Adaptation is one of the core characteristics of living organisms, wherever it refers to proximate adjustments at individual level to inner or outer events, or to ultimate evolutionary processes at species-level. Biology and medicine have for a long time considered the non-specific symptoms of sickness (i.e. drowsiness, hypophagia, curled-up posture, fever) as signs of general debilitation caused by pathogens and temporary inability to adapt to environmental demands.
But as emphasized by Theodosius Dobzhansky, “nothing in biology makes sense except in the light of evolution” . Considering that living organisms have always lived surrounded by pathogenic microorganisms and will continue to do so, it has been proposed that non-specific symptoms of infection and inflammation could represent specific forms of adaptation to the presence of systemic protozoa, bacteria or viruses [2-6].
Indeed, throughout their evolutionary history, all species have been exposed to, and have successfully resisted the noxious effects of various invading micro-organisms. Thus, in the evolutionary ‘arm-race’, microorganisms have acted as potent selective pressures that have selected animal organisms over millennia on their basis to fight and adapt to infection, while micro-organisms were reciprocally selected on the basis of a hosts’ resistance capabilities [7, 8]. Several studies have pointed out the emergence of immune strategies in mammals in order to fight infection [9, 10]. Moreover, an extensive set of data reveal the dense cross-talk between neuroendocrine and immune systems and supports the evolution of non-immune (e.g. behavioral) defensive strategies against pathogens.
During the last decade, the results of various neuro-immune and behavioral studies have established the behavioral symptoms of infection (i.e. drowsiness, hypophagia, curled-up posture, fever) as defensive behavioral processes supporting immune and physiological responses to pathogens (see Figure 1). It has been demonstrated that these specific defensive behaviors (i.e. sickness behavior) are triggered through the action of pro-inflammatory cytokines on the brain, and reflect the onset of a motivational reorganization, specifically devoted to counter the pathogenic micro-organisms, while preserving behavioral flexibility . This behavioral flexibility is one of the core characteristics of motivational systems and ensures the possibility to interrupt the sickness defensive sequence to engage in other specific defensive responses in response to external threats (i.e. predator, competing conspecifics, etc). Such motivational and behavioral dynamics illustrate the close interactions between stress, emotions and immunity.
Figure 1. Relation between pathogen load/virulence and the intensity of behavioral support to immune and physiological processes For low pathogen loads, immune and physiological responses are sufficient to fight infection. For higher loads, behavioral homeostasis takes place and sickness behaviors are expressed to facilitate pathogen’s clearance.
Influence of immunity on stress and emotional processes
During the past decades, various studies have pointed-out a possible relationship between stress, depression and cytokines. For instance, a positive correlation has been observed between the onset of an infection and a temporary depressive-like episode [11-14]. Moreover, a chronic activation of the cytokine network, as in multiple sclerosis or rheumatoid arthritis, has also been correlated with a depressive mood . Finally, the intensity of post-partum depression has been correlated with the increased liberation of cytokines at childbirth . Such findings inspired the neuroimmune hypothesis of depression as resulting from an over-expression of cytokines [17-20]. Further studies showed that the administration of cytokines such as interleukin (IL)-2 or interferon (IFN) induces depressive symptoms in cancer patients [21, 22]. Moreover, the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which is a common response to a systemic increase in cytokines, is also observed during depressive episodes [21, 23]. Experimental studies in animal models support these findings. Depressive-like symptoms in animals are mostly assessed through anhedonic responses (i.e. the incapacity to experience pleasure), estimated by the decreased level of stimulating potency of positive reinforcers. For example, the administration of cytokines such as IL-1 or the potent cytokine inducer lipopolysaccharide (LPS) has been found to induce such anhedonic effects in rats or mice by decreasing intake of palatable fluid solutions (e.g. sweetened water or milk) [19, 24]. However, some studies showed that these effects were blocked by a chronic antidepressant treatment  but not others .
As hedonism in animals is assessed through preference and/or consumption of sweet solutions, taste reactivity in freely-drinking animals has been used to overcome possible biases due to the effect of cytokines on food and fluid intake. The taste reactivity is assessed through specific orofacial patterns that represent the expression of an emotional response (i.e. hedonic vs. aversive) to the sampled food or fluid. In such a paradigm, rats or mice express specific hedonic responses to palatable sweet solutions, whereas they produce aversive expressions in response to bitter tastes. It has been shown that reactivity patterns to quinine and sucrose were unaltered by LPS treatment in rats (250 µg/kg, i.p.), for both threshold and standard concentrations . Confirming results were reported where LPS treatment in rats (200 µg/kg, i.p.) did not alter the palatability of a sucrose solution infused intra-orally .
