Introduction

The idea that a pathway of interaction existed between the brain and the immune system has been suggested for many years. However, only the evidence gathered over the past 25 years has provided important details about the mechanisms. The clues for bidirectional communication early on related to the effects of stress on immune function and that psychological factors could alter the onset and course of autoimmune disease (Ader 1996). A list of selected findings contributing to our understanding is shown in Table 1.1. The classical (Pavlovian) conditioning of host defense mechanisms and antigen-specific immune responses was first suggested and studied in the 1920s (Metal'nikov and Chorine 1926) and later in the 1970s (Ader and Cohen 1975).

A number of years ago, stress was shown to increase the susceptibility of mice to virus infection (Rasmussen, Marsh, and Brill 1957) and lesioning studies of the anterior hypothalamus were shown to be associated with diminished immune reactivity (Cross, Markesbery, Brooks, and Roszman 1980; Stein, Schiavi, and Camerino 1976). Reconstitution of antibody production in hormonally deficient mice was observed after treatment of animals with somatotrophic hormone, thyrotropic hormone, and thyroxin (Pierpaoli, Baroni, Fabris, and Sorkin 1969).

Studies identifying neural receptors on cells of the immune system, and identifying nerve fibers in compartments of lymphoid organs all supported the idea of a dynamic interaction between the immune and nervous system (Besedovsky, delRey, Sorkin, DaPrada, and Keller 1979; Hadden, Hadden, and Middleton 1970; Hadden, Hadden, Middleton, and Good 1971). Later, it was shown that nerve fibers are localized in precise compartments of both primary and secondary lymphoid organs in close contact with T lymphocytes and macrophages (Felten et al. 1987; Williams, Peterson, Shea, Schmedtje, Bauer, and Felten 1981).

In addition, it was shown that the immune system as a consequence of antigenic challenge altered the firing rate of hypothalamic neurons suggesting the bidirectional nature of communication between these two systems (Besedovsky, Sorkin, Keller, and Miller 1977). Supernatant fluids from activated leukocytes could mimic this phenomenon (Besedovsky, delRey, and Sorkin 1981), and it is now clear that a wide range of lymphocyte products influence the synthesis and secretion or release of neuroendocrine hormones and neurotransmitters (Blalock and Smith 1980; Smith and Blalock 1981; Weigent and Blalock 1995).

Table 1.1. Major selected discoveries in bidirectional communication.

Principal finding

References

Classical conditioning of the immune response

Stress increases the susceptibility of mice to virus infection

Lymphocytes have adrenergic receptors that influence immunity

Reconstitution of antibody production in hormonally deficient mice by somatotropic hormone, thyrotropic hormone, and thyroxin

The immune system is subject to classical conditioning

Nervous system is capable of responding to a signal emitted during an immune response

Lesioning of the anterior hypothalamus is associated with diminished immune reactivity

Products of activated cells of the immune system can affect endocrine responses under CNS control

Lymphocytes were discovered to be a source of pituitary hormones

The lymphokine interleukin-1 was demonstrated to induce ACTH production suggesting communication between the CNS and immune system was bidirectional

Nerve fibers are localized in precise compartments of both primary and secondary lymphoid organs in close contact with T lymphocytes and macrophages

A variety of psychosocial events interpreted as being stressful are capable of influencing immunity

Alteration of sleep by infection

Metal'nikov and Chorine 1926 Rasmussen, Jr. et al. 1957 Hadden et al. 1970; Hadden et al. 1971 Pierpaoli et al. 1969

Ader and Cohen 1975 Besedovsky et al. 1977

Stein et al. 1976; Cross et al. 1980

Besedovsky et al. 1981

Blalock 1994; Blalock and Smith 1980; Smith and Blalock 1981

Woloski 1985

Williams et al. 1981; Felten et al. 1987

Glaser et al. 1987

Totl and Krœger llPP

Our studies reviewed, in part, below, initially showed that cells of the immune system could be a source of pituitary hormones and neurotransmitters and that immune-derived cytokines could function as hormones and hypothalamic-releasing factors (Weigent and Blalock 1995; Woloski, Smith, Meyer, Fuller, and Blalock 1985). Thus, it now seems clear that the proposition put forward over 20 years ago that the immune system serves as a sensory organ acting as a "sixth" sense (Blalock

1984) is essentially true. What seems clear is that two pathways link the immune system with the brain. One is the autonomic nervous system activity and the other neuroendocrine outflow from the pituitary. The molecules released are recognized by the immune system via specific cell-surface receptors. In addition, it is clear that activation of the immune system is accompanied by changes in autonomic, hypothalamic, and endocrine processes as well as by changes in behavior (Glaser et al. 1987).

Cytokines influence the activation of the hypothalamic-pituitary-adrenal axis and are influenced by glucocorticoids, depending on their concentration (Berkenbosch, Van Oers, Del Rey, Tilders, and Besedovsky 1987). Thus, the exchange of information between the immune system and the brain is bidirectional (Fig. 1.1). The immune system contributes to the brain's function by serving a sensory role while the brain adopts an immune function by participating in and/or coordinating the immune response.

Collectively, this interaction adds another level of complexity to understanding the influences of behavior including sleep (Toth and Krueger 1988) on immunity and vice versa. This chapter will review studies that describe the pathways for bidirectional communication between the brain and the immune system (Fig. 1.1).

Figure 1.1. Neural and hormonal pathways of bidirectional communication.
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