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The CNS was once thought to be "immune privileged," but this is being challenged as new evidence show that the CNS may play a huge role in the immune system. The CNS regulates the immune system through neuroendocrine pathways and the HPA axis is the most important neuroendocrine pathway. The HPA axis is responsible for modulating inflammatory responses that occur throughout the body.

During an immune response, proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and pass through the blood brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause an individual to have the "sickness behavior," which includes symptoms such as fatigue, depression, and mood changes. The "sickness behavior" is believed to be adaptive and helps prevent system failure. HPA axis activation by the immune system is meant to have a negative feedback and prevent inflammatory and autoimmune diseases. People with allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis have been shown to have a deficient HPA axis.

When the HPA axis is activated by stressors, such as an immune response, high levels of glucocorticoids are released into the body and suppress immune response by inhibiting the expression of proinflammatory cytokines (e.g. IL-1,TNF alpha, and IFN gamma) and increasing the levels of anti-inflammatory cytokines (e.g. IL-4, IL-10, and IL-13) in immune cells, such as monocytes and neutrophils. Glucocorticoids have been used as medication for anti-inflammatory purposes since the 1940s. How glucocorticoids are able to suppress expression of proinflammatory cytokines is still not known. What is known about glucocorticoids is that they enter the plasma membrane of immune cells, act as ligands and bind to cytosolic glucocorticoid receptors (GRs). Upon ligand binding, GRs homodimerize, and translocate to the nucleus of the cells and bind to glucocorticoid-response elements (GREs), directly regulating gene expression. Cytokines are not regulated by these GREs, but potent inhibitors of transcription factors involved such as NF-kB, MAPKs, AP-1, STAT3, and JAK-STAT are believed to be activated by this pathway. Other models suggest that GRs bound to ligands can compete for co-factors with NF-kB or directly inhibit NF-kB.

However, chronic stress can prolong activation of HPA axis and lead to diseases because of immunosuppression. Studies have shown that people with chronic stress have weaker and delayed response to vaccines. Paradoxically, other researches found that chronic stress does not lead to immunosuppression, but to hyper activation of the immune response. A proposed explanation for this is that the HPA becomes exhausted after prolonged activation and is fatigued. Also, GRs become desensitized to GCs and proinflammatory cytokines are increased as a result.