Autoimmunity Reviews 5 (2006) 523 527 www.elsevier.

com/locate/autrev

The immune system and happiness

Yoram Barak
Psychogeriatric Department, Abarbanel Mental Health Center, Bat-Yam and the Sackler School of Medicine, Tel-Aviv University, 15 KKL Street, Bat-Yam, Israel Available online 21 March 2006

Abstract Human ability to experience negative and positive emotions has an evolutionary perspective and the presence of feelings designed to influence behavior should thus be reflected in physiological and immune interactions. The complex interactions between the immune system and the central nervous system have been studied extensively in schizophrenia and depression. On the other hand, effects of positive human emotions, especially happiness, on physiological parameters and immunity have received very little attention. Emotions are intimately involved in the initiation or progression of cancer, HIV, cardiovascular disease, and autoimmune disorders. The specific physiological responses induced by pleasant stimuli were recently investigated with the immune and endocrine systems being monitored when pleasant stimuli such as odors and emotional pictures were presented to subjects. The results revealed that an increase in secretory immunoglobulin A and a decrease in salivary cortisol were induced by pleasant emotions. The mechanisms by which positive as opposed to negative states are instantiated in the brain and interact with the immune system are not yet understood. The present review investigates relations among physiological measures of affective style, psychological well-being, and immune function. There is data to support the hypothesis that individuals characterized by a more negative affective style poorly recruit their immune response and may be at risk for illness more so than those with a positive affective style. Future research is needed to expand our knowledge of the physiological and immune interactions of positive emotional states and their beneficial effects on health. 2006 Elsevier B.V. All rights reserved.
Keywords: Happiness; Affective style; Immunity

Contents 1. Introduction . . . . . . . . . . . . 2. Physiology of happiness . . . . . . 3. What affects happiness? . . . . . . 4. Happiness and the immune system. Take-home messages . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 524 525 526 526 526

Corresponding author. Tel./fax: +972 3 5552738. E-mail address: mdybarak@netvision.net.il. 1568-9972/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2006.02.010

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1. Introduction The study of happiness is a relatively new-comer to the field of clinical neuropsychology but has already made some interesting contribution to our understanding of human behavior [1]. The concept of happiness needs rigorous definition prior to embarking on its evolution, physiology and interaction with the immune system. The Webster definition of happiness is as follows: Characterized by good luck; fortunate. Enjoying, showing, or marked by pleasure, satisfaction, or joy. Being especially well-adapted; felicitous. Cheerful; willing. The origin of the modern English term is: Hap meaning fortune, derived in Middle English, from Old Norse: happ [2]. The ability to feel, express and perceive emotions is evolutionary. There is a varied menu of emotions that are designed to influence our behavior and these are linked to physiological and immune reactions probably mediated via the central nervous system (CNS) [3]. Whenever an emotional pattern is influenced by genetic constitution, thereby fulfilling the definition of being innate, it is expected to be intimately involved with other major systems in the human organism. Happiness is influenced by human genetic inheritance as reflected by the cross-cultural universality of concepts describing this state and the general recognition that there is a genetic component to the human mood [4]. There exist two links between life sciences and the study of happiness: a) the evolutionary perspective and b) the neurological approach. The discipline referred to as affective neuroscience [5] focuses on knowledge regarding neurological correlates of emotions, including those that affect happiness. The evolutionary perspective points towards two lines of reasoning: a) the relevance of the environment, and b) the relevance of sensations [6]. In the present review we shall briefly describe the neurological approach only. All mammals have brains capable of experiencing pleasure and thus when offered the opportunity will indulge in stimuli that activate the relevant brain circuits [5]. Humans are unique in that we are able to understand and manipulate situations and our environment in order to both procure large quantities of naturally occurring rewarding stimuli and to create a number of engineered substitutes, such as narcotics, artificial sweeteners, and pornography. However, it must be emphasized that the human CNS is not always in the course of harvesting an overt reward or enduring a punishment. The more tangible feelings occupy the mind for only a fraction of the day. On the other hand, some moods can saturate the day; either in a negative sense such as

