Reciprocal Communication between the Nervous and Immune Systems: Crosstalk, Back-talk and Motivational Speeches

As it is not proper to cure the eyes without the head, nor the head without the body, so neither is it proper to cure the body without the soul.

(Socrates, 400 BCE)

The brain is a privileged organ, which requires protection from both the external world and internal environment of the body to shield it from infectious invasion, toxic insults, and spurious activation or inhibition. Despite its protected status, the central nervous system (CNS) must integrate information from the senses about the external world with an understanding of the internal milieu in order to coordinate behavioural and neuroendocrine responses and ensure optimal functioning and survival. Some information regarding the internal milieu is conveyed by the peripheral nervous system that relays sensory and motor impulses between the CNS and the internal organs, skeletal muscles, and body surface. Since the 1980s, evidence has been accumulating for a bidirectional flow of information between the CNS and the immune system, which can provide additional information about the state of the internal environment.

The immune system repels disease-causing organisms and responds to injury by distinguishing between self and non-self as it monitors the internal milieu. Analogous to the CNS, the immune system is made up of dedicated cells with specialized functions that are capable of establishing a memory of past events and which organize, coordinate and mount a series of specific activities (i.e., immune response) through the use of signalling messengers. For the past two decades there has been a growing appreciation that the immune system can be viewed as a sensory organ that detects pathogens and tissue injury in the internal environment and signals their presence to the CNS during immune activation. An emerging view is that just as it is important for survival that the brain responds to sensory information of an approaching predator with a characteristic neurobehavioral response of fear and arousal, it may also be adaptive to respond to internal evidence of an infection with a characteristic set of neurobehavioral responses that include rest and isolation. What has only recently been appreciated is the extent of the reciprocal regulation that exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The very new implications of this reciprocal regulation for health and disease, specifically as it relates to neuropsychiatric disorders, are the topic of this issue of the International Review of Psychiatry.

Health is life accompanied by silence from the vital organs, etc. A state of health is a subject's unawareness of his body. Inversely, awareness of the body derives from a sense of limits, threats, obstacles to health.

(Leriche, 1939)

The term psychoneuroimmunology (PNI) was first introduced in publication by Ader in [1981] when they applied it to the role of the CNS in the interplay between behaviour and the immune system (Ader et al., [1981]). The term PNI has been used in the public press to suggest a source of scientific support for mind–body therapies for which there is little experimental evidence or rationale. As used here, PNI is the scientific field of study investigating the reciprocal links among the nervous system, the endocrine system, and the immune system, and the implications of these interactions for mental health. Work on this area has evolved over the last 25 years into explorations that focus on three types of interactions between the CNS and the immune system: (1) CNS modulation of immunity; (2) immune modulation of CNS; and (3) bidirectional modulation of CNS and immunity.

During the 1980s, techniques to study the effects of the immune system on the brain were indirect. Work done during that time suggested that stress suppresses the immune response (Fleshner & Laudenslager, [2004]). Acute, short-term stressors, such as tail shock and restraint, were shown in vitro to suppress the activation of lymphocytes in response to mitogen stimulation, and to suppress natural killer cell cytotoxic activity. This was interpreted as evidence that stress was associated with modulation of immune response and increased risk for medical illnesses. Some researchers noted that the in vitro setting was oversimplified because it removed the cells under investigation from their in vivo neuroendocrine context. Also, the lymphocytes tested were from the peripheral blood and not CNS, making conclusions about the effects on the brain indirect. Later work demonstrated that stressors can enhance as well as suppress immune response elements. For example, uncontrollable stressors in rats increase acute phase proteins, interleukin-6 (IL-6), complement function and circulating neutrophils (Fleshner & Laudenslager, [2004]).

One potential way to resolve some of these differences involves a consideration of the temporal profile of the stressors. Whereas acute stress is likely to lead to an activation of a pro-inflammatory response, this response will culminate in hypothalamic–pituitary–adrenal (HPA) axis activation and glucocorticoid production (O’Connor et al., [2003]; Webster et al., [2002]). Glucocorticoids are immunosuppressive, thereby providing a homeostatic regulation of the pro-inflammatory response. With prolonged stress, resistance to the effects of chronically elevated glucocorticoids leads to increased pro-inflammatory response to subsequent stress (O’Connor et al., [2003]). This is consistent with findings from patients with multiple sclerosis where chronic stress leads to increased immune activation as evidenced by brain lesions, whereas acute stress leads to no such increase (Mohr & Pelletier, [2005]).

