the face of acute illness, we have striking changes in our motivation and in our behavior, and these adaptive changes help us prioritize rest and isolation to overcome illness more quickly. These behavior changes are strongly influenced by cytokine signaling to the brain from immune cells responding to infection. In the long-term, however, these changes in sickness or stress-induced behaviors can become maladaptive, and the risk factors underlying this shift from a healthy immune response to a prolonged or pathological one are under intense investigation within the biomedical community.

Despite hundreds of years of prevailing dogma that the brain is “immune privileged”, we now know that the immune, endocrine, and nervous systems communicate via a number of well-defined routes. There is growing evidence that the nervous and immune systems co-evolved to keep us well. Our immune system can “learn”, changing its activity based on associations between environmental stimuli and perturbations in immune function. Cytokines or immune activation in the periphery potently activate the HPA axis leading to catecholamine and stress hormone release, which regulate immune responses. Stressor perception alone is also sufficient to profoundly impact the immune system via this response. The autonomic nervous system directly innervates the tissues of the immune system in the periphery. Immune activation of afferent fibers rapidly signals the brain to activate and mobilize the immune cells in the body via an efferent inflammatory reflex. Soon after, parasympathetic activation and release of anti-inflammatory acetylcholine leads to a tamping down of inflammation and return to homeostasis.

Microglia are specialized macrophages that colonize the developing brain and spinal cord from the fetal yolk sac early in development. They are the primary immune cells of the CNS and thus primary producers of cytokines, chemokines, and other neuromodulatory substances. Microglia were virtually ignored for the vast majority of neuroscience research, but we now know that they play critical roles in synaptic plasticity via actions such as pruning and phagocytosis of neural stem cells in the healthy CNS, in addition to their roles as immune cells. Given that they wear two hats—both building a normal brain and responding to immune activation and other threats to homeostasis—there is intense interest in the possibility that aberrant immune activation by diverse environmental factors or exposures during discrete windows of development and even aging could lead to pathology. These data can hopefully lead to novel treatments or interventions.