anxiety, or a positive sense such as love. Most people however, seem to sense life as being more or less good [7]. In view of these reports the concept of default positive mood (the CNS is designed to offer a positive frame of mind as long as the situation does not dictate otherwise) has been tested and indeed several studies infer that, when basic needs are met, most people enjoy life and are optimistic [8]. Herein we can approach the complex issue of health and happiness. While health is obviously important for happiness, it is more difficult to evaluate to what extent happiness can procure health. The idea that positive mood can offer a biological advantage, has been substantiated by a reported correlation between positive emotions and longevity [9]. In addition, Peterson et al. in 1998 [10] found evidence for an inverse relationship between pessimism and longevity. We have thus to understand the effects of positive emotions on the human organism in order to design environmental, inter-personal and chemical interventions that will enhance our happiness so that our lives are to be of better quality, longer and procreative. Achieving these goals can only be possible if we begin to untangle the complicated physiology and immunology of happiness. 2. Physiology of happiness Emotional responses are components of complex physiologic interactions that affect the body's ability to remain or become healthy or to resist or overcome disease. Health-enhancing and health-impairing behaviors, including diet, exercise, smoking, and protection from exposure to harmful environmental factors can compromise or benefit health. Evidence that biobehavioral factors are linked to health in integrated, complex ways continues to mount, and knowledge of these influences has implications for medical outcomes and health care practice [11]. Experimental evidence is still inconsistent however, the weight of data from studies of health and behavior suggests that emotional states influence the etiology and progression of disease and contribute to overall host resistance or vulnerability to illness. In general, psychosocial or behavioral factors exert their influence on health or illness in three basic ways [12]. The first pathway is of relevance to the present review as it describes the pattern of these influences involving direct biological changes that parallel, precede, are induced by, or occur as part of an emotional reaction. It has been shown that stress involves increases in blood pressure, heart rate, and sympathetic arousal

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and is associated with hematological changes that can contribute directly to heart disease, hypertension, or cardiac events. Whether these immune system changes are strong or prolonged enough to enhance vulnerability to infection or illness is not clear, but they have been implicated in the etiology and progression of viral infections, wound healing, cancer, and HIV disease [13]. But can we infer that positive emotional stimuli and change will beneficially affect our organism? Watanuki and Kim have recently focused in an elegantly designed study on the physiological responses induced by pleasant stimuli [14]. They studied various physiological responses of the CNS, autonomic nervous system, immune system and endocrine system when pleasant stimuli such as odors, emotional pictures and a typical Japanese comical story-telling were presented to subjects. The results revealed that EEG activities of the left frontal cortex were enhanced by a pleasant odor and an increase in secretory immunoglobulin-A and a decrease in salivary cortisol were induced by linguistic pleasant emotion. The different systems involved in the induction of pleasant emotions are evoked by CNS selfstimulation and particularly the reward system. Anatomically the focal brain site closely related to the reward system is the medial forebrain bundle. The amygdala complex displays intricately connected fiber networks that link with the reward system and summate the input and output of this system. Thus, the amygdala acts as the center for integrating pleasant emotions. The amygdala differentiates all modalities of sensory input and discriminates stimuli important for the living system while the hypothalamus plays the role of emotional expression. When corticotrophin releasing hormone is secreted from the hypothalamus, cortisol and catecholamines are then released from the adrenal glands via the pituitary gland, with the former and latter forming the hypothalamuspituitaryadrenal and sympathetic adrenomedullary axes, respectively. Activities of the hypothalamuspituitaryadrenal system can be monitored by the salivary cortisol levels, while those of the sympathetic adrenomedullary system can be evaluated by the cardiovascular responses. As secretory immunoglobulin, a parameter of immune system activity, is closely related with both these systems, its levels should be measured as well. The seminal study by Watanuki and Kim focused on the effects of pleasant emotion induced by olfactory, visual and linguistic stimuli on physiological responses. The authors employed the olfactory stimulus as a direct input to the amygdala while the visual stimulus served as an input for socially related pleasant group stimuli. Finally, the pleasant emotion derived from linguistic inputs was used to test the

physiologic response of this specialized communication skill unique for humans. 3. What affects happiness? However, the CNS is not a closed system and its interaction with environmental variables as well as with biological correlates of well-being is of utmost importance in determining the two-way effects of pleasant emotions. Two types of well-being, eudaimonic and hedonic, have evolved amongst humans. Eudaimonic is primarily a concept of intrapsychic self-development and personal growth while hedonic well-being is concerned with positive feelings such as happiness and contentment. Hedonic well-being shows minimal linkage to biomarkers in contrast to eudaimonic wellbeing [15]. It is conceivable that eudaimonic and not hedonic well-being is directly related to a genetically determined set-point of emotional states while the hedonic expression of emotions is more closely associated with objective social circumstances. This is reflected by the 2001 work of Rowe [12] that discusses the influence of genetic load on mental states of happiness. Happiness is surprisingly immune to objective social circumstances probably due to a biological set-point for happiness rendering the effects of most life events transitory. This biological individuality needs to be considered in any understanding of human behavior, including the pursuit of happiness. In brief, the author's theory is that genes form the recipes for our nervous systems. People with different nervous systems thus have different tastes and preferences creating different circumstances for themselves. There are numerous observations that support this way of conceptualizing human behavior although it must be acknowledged that this is not universally accepted by many researchers in the fields of behavioral sciences. Happiness may be explained through life events. One might assume that a happy person has a big income, owns a second home, is married with two children, is an athlete, and just won $500,000 in a state lottery. We can also imagine that the happy person has outgoing and emotionally warm parents who loved him dearly. Thus, an attribution is commonly made that life events are the cause of a person's levels of happiness. All too frequently and without scientific rigor attributions are made for levels of happiness. However, when we study happiness, as in a recent study of 5000 adults, happiness showed remarkable stability over 10 years. People at the top of the happiness rank order tended to stay at the top; those people at the bottom tended to stay miserable. The set-point of happiness is probably heavily weighted by

