Norman Cousins Lecture
Human psychoneuroimmunology: 20 Years of discovery

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Abstract

An important component of psychoneuroimmunology research is to reveal the myriad ways that behaviors and health are inter-related, with a focus on the immunological mechanisms that underlie these interactions. Research in human psychoneuroimmunology has shown that immunoregulatory processes are an integral part of a complex network of adaptive responses. As such, this review provides a perspective from our laboratory over the last 20 years to define the inter-relationships between behavior and immunity; to identify the hypothalamic pituitary adrenal (HPA) and autonomic mechanisms that link the central nervous system and immune responses; to examine the clinical implications of immune alterations during depression or life stress on inflammatory and infectious disease risk; and to explore the reciprocal role of immune mediators on behavior in humans.

Introduction

Increasing public health attention has focused on the contribution of psychosocial factors, behaviors, and behavioral disorders to chronic disease and health. In two separate reports from the Institute of Medicine, Health and Behavior (IOM, 1982) and Health and Behavior (IOM, 2001), research efforts aimed at understanding the interplay among biological, behavioral, and social factors in health and disease have been identified and integrated. This broad examination of mind–body interactions and health has shown many reciprocal links among the central nervous system, which recognizes and records experiences; the autonomic and neuroendocrine system, which produces neurotransmitters and hormones that govern many bodily functions; and the immune system, which organizes responses to infections and other challenges. Research in the field of psychoneuroimmunology provides an integrative frame across these physiological mechanisms, and brings together the study of these systems to reveal the myriad ways that behaviors and health are inter-related, with a focus on the immunological mechanisms that underlie these interactions. As such, this review provides a 20 years overview from our laboratory to define the inter-relationships between behavior and immunity; to identify the hypothalamic pituitary adrenal (HPA) and autonomic mechanisms that link the central nervous system and immune responses; to examine the clinical implications of immune alterations during depression or life stress on inflammatory and infectious disease risk; and to explore the reciprocal role of immune mediators on behavior in humans.

Section snippets

Documenting immune alterations

The nascent field of human psychoneuroimmunology emerged as interdisciplinary effort to understand the links between brain, behavior, and the immune system, as epidemiologic evidence demonstrate the influence of psychological stress and depression on morbidity and mortality risks. Early studies in animals had found that stress was associated with increased susceptibility to infectious disease (Rasmussen et al., 1957), as well as inflammatory disease (e.g., adjuvant-induced arthritis) (Amkraut

CRH: a central neuropeptide model of stress

Psychological stress serves as an excellent clinical model to learn more about the interactions between the brain and immune system, as stressed patients exhibit prominent abnormalities of behavior (e.g., depressed mood, impaired sleep), along with dysregulation of the neuroendocrine- and sympathetic nervous systems (SNS), which were hypothesized to be key efferent pathways in the regulation of immunity by the brain (Fig. 1). However, as noted above, these initial studies were primarily

HPA effector mechanisms

CRH as a neuropeptide model of stress was also used to probe the links between the central nervous system and the peripheral immune system, and to define physiologically relevant effector mechanisms. Toward this aim, initial studies focused on the release of adrenocorticopic hormone (ACTH) and glucocorticoids following CRH, given that HPA axis activation occurs with stress and in vitro doses of glucocorticoids induce marked declines in cellular and NK immune responses. Whereas footshock stress

Sympathetic effector mechanisms

Noradrenergic innervation of lympoid tissue is well-described, and lymphocytes express β-adrenergic receptors, mainly of the β2 subtype as previously reviewed (Friedman and Irwin, 1997). In vitro studies had further shown that catecholamines and neuropeptide Y (NPY), a sympathetic neurotransmitter that is co-localized with norepinephrine in the sympathetic terminal, are capable of suppressing cellular and natural immune responses at physiologic levels (Friedman et al., 1995). Hence, we examined

Sleep: a salient behavioral mechanism

Sleep is a dynamic behavioral state, which serves a role in the homeostatic regulation of sympathetic and neuroendocrine activity (Fig. 1). In contrast to other behavioral states that rely, for example, on subjective reports, the behavioral dynamics of sleep can be objectively quantified by polysomnography to provide an index of the amount and depth of sleep. Polysomnographic recording of sleep can be further utilized to identify changes in the electroencephalographic (EEG) brain activity

Cardiovascular disease

Measures of subchronic systemic inflammation are implicated as prognostic factors in patients with cardiovascular disease (Volpato et al., 2001). Given evidence that depression can lead to inflammation, it is possible that this is one mechanism that underlies the association between depression and mortality risk in patients with acute coronary syndrome. However, depression and inflammation likely combine in complex ways to influence coronary artery disease. Clinical studies suggest that chronic

Cytokines to behavior

Communication between the brain and the immune system does not flow only from the brain to the immune system, but also from the innate immune system to the brain. An emerging hypothesis generated from the findings of immune activation in depression was that cytokine abnormalities might contribute to depressive symptoms including disordered sleep and fatigue (Dantzer, 2001). Basic research in the neurosciences has shown that proinflammatory cytokines can signal the central nervous system, and

Conclusions

The immune system is highly integrated with other physiological systems. It is sensitive to virtually every hormone, and sympathetic, parasympathetic, and sensory nerves innervate the organs of the immune system. In turn, the nervous, endocrine, and immune systems communicate bidirectionally through common hormones, neuropeptides, and cytokines. Hence, one conceptual theme of this review is that behavioral responses are key in the activation of neuroendocrine and autonomic pathways, which in

Acknowledgments

The author thanks that the contributions of the many colleagues who have made this work possible over the last two decades including Drs. Pike, Weiner, Bloom, Bower, Breen, Britton, Brown, Cole, Davis, Doering, Ehlers, Frasure-Smith, Ganz, Gillin, Grant, Hauger, Hayward, Lavretsky, Lesperance, Levin, Maisel, Martinez-Maza, Mills, Nicassio, Olmstead, Oxman, Rivier, Schuckit, Smith, Vale, Zautra, and Ziegler, as well students and trainees Drs. Caldwell, Cho, Collado-Hidalgo, Cover, Eisenberger,

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