The 1990s saw the ascendance of the concept of ‘sickness behaviour’. Hart suggested that the symptoms we experience when we are ill (fever, fatigue, increased sleep, loss of appetite, inattention to grooming, and/or depressed affect) are part of an adaptive response of the CNS to signalling from the immune system (Fleshner & Laudenslager, [2004]). Work done in experimental models showed that sick animals exhibit fever, increased sleep, and alterations in the chemical and cellular composition of their blood (Dantzer, [2004]). Hormonally, there is activation of both the HPA axis and sympathetic nervous system. Behaviourally, sick animals show diverse changes, including decreased food and water intake, decreased activity and exploration, and decreased social and sexual behaviour. These behavioural alterations in animals that were infected or made to undergo immune activation in many ways resemble depression.

Mind-cure gives to some of us serenity, moral poise, and happiness, and prevents certain forms of disease as well as science does, or even better in a certain class of persons.

(William James, 1902)

As most, if not all, of these behavioural changes require alterations in brain function, information about infection/inflammation-induced peripheral immune activation must somehow be relayed to the CNS in order for sickness responses to occur. Through mechanisms that are still being fully elucidated, sickness responses primarily reflect de novo synthesis of pro-inflammatory cytokines in the CNS (Watkins & Maier, [2005]). Glia (microglia and astrocytes) are the predominant sources of cytokines, but neurons may contribute as well. Peripheral cytokine activation may signal directly to the brain, stimulating local cytokine production via entry at circumventricular structures or active transport processes across the blood-brain barrier (Webster et al., [2002]). Indirect signalling could be mediated by second messengers generated by binding of cytokines to endothelial cells. Alternatively, vagal nerve afferents have also been implicated in relaying information about inflammation from the periphery to the nucleus tractus solitarius in the CNS (Watkins & Maier, [2005]). In addition to communicating information about the status of the immune system, the vagus nerve can potently modulate peripheral immune reactions through the release of acetylcholine that binds to nicotinic acetylcholine receptors on macrophages and inhibits secretion of tumour necrosis factor alpha (TNF-α) and interleukin-1 (IL-1). In a dramatic demonstration of this potent effect on the peripheral immune response, vagal nerve stimulation can suppress the systemic shock-like response after injection of endotoxin (Tracey, [2002]).

[Psychoneuroimmunology] … has now matured to the point where there is compelling evidence, advanced by scientists from many fields, that an intimate relationship exists between the brain and the immune system … An individual's emotional makeup, and the response to continued stress, may indeed be causative in the many diseases that medicine treats but whose (origin) is not yet known.

(Noel Hershfield, University of Calgary)

The immune and nervous systems maintain extensive bidirectional communication (Marques-Deak et al., [2005]). Neurotransmitters such as acetylcholine modulate immune activity, and neuroendocrine hormones of the HPA axis regulate inflammation. The immune system modulates brain activity, including body temperature, sleep and feeding behaviour, primarily through cytokine signalling. How these bidirectional interactions affect health and disease are only now being explored and appreciated.

This issue commences with a comprehensive primer on the immune system by Kerr et al., with special attention paid to those aspects that relate to the nervous system. Then the role of the immune system in mediating behavioural aspects of eating and sleeping are explored by Asarian and Langhans, who discuss anorexia, and Black, who discusses a potential autoimmune aetiology of narcolepsy. The role of inflammation in modulating mood and causing depression are explored in two articles, one discussing the role of the cytokine interferon-alpha in causing depression in hepatitis C patients (Angelino & Treisman) and the other evaluating evidence supporting a role for cytokines in causing immune-mediated depression (Pucak & Kaplin). Three general neuropsychiatric conditions in which the immune system is potentially implicated are then reviewed: (1) autism (Pardo et al.); (2) Tic/obsessive-compulsive disorder (OCD) (Hoekstra & Minderaa); and (3) Alzheimer's dementia (Rosenberg). Finally, the reciprocal relationship between the immune and nervous systems, whereby stress and depression lead to activation of the HPA axis and immune system impairment resulting in the development and progression of cancer, is discussed by Reiche et al.

In retrospect, it should not have been a surprise to discover that the nervous and immune systems communicate with one another to allow for behavioural responses to inflammation and the regulation of the immune system by external environmental factors that provoke an emotional response. Surprising or not, however, the interface between immunity and the brain is a new area of active investigation that promises to explain some old associations and to guide new avenues of research that may lead to novel treatments in the future. That these findings will relate to neuropsychiatric conditions associated with autoimmune diseases, which affect 5% of the general population, does not require much of a stretch of the imagination (Marrack et al., [2001]). Given the pace of current investigation being focused on this area, what light these findings will shine on the pathogenesis of idiopathic psychiatric conditions, such as depression and OCD, will hopefully soon be visible.

It is known … that passions of the psyche produce changes in the body that are great, evident and manifest to all. On this account … the movements of the psyche … should be kept in balance … and no other regimen should be given precedence.

(Moses Maimonides, 12th century)