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our genetic loading and through our genes we create environments that are appropriately emotionally constructed. 4. Happiness and the immune system The first study in the modern era to focus on the immunological effects of positive emotions was published in 1974 by Solomon and colleagues [16] who described the mechanism through which emotions cause perturbations in the immune system. There is a growing body of data that has accumulated since the early attempts to define the interactions of human mood, affect, emotional states and the immune system. One part of the puzzle researchers are trying to solve deals with humor and optimism as reflecting positive modes of coping and interacting with life events while the second part of this puzzle is approached through the study of affective styles and well-being as representing enduring psychological states rather than transient traits. Studies on immune function in anxiety disorders are sparse, and their findings are also inconsistent. A clinical level of anxiety seems to reduce immune function, whereas a subclinical level of anxiety seems to enhance immunity. The latter may be a transient phenomenon occurring prior to the down-regulation of immune function, reflecting the body's defense to a stressor [17]. In this context of assessing the host's defenses against stress humor was studied. Although the relationship between humor and immune function is an interesting topic, there is limited research available. Salivary IgA concentration is reported to increase significantly after subjects viewed a humorous videotape but did not change significantly after viewing a didactic videotape [18]. Thus, enhancement of the immune system could be one link between anecdotal claims of the relationship between positive emotional state and healing. Further to the study of humor it is accepted by most researchers that optimism may be conceptualized as a buffer against stressor-related changes in the immune system. Recent research proposes that when facing conflicting goals, optimists are more likely to remain engaged with both goals and to experience higher short-term stress as a consequence [19]. Optimists were therefore predicted to fare worse than pessimists immunologically when facing goal conflict but to fare better when not facing goal conflict. Indeed, optimism is associated with higher numbers of CD4+ cells among students who were less likely to have academicsocial conflict and with lower numbers of CD4+ cells among students who were more likely to have conflict. These results are replicated using delayed-

type hypersensitivity testing. Optimists may be subject to short-term physiological costs in their persistence to gain long-term rewards. Further studies have demonstrated that optimism is associated with better mood, higher numbers of helper T cells, and higher natural killer cell cytotoxicity. Among the immune parameters, mood partially accounted for the optimismhelper T cell relationship, and perceived stress partially accounted for the optimismcytotoxicity relationship [20]. Finally, a large scale study was undertaken at the USA based Laboratory for Affective Neuroscience designed to investigate relations among physiological measures of affective style, psychological well-being, and immune function. Negative and positive affects were elicited by using an autobiographical writing task. Electroencephalography and affect-modulated eyeblink startle were used to measure trait and state negative affect. Participants were vaccinated for influenza, and antibody titers after the vaccine were assayed to provide an in vivo measure of immune function. Higher levels of right-prefrontal electroencephalographic activation and greater magnitude of the startle reflex reliably predicted poorer immune response. These data support the hypothesis that individuals characterized by a more negative affective style mount a weaker immune response and therefore may be at greater risk for illness than those with a more positive affective style [21]. Take-home messages Happiness and other positive emotions have been studied in the psychological domain with little data as to its physiology and immune interaction. Emotions are intimately involved in the initiation or progression of cancer, HIV, cardiovascular disease, and autoimmune disorders. Existing data supports the hypothesis that individuals characterized by a more negative affective style poorly recruit their immune response and may be at risk for illness more so than those with a positive affective style. Eudaimonic well-being, addressing ideas of selfdevelopment, personal growth and purposeful engagement is associated with immune biomarkers reflecting a more stable system configuration.

References
[1] Veenhoven R. Advances in understanding happiness. Rev Quebec Psychol 1997;18:2974. [2] http://www.m-w.com/.

