Sickness Behavior

The primary illustration of the immune system's, influence on the CNS involves a collection of responses to infection termed sickness behavior. In the early 1960s, researchers examining the activity of various mitogens determined that simple activation of the immune system resulted in a collection of behaviors

Figure 2 Bidirectional communication between the immune system and the brain begins with the activation of macrophages by foreign particles. Activated macrophages secrete various cytokines that stimulate the vagus nerve. The vagus then sends a neural signal to several brain regions, including the nucleus tractus solitarius (NTS) and hypothalamus (H), whose activation leads to symptoms of illness such as fever and loss of appetite. In addition, the activated immune system also triggers activation of the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which results in immunosuppression. IL, interleukin; TNF, tumor necrosis factor.

Figure 2 Bidirectional communication between the immune system and the brain begins with the activation of macrophages by foreign particles. Activated macrophages secrete various cytokines that stimulate the vagus nerve. The vagus then sends a neural signal to several brain regions, including the nucleus tractus solitarius (NTS) and hypothalamus (H), whose activation leads to symptoms of illness such as fever and loss of appetite. In addition, the activated immune system also triggers activation of the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), which results in immunosuppression. IL, interleukin; TNF, tumor necrosis factor.

normally seen in sick animals. In these studies, animals were typically injected with lipopolysaccharide (LPS), a fragment of the cell wall of gram-negative bacteria such as Escherichia coli bacteria. LPS does not cause infection in the animal but, rather, triggers the typical cascade of immune responses to infection. Although the animals were not injected with any disease-causing agent, they still exhibited reduced food consumption and decreased levels of general activity, suggesting that these sickness behaviors were triggered solely in response to immune system activation. However, the mechanism through which an exogenously administered mitogen could trigger this type of response was unknown.

A hint of a possible mechanism was provided by early attempts to treat cancer patients with various cytokine therapies. Cancer researchers searching for therapeutic agents that could elevate immune responses and help to combat the disease examined the efficacy of a variety of cytokines [including IL-1, IL-4, IL-6, IL-12, and tumor necrosis factor (TNF)] in slowing cancer progression. Clinical trials conducted with both healthy and ill individuals demonstrated serious side effects of cytokine administration, such as fever, anorexia, general malaise or depression, irritability, and delirium. Again, these symptoms parallel those seen in illness and suggest that cytokine activation may serve a primary role in initiating these sickness behaviors.

Subsequent research supported this hypothesis and demonstrated that sickness behavior results from an initial cytokine cascade triggered largely by the activation of macrophages. As mentioned earlier, macrophages are cells of the innate immune system which engulf foreign particles that have entered the body and release cytokines upon activation. Cytokines relay the message of immune system activation to the CNS, which evokes a number of changes in behavior designed to mobilize the body's resources to combat infection. These behavioral changes are typically referred to as sickness behavior and consist of depressed levels of general activity, decreased bodily care, reduced consumption of food and water, temperature change (usually fever), and increased sleeping.

The symptoms of sickness behavior are the result of the acute-phase immune response to bacteria, viruses, or other stimuli and thus remain constant despite differences in the particular invading pathogen. The primary function of sickness behavior is to conserve energy by limiting expenditure so that energy reserves may be put into generating fever. Fever is an adaptive symptom because it slows the growth of many pathogens and increases the activity of both nonspecifc and specific immune system processes. Because fever is the result of an increase in the hypothalamic set point for body temperature, the organism is motivated to seek out warm places. Other symptoms of sickness behavior, such as increased sleep and decreased levels of general activity, are designed to conserve energy. In addition, a sick individual also experiences anorexia and adipsia, which may appear counterintuitive, because the individual should be motivated to consume in an effort to increase energy reserves that may be used for fever generation. However, an organism that is foraging for food and water is exposed to predation and is exposing body surfaces to the elements, resulting in a loss of heat that has already been generated. The reduction of foraging efforts during sickness allows the organism to conserve energy by reducing activity and complements other symptoms, such as increased amounts of sleep. Anorexia is also beneficial by reducing iron levels in the blood, which can slow pathogen replication. Although sickness behavior is an unpleasant state for an organism, this pattern of behavior allows for more efficient destruction of pathogens and more speedy recovery. Therefore, sickness behavior represents an evolved strategy designed to limit infection, conserve energy, and promote recovery of the organism.

The primary cytokines that have been implicated in the production of sickness behavior are IL-1a/b and TNF-a. Many other cytokines have been shown to play a role in sickness behavior, but IL-1 has been the most studied due to its discovery as the first endogenous pyrogen. In addition to stimulating fever, IL-1 appears to be primarily involved in producing the reduction in social activities that occur during sickness. However, although individual cytokines appear to serve specific roles in sickness behavior, there is much overlap in their activities, and cytokines have been shown to compensate for each other in triggering certain behaviors. For instance, research has demonstrated that intracerebroventricular injection of an IL-1 receptor antagonist did not alleviate the effects of intraperitoneal (ip) LPS on social behavior. This suggests that other cytokines may have compensated for the absence of IL-1 effects by producing a reduction in social behavior, demonstrating the complex nature of cytokine involvement in triggering sickness behavior following immune system activation.

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