Norman Cousins LectureHuman psychoneuroimmunology: 20 Years of discovery
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,
References (76)
- et al.
Depressed lymphocyte function after bereavement
Lancet
(1977) - et al.
Familial cancer, emotional distress, and low natural cytotoxic activity in healthy women
Ann. Oncol.
(1993) - et al.
Psychological risk factors for HIV pathogenesis: mediation by the autonomic nervous system
Biol. Psychiatry
(2003) Cytokine-induced sickness behavior: Where do we stand?
Brain Behav. Immun.
(2001)- et al.
Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes
Biol. Psychiatry
(2007) - et al.
Modulation of immune cell function by the autonomic nervous system
Pharmacol. Ther.
(1997) - et al.
Neuropeptide Y inhibits in vivo specific antibody production in rats
Brain Behav. Immun.
(1995) - et al.
Chronic pulsatile administration of corticotropin releasing hormone into the central nervous system downregulates amygdala CRH receptors and desensitizes splenic natural killer cell responses
Brain Res.
(1993) Effects of sleep and sleep loss on immunity and cytokines
Brain Behav. Immun.
(2002)- et al.
Nocturnal catehcolamines and immune function in insomniacs, depressed patients, and control subjects
Brain Behav. Immun.
(2003)
Plasma cortisol and natural killer cell activity during bereavement
Biol. Psychiatry
Impaired natural killer cell activity during bereavement
Brain Behav. Immun.
Sleep deprivation as a probe of homeostatic sleep regulation in primary alcoholics
Biol. Psychiatry
Benzodiazepines antagonize central corticotropin releasing hormone-induced suppression of natural killer cell activity
Brain Res.
Reduction of immune function in life stress and depression
Biol. Psychiatry
Nocturnal proinflammatory cytokine-associated sleep disturbances in abstinent African American alcoholics
Brain Behav. Immun.
Depressive disorders and immunity: 20 years of progress and discovery
Brain Behav. Immun.
Central corticotropin-releasing factor suppresses natural killer cytotoxicity
Brain Behav. Immun.
Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk
J. Am. Coll. Cardiol.
Dissociation of inflammatory markers and natural killer cell activity in major depressive disorder
Brain Behav. Immun.
Cellular adhesion molecule expression, nocturnal sleep, and partial night sleep deprivation
Brain Behav. Immun.
Central corticotropin releasing hormone reduces cellular immunity
Brain Behav. Immun.
Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial
Lancet
Stress, early experience and adjuvant-induced arthritis in the rat
Psychosom. Med.
Severe herpes virus infections in an adolescent without natural killer cells
N. Engl. J. Med.
Fatigue and proinflammatory cytokine activity in breast cancer survivors
Psychosom. Med.
T-cell homeostasis in breast cancer survivors with persistent fatigue
J. Natl. Cancer Inst.
Impaired response to HAART in HIV-infected individuals with high autonomic nervous system activity
Proc Natl Acad Sci USA
Inflammatory biomarkers for persistent fatigue in breast cancer survivors
Clin. Cancer Res.
Immunity and depression:insomnia,retardation, and reduction of natural killer cell activity
J. Behav. Med.
Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty
Annu. Rev. Med.
Interleukin-6 and tumor necrosis factor-alpha production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways
Psychosom. Med.
Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product
J. Immunol.
Brain corticotropin releasing hormone- and interleukin-1 β-induced suppression of specific antibody production
Endocrin
Neuropeptide Y and natural killer cell activity: findings in depression and Alzheimer caregiver stress
FASEB J.
Major depressive disorder, alcoholism, and reduced natural killer cell cytotoxicity: role of severity of depressive symptoms and alcohol consumption
Arch. Gen. Psychiatry
Cellular immunity to varicella-zoster virus in patients with major depression
J. Infect Dis.
Central corticotropin releasing hormone activates the sympathetic nervous system and reduces immune function: Increased responsivity of the aged rat
Endocrin
Cited by (160)
Mind-body practices in chronic inflammatory arthritis
2024, Joint Bone SpineMind-body practices in chronic inflammatory arthritis
2023, Revue du Rhumatisme (Edition Francaise)Employment and family income in psychological and immune outcomes during bereavement
2023, PsychoneuroendocrinologySocial cohesion and loneliness are associated with the antibody response to COVID-19 vaccination
2022, Brain, Behavior, and Immunity