Y. Barak / Autoimmunity Reviews 5 (2006) 523527 [3] Spanagel R, Weiss F. The dopamine hypothesis of reward: past and current status. Trends Neurosci 1999;22:5217. [4] Grinde B. Happiness in the perspective of evolutionary psychology. J Happiness Studies 2002;3:33154. [5] Panksepp J. Affective neuroscience. Oxford: Oxford University Press; 1998. [6] Pani L. Is there an evolutionary mismatch between the normal physiology of the human dopaminergic system and current environmental conditions in industrialized countries. Mol Psychiatry 2000;5:46575. [7] Diener E, Lucas RE. Personality and subjective well-being. In: Kahneman D, Diener E, Schwarz N, editors. Well-being: the foundations of hedonistic psychology. New York: Russell Sage Foundation; 1999. [8] Myers DG, Diener E. The pursuit of happiness. Sci Am 1996;5: 546. [9] Danner DD, Snowdon DA, Friesen WV. Positive emotions in early life and longevity: findings from the nun study. J Person Soc Psychol 2001;80:80413. [10] Peterson C, Seligman MEP, Yurko KH, Martin LR, Friedman HS. Catastrophizing and untimely death. Psychol Sci 1998;9: 12730. [11] Baum A, Posluszny DM. Health psychology: mapping biobehavioral contributions to health and illness. Annu Rev Psychol 1999;50:13763. [12] Rowe DC. Do people make environments or do environments make people? Ann NY Acad Sci 2001;935:6274.

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[13] Andersen BL, Kiecolt-Glaser JK, Glaser R. A biobehavioral model of cancer stress and disease course. Am Psychol 1994;49: 389404. [14] Watanuki S, Kim YK. Physiological responses induced by pleasant stimuli. J Physiol Anthropol Appl Human Sci 2005;24: 1358. [15] Ryff CD, Singer BH, Dienberg Love G. Positive health: connecting well-being with biology. Philos Trans R Soc Lond B Biol Sci 2004;359:138394. [16] Solomon GF, Amkraut AA, Kasper P. Immunity, emotions and stress. With special reference to the mechanisms of stress effects on the immune system. Ann Clin Res 1974;6:31322. [17] Koh KB. Emotion and immunity. J Psychosom Res 1998;45: 10715. [18] Dillon KM, Minchoff B, Baker K. Positive emotional state and enhancement of the immune system. Int J Psychiatry Med 1985;15: 137. [19] Segerstrom SC. Optimism, goal conflict, and stressor-related immune change. J Behav Med 2001;24:44167. [20] Segerstrom SC, Taylor SE, Kemeny ME, Fahey JL. Optimism is associated with mood, coping, and immune change in response to stress. J Pers Soc Psychol 1998;74:164655. [21] Rosenkranz MA, Jackson DC, Dalton KM, Dolski I, Ryff CD, Singer BH, et al. Affective style and in vivo immune response: neurobehavioral mechanisms. Proc Natl Acad Sci USA 2003;100:1114852.

ADAMTS13-binding IgG are present in patients with thrombotic thrombocytopenic purpura Antibodies of ADAMTS13 were reported to be found in patients with thrombotic thrombocytopenic purpura (TTP). In this study, Tsai HM. et. al. (Thrombosis 95:886-92) analyzed the ADAMTS13-binding IgG levels in six groups of individuals: normal, random hospitalized patients, acute TTP, TTP after receiving plasma therapy, TTP in remission, and other types of thrombotic microangiopathy (TMA). The results showed that ADAMTS13binding IgG levels were elevated in 100% of the acute TTP group, 75% of the TTP group after receiving plasma therapy, and 40% of the remission group. Overall, the ADAMTS13-binding IgG levels correlated with the inhibitory activity levels against ADAMTS13 (r = -0.69, p b 0.0001). Elevated IgG binding levels were also detected in 5%-15% of the normal, random, and other TMA control groups. Serial measurement in a patient that had two exacerbations of TTP within the first three weeks revealed that the ADAMTS13 activity levels remained elevated, suggesting that ADAMTS13 analysis may provide valuable insight to the disease status, for diagnosis and management of TTP. Abnormal intracellular distribution of NFATI in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features In the immunity of systemic lupus erythematosus (SLE), impaired T cell receptor (TCR) signaling and altered cytokine production are in the center of pathogenesis, although, little is known about NFAT (nuclear factor of activated T cells)in lupus T lymphocytes. TCR stimulation activates NFAT1 through Ca2+/calcineurin (Cn) pathway, facilitating nuclear translocation of NFAT1 from cytosol. Therefore, Fujii Y. et. al. (Clin Immunol 2006; 119: 297-306) investigated relationship of disease activity/ features and intracellular NFAT1 localization in T lymphocytes from active lupus patients by fractionation. Results showed no significant relationship between disease activity and NFAT1 distribution. However, interestingly, we observed skewed NFAT1 distribution in pellet in patients with active lupus nephritis or pleuritis. In vitro cyclosporine A treatment suggested autonomously activated Ca2+/Cn pathway in lupus T lymphocytes. Considering these results, NFAT1 might be presenting the clinical heterogeneity in SLE.