However, LPS treatment modified the reactivity pattern to saccharin: LPS-treated rats displayed less hedonic and more aversive responses to a standard concentration of saccharin (5 mM) compared to controls [26, 28, 29]. At a threshold concentration of saccharin, LPS- and saline-injected animals did not differ from each other [26, 28, 29]. Interestingly, saccharin (contrary to sucrose) is known to exert bitter-like taste properties . Thus, while these results support some consistent relationships between systemic cytokine levels and sensory pleasure, they specify the immune-to-emotion relation in favor of an increased finickiness rather than anhedonia per se. More specifically, LPS-induced changes in taste reactivity to saccharin can be interpreted as alliesthesia (i.e. the change in the valence of a given stimulus according to physiological changes) . In this case, an appetitive concentration of saccharin would be submitted to a negative alliesthesia process in LPS-treated subjects, resulting in an increase in its aversive properties and a decrease in its hedonic aspects. This hypothesis was confirmed by a series of taste-reactivity tests in rats submitted to an increasing concentration of quinine added to an appetitive concentration of sucrose. As predicted, the greater the quinine concentration, the greater was the shift from appetitive to aversive reactions, but this shift appeared earlier in LPS-treated animals .
These emotion-based behavioral changes illustrate a form of adaptation to the presence of pathogen. Indeed, the taste of a nutrient reliably reveals its composition, and the taste response patterns species have been shaped by their dietary evolutionary history. For example, the sweet taste of a ‘natural’ nutrient correlates with its caloric density, whereas its bitter taste signals its potential toxicity. Thus, sugars prevalent in fruits, are potent oral appetitive stimuli for omnivores such as rodents. In contrast, bitter-eliciting alkaloids found in plants are potent aversive stimuli for rodents. The spontaneous attraction for sweet nutrients and aversion of bitter food in rats therefore has adaptive value and shaped species-specific food preferences. The upholding of the aversive response to quinine in LPS-treated rats suggests that sick animals keep their full capabilities to reject potentially toxic food. Moreover, the upholding of the hedonic response to sucrose in cytokine treated animals suggests that sick animals can continue to ingest high-benefit food. However, since saccharin has mixed gustatory properties (i.e. a mixture of sweet- and quinine-like properties), the negative alliesthesia (i.e. increased finickiness) occurring for a standard appetitive concentration of saccharin in LPS-treated rats, corresponds to an increased sensitivity of these animals to the aversive component of saccharin and a decreased responsiveness to its hedonic component. This suggests a decreased rejection threshold, preventing sick animals from absorbing any toxic compound that, although normally tolerated in healthy animals, could compete with the health-restoring processes in sick animals .
As these cytokine-related changes in finickiness signal modification in emotional processes (pleasure vs. displeasure) occurring along an immune challenge, they call for further studies extending the investigation of immune-to-emotion relationships in different behavioral areas.
The forced-swimming test (FST) is a classical experimental procedure to investigate behavioral reactivity of rodents and assess antidepressant properties of chemical compounds. In this test, rodents, forced to swim in a narrow inescapable tank of water in a first test session, will develop later a characteristic immobility that has been argued to represent ‘behavioral despair’ , which is usually regarded as a depressive-like symptom since this, it has been reversed by a wide range of clinically active antidepressant drugs. The effects of cytokines on FST have been investigated and provided initially contradictory results. For example, data obtained after administration of IL-1 reported an increase in depressive-like behavior in one case, and a decrease in another .
The behavioral consequences of a LPS treatment in the FST was further investigated and showed that when administered prior to the first exposure, LPS did not induce differences in treated rats compared to controls, regarding durations of immobility, climbing or swimming . These results contrast with previous findings in mice in which the injection of human IFN increased immobility in a single session test . However, the full behavioral investigation of mice submitted to a two-session FST revealed that LPS treated mice increase their defensive behaviors (i.e. climbing, swimming) during the first exposition while decreasing them in the second session occurring 24h later (higher immobility time) . Moreover, a sub-chronic treatment with a tricyclic antidepressant (imipramine) blocked the enhancement of active defensive behaviors during the first exposition in LPS treated group and decreased the ‘behavioral despair’ in the second exposition. This data suggest that the immune activation, through the increased emotional reactivity to the negative features of a given situation (i.e. the aversive exposition to water for mice), would increase defensive motivation of subjects, but on the other hand, increase their vulnerability to the deleterious emotional consequences of failure in defensive strategies (i.e. incapacity to escape) .
