The immune system affects brain and behaviour, especially via the effects of immune cytokines on the central nervous system.(42) Although cytokines are relatively large molecules, some, particularly IL-1, can cross the blood-brain barrier via active transport. IL-1 is also produced in the brain by both microglia, which are macrophages resident in the central nervous system, and astrocytes. Peripheral IL-1 can affect the brain, including its production of cytokines, via stimulation of the vagus afferent fibres. There are cytokine receptors in the brain, including those for IL-1, IL-8, and interferon, on both glial cells and neurones. Cytokines play a role in the development and regeneration of myelin-producing oligodendrocytes. Brain cytokines play a role in immune effector mechanisms as regulated by the brain, including a role in brain infection and inflammation. Cytokines are relevant to the progression of multiple sclerosis, gliomas, HIV-associated dementia, brain injury, and probably Alzheimer's disease. Proinflammatory cytokines, particularly IL-1 and tumour necrosis factor, are responsible for sickness behaviour that includes fever, sleepiness, anorexia, and fatigue. Sickness behaviour is adaptive. Microbes grow less well at high body temperature, which also is immunostimulatory. Production of IL-1 is facilitated by slow-wave sleep. Low blood sugar 'starves' bacteria. Fatigue conserves energy for battling infection. Not 'listening to the body', ignoring sensory messages that are immunologically induced, and not modifying behaviour appropriately for illness can adversely affect the course of infection. There is some evidence that chronic fatigue syndrome, which may occur following a viral infection, physical exhaustion, or psychological stress, and which may be accompanied by depression, is related to inappropriate cytokine signalling, as if there were infection, and elevated levels of IL-1 have been reported. (43) Chronic fatigue syndrome is associated with low levels of cortisol, unlike depression where the cortisol level is usually elevated. Evidence of immunosuppression and activation occur in both chronic fatigue syndrome and depression. IL-1 can produce both cognitive defects and lowered pain threshold in animals. Cognitive defects, myalgias, and headaches are often prominent symptoms of chronic fatigue syndrome. Therapeutic use of cytokines, particularly interferon, can produce psychiatric symptoms—psychotic, affective, or anxious.
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