The Scientific Journals

By : Esther M. Sternberg and Philip W. Gold

The immune response is an elegant and finely tuned cascade of cellular events aimed at ridding the body of foreign substances, bacteria and viruses.

One of the major discoveries of contemporary immunology is that white blood cells produce small proteins that indirectly coordinate the responses of other parts of the immune system to pathogens. For example, the protein interleukin-1 (IL-1) is made by a type of white blood cell called a monocyte or macrophage. IL-1 stimulates another type of white blood cell, the lymphocyte, to produce interleukin-2 (IL-2), which in turn induces lymphocytes to develop into mature immune cells. Some mature lymphocytes, called plasma cells, make antibodies that fight infection, whereas others, the cytotoxic lymphocytes, kill viruses directly. Other interleukins mediate the activation of immune cells that are involved in allergic reactions.

The interleukins were originally named to reflect what was considered to be their primary function: communication between (“inter-”) the white blood cells (“leukins”). But it is now known that interleukins also act as chemical signals between immune cells and many other types of cells and organs, including parts of the brain, and so a new name—“cytokine”—has been coined. Cytokines are biological molecules that cells use to communicate.  Each cytokine is a distinct protein molecule, encoded by a separate gene, that targets a particular cell type. A cytokine can either stimulate or inhibit a response depending on the presence of other cytokines or other stimuli and the current state of metabolic activity. This flexibility allows the immune system to take the most appropriate actions to stabilize the local cellular environment and to maintain homeostasis.

Cytokines from the body’s immune system can send signals to the brain in several ways. Ordinarily, a  “bloodbrain barrier” shields the central nervous system from potentially dangerous molecules in the bloodstream. During inflammation or illness, however, this barrier becomes more permeable, and cytokines may be carried across into the brain with nutrients from the blood. Certain cytokines, on the other hand, readily pass through at any time. But cytokines do not have to cross the blood-brain barrier to exert their effects. Cytokines made in the lining of blood vessels in the brain can stimulate the release of secondary chemical signals in the brain tissue around the blood vessels.

Cytokines can also signal the brain via direct nerve routes, such as the vagus nerve, which innervates the heart, stomach, small intestine and other organs of the abdominal cavity. Injection of IL-1 into the abdominal cavity activates the nucleus of the tractus solitarius, the principal region of the brain stem for receipt of visceral sensory signals. Cutting the vagus nerve blocks activation of the tractus nucleus by IL-1. Sending signals along nerve routes is the most rapid mechanism—on the order of milliseconds—by which cytokines signal the brain.

Activation of the brain by cytokines from the peripheral parts of the body induces behaviors of the stress response, such as anxiety and cautious avoidance, that keep the affected individual out of harm’s way until full healing occurs. Anyone who has experienced lethargy and excess sleepiness during an illness will recognize this set of characteristic responses as “sickness behavior.”

Hypothalamus-Pituitary-Adrenal (HPA) Axis HPA AXIS is a central component of the brain’s neuroendocrine response to stress. The hypothalamus, when stimulated, secretes corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies blood to the anterior pituitary. CRH stimulates the pituitary (red arrows show stimulatory pathways) to secrete adrenocorticotropin hormone (ACTH) into the bloodstream. ACTH causes the adrenal glands to release cortisol, the classic stress hormone that arouses the body to meet a challenging situation. But cortisol then modulates the stress response (blue arrows indicate inhibitory effects) by acting on the hypothalamus to inhibit the continued release of CRH. Also a potent immunoregulator, cortisol acts on many parts of the immune system to prevent it from overreacting and harming healthy cells and tissue.

Neurons and nonneuronal brain cells also produce cytokines of their own. Cytokines in the brain regulate  nerve cell growth and death, and they also can be recruited by the immune system to stimulate the release of CRH. The IL-1 cytokine system in the brain is currently the best understood—all its components have been identified, including receptors and a naturally occurring antagonist that binds to IL-1 receptors without activating them. The anatomical and cellular locations of this IL-1 circuitry are being mapped out in detail, and this new knowledge will aid researchers in designing drugs that block or enhance the actions of such circuits and the functions they regulate.

Excessive amounts of cytokines in the brain can be toxic to nerves. In genetically engineered mice, transplanted genes that overexpress cytokines produce neurotoxic effects. Some of the neurological symptoms of AIDS in humans also may be caused by overexpression of certain cytokines in the brain. High levels of IL-1 and other cytokines have been found in the brain tissue of patients living with AIDS, concentrated in areas around the giant macrophages that invade the patients’ brain tissue.

Any disruption of communication between the brain and the immune system leads to greater susceptibility to inflammatory disease and, frequently, to increased severity of the immune complications. For instance, animals whose brain-immune communications have been disrupted (through surgery or drugs) are highly liable to lethal complications of inflammatory diseases and infectious diseases.

INTERACTION BRAIN AND IMMUNE SYSTEM Brain and immune system can either stimulate (red arrows) or inhibit (blue arrows) each other. Immune cells produce cytokines (chemical signals) that stimulate the hypothalamus through the bloodstream or via nerves elsewhere in the body. The hormone CRH, produced in the hypothalamus, activates the HPA axis. The release of cortisol tunes down the immune system. CRH, acting on the brain stem, stimulates the sympathetic nervous system, which innervates immune organs and regulates inflammatory responses throughout the body. Disruption of these communications in any way leads to greater susceptibility to disease and immune complications.

Susceptibility to inflammatory disease that is associated with genetically impaired stress response can be found across species—in rats, mice, chickens and, though the evidence is less direct, humans. For instance, the Lewis strain of rat is naturally prone to many inflammatory diseases because of a severe impairment of its HPA axis, which greatly diminishes CRH secretion in response to stress. In contrast, the hyperresponsive HPA-axis in the Fischer strain of rat provides it with a strong resistance to inflammatory disease.

Evidence of a causal link between an impaired stress response and susceptibility to inflammatory disease comes from pharmacological and surgical studies. Pharmacological intervention such as treatment with a drug that blocks cortisol receptors enhances autoimmune inflammatory disease. Injecting low doses of cortisol into disease-susceptible rats enhances their resistance to inflammation. Strong evidence comes from surgical intervention. Removal of the pituitary gland or the adrenal glands from rats that normally are resistant to inflammatory disease renders them highly susceptible. Further proof comes from studies in which the  transplantation of hypothalamic tissue from disease-resistant rats into the brain of susceptible rats dramatically improves their resistance to peripheral inflammation.

These animal studies demonstrate that disruption of the brain’s stress response enhances the body’s response to inflammatory disease, and reconstitution of the stress response reduces susceptibility to inflammation. One implication of these findings is that disruption of the brain-immune communication system by inflammatory, toxic or infectious agents could contribute to some of the variations in the course of the immune system’s inflammatory response.

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