Taken together, these results suggest that cytokine-induced sickness would potentiate the reactivity of subjects to negative features of a specific stimulus or situation. In humans several findings relate such negative changes in mood with transient respiratory tract infections. For instance, it has been shown that infection with the influenza virus is associated with more negative mood and increased irascibility .
Such hyper-reactivity could be interpreted in terms of motivational changes, triggering increased defensive behaviors to a potential or actual threat. However, the higher emotional response that was elicited by the threat would imply more severe consequences in the case of a failure to cope with the situation. On one hand, higher emotional reactivity of cytokine-treated subjects increases their defensive motivation (and therefore promotes their immediate survival skills), but on the other hand, it makes them more vulnerable to the deleterious emotional consequences of a failure (see Figure 2).
Figure 2. When a subject is challenged by an external threat, the related emotional response supports the expression of adapted stress-related defensive strategies When these strategies are successful (a), threat is reduced and emotion is down-regulated. In case of failure however (b), the threat remains, so as emotional arousal and associated physiological responses, thus facilitating the development of depressive-like disorders. Finally, the shared physiological parameters between inflammation and stress enhance emotional arousal to an external threat (c), facilitating the expression of defensive repertoire, but also facilitating the development of depressive-like symptoms in case of failure .
A mechanism called ‘excitation transfer’, originally described by Dolf Zillman , could account for these emotional changes occurring along an immune challenge. The excitation transfer consists in the enhancement of the emotional arousal to a stimulus by a previous event that triggers shared physiological parameters. In other words, when a subject is submitted to an external threat, he first evaluates the threat (cognitive process), then develops an emotional response sustained by physiological arousal (activation of the HPA axis for example) and supports the expression of defensive behaviors. For example, it was showed that naïve human subjects taunted with insults in a gymnasium responded more aggressively if the provocation occurred after a sport training session (i.e. after physiological arousal due to physical exercise). However, such a transfer of arousal is non-specific. Thus, contextual and situational factors will determine what these behavioral outcomes will be: sexual, aggressive, or depressive-like .
The possible mechanisms supporting such phenomena could be at least partly understood through the metabolic and physiological consequences of inflammation and its relations with stress responses (see Figure 3). It is now well established that one of the prominent physiological responses to LPS-induced cytokine release is the potent activation of the HPA axis . Not only is LPS-induced sickness known to induce HPA activation, also involved in the physiology of stress , but physiological aspects of inflammation have also been argued to be stress-related . Moreover, it has been demonstrated that a single administration of IL-1 increased CRH and ACTH mRNA in the hypothalamic paraventricular nucleus, paralleling a long-lasting sensitization to novelty stress . Finally, it has been shown that a chronic antidepressant treatment attenuated LPS-induced increased of plasma ACTH and corticosterone in rats .
Therefore, since the HPA axis is one of the core neuroendocrine elements involved in the stress response, it is likely that the LPS-induced potentiation of despair could be physiologically supported by HPA/cytokine interactions. Therefore, in the case of emotion-immunity interactions, peripheral effects of inflammatory cytokines (i.e. endocrine and vegetative changes) would enhance the emotional arousal generated by the stressful situation (e.g. immersion in a water tank), and therefore would increase the behavioral response to the threat through addition of physiological arousals. Consequently, as the defenses and underlying emotional responses are increased, the behavioral and emotional consequences of the failure of subjects’ defensive strategies are increased.
Figure 3. Cross-talk between immune response (response to an internal threat) and stress response (response to an external threat)
Another model, which is commonly used to study the expression of defensive behaviors in laboratory animals following an acute stress, is the response to predator cues. Indeed, predator-prey interactions lead to the development of specific behavioral anti-predatory responses in preys to avoid direct interaction with predators. The detection of the predator comes from the ability of prey species to respond to different kind of cues that underlie different level of threat . The defensive responses of prey species to olfactory cues of predator offer a valuable setting to study the interactions between cytokine-related sickness and emotions. In laboratory rodents, threatening stimuli induce the expression of increased vigilance or risk-assessment behaviors that are displayed in order to provide information about the predator. Contrary to a direct exposition to a freely moving cat, which mainly induces long lasting duration retreat to the nest, exposition to cat odors induces risk-assessment behaviors such as cautious approach/investigation or sensory scanning (visual or olfactive) of the source of the stimulation . Another type of behavior displayed when an animal is exposed to predator cues is an increased use of temporary shelters. In a semi natural environment, small rodents exposed to feline cues increase their use of burrows .
