[How does the immune system communicate with the brain?]

It is now evident, that the immune system and the central nervous system (CNS) are functionally connected and interact with one another. The entrance of pathogenic micro-organisms or their products into the body evokes an array of systemic responses, i.e. acute-phase proteinemia, neutrophilic leucocytosis, changes in the circulating levels of various hormones, and fever with specific changes of behaviour. It is now generally recognised that many of these responses are modulated by the brain. Until 1995 it was thought that the transport of immune signals to the brain is mediated by a humoral mechanism, mainly by certain cytokines, produced by activated monocytes and macrophages. The mechanism for the transfer of cytokines through the blood-brain barrier was however not completely understood until recently. It was also not clear, how the fast febrile phase can be signalled within 15 min, if the sequence: external pyrogen-->monocytes-->cytokines-->prostaglandins-->stimulation of the hypothalamus-->fever, requires 40-60 minutes to be activated. In addition to the "classical" humoral mode of transfer, it has recently been proposed that the immune signals are transported to the brain by certain peripheral nerves, predominantly by the vagus. The macrophages of the liver (Kupfer cells) start producing small amounts of cytokines in response to their activation by bacterial lipopolisaccharides, coupled into a complex with the already pre-activated anaphylatoxic component of the complement. These cytokines can immediately activate adjacent sensory paraganglia of the hepatic vagus nerve, which carries these stimuli to the nucleus tractus solitarius, which in turn sends them out to the hypothalamus via the ascending noradrenergic pathways. This fast avenue of communication between the immune system and the brain is activated not only in pathological situations, corresponding to fever, but is an important component of systemic homeostasis, e.g. regulation of body temperature.