Recently, the main component from mustelids anal gland, known as 2-propylthietane (2-PT), has been experimentally submitted to LPS-treated mice observed in a semi-natural environment consisting in a vast open area with various scattered shelters . Indeed, this sulfur-compound has been shown to reliably induce avoidance responses in rodents  as well as neuroendocrine changes such as HPA activation [49, 50]. Results showed that the acute inflammatory episode induced by LPS injection reduced exploratory behaviors in mice compared to control animals . However, LPS-treated mice expressed higher quantity of species-specific defensive behaviors such as flat back approaches (FPA) and stretched attend postures (SAP) when exposed to the predator odor cues . Moreover, LPS-treated mice stayed longer concealed in shelters before reaching their home-nest compared to control animals.
Further analysis of the spatial behaviors was assessed as well as the different strategies displayed by animals to reach home-nest. The first strategy consists in joining the home-nest area from the open starting point, in a more or less direct single course and without using other concealed places (i.e. shelters). The second strategy consists in reaching the home-nest in several steps, running from a covered shelter to another. In the first strategy, the time exposed in the open area is longer, but the total time spent on the outside is lesser. On the opposite, the second strategy could appear safer as the time spent uncovered is lesser, but the total time to reach the home-nest is longer. Finally, a third alternative strategy is to pick a shelter and stay undercover without reaching the home-nest. In the standard condition (i.e. without predator cues), control and LPS-treated mice displayed identical proportions in individual strategies and animals expressed equally the two first strategies (i.e. reaching the nest in a single course or in several steps) but never the third (abandon the nest). However, when the predator odor was present, LPS-treated animals expressed either the first or the third strategy, i.e. reaching the home-nest in a single run or abandon the nest .
Underlying supporting mechanisms in cytokine-treated mice could be a more salient perception of the threat inducing a stronger emotional response to the stimuli. This increased emotional arousal when the predator odor is present could sustain the expression of an increased vigilance towards the stimulus. This interpretation is confirmed by the expression of a higher rate of risk-assessment behaviors (FBA and SAP) when the sick animals are exposed to the predator cues. Indeed, the relative expression of risk-assessment behaviors have been shown to reflect attention directed towards a threatening stimulus as an information-gathering process . In addition, such predator-oriented behaviors (defensive approaches) are commonly interpreted as anxiety-like behaviors by opposition with actual avoidance of the threatening source reflecting fear (defensive avoidance) . This assumption has been observed in mice in the Mouse Defense Test Battery developed  in which risk assessment behaviors have been compared with specific symptoms displayed in generalized anxiety such as hyper-attentiveness and increased vigilance .
Taken together, these results suggest that cytokine-induced sickness in animals would increase the aversive appraisal of the potential life-threatening cues from their environment resulting in an increase in anxiety-like defensive behaviors. Such results support the hypothesis of a cytokine-induced reinforced emotional arousal supporting the expression of defensive behaviors, but, depending on contextual factors, could also facilitate the development of anxiety-like or depressive-like behaviors.
Psychosocial stress and autoimmune disorders
Any form of immediate threat to a person’s wellbeing is a stressful event triggering a transient response arousing the whole body. Both the sympathetic nervous system and the endocrine systems are involved in this response. The sympathetic nervous system stimulates the adrenal medulla to secrete catecholamines (i.e. adrenaline and noradrenaline). This results in a whole set of phenomena such as an increase in respiration, heart rate, blood pressure and an inhibition of digestive processes. These changes aim to cope with or remove the threat. Once the threat is removed, the parasympathetic nervous system is activated and arousal tapers off over the next 20-60 minutes. Prolonged stress (i.e. chronic stress), however, follows a different route. The hypothalamus produces corticotrophin releasing hormone, which in turn stimulates the pituitary to produce adrenocorticotropin, which then stimulates the adrenal cortex to release stress related corticosteroid hormones, the most important being cortisol. However, corticosteroids have long-lasting effects. Importantly, if stress is prolonged, persistent high levels of these hormones could be detrimental to the body systems, altering immunity and presumably increasing susceptibility to illnesses, including infectious diseases.
A large set of experimental (animal) and clinical (human) studies over the past thirty years have clearly established that a vast array of stressors (ranging from daily hassles to traumatic events) can alter various aspects of the immune response [54, 55]. Table 1 lists the main example of illnesses and diseases linked to emotional responses to stressful events .
Table 1. List of the main illnesses and diseases known to be associated with deleterious relations between emotional/stress responses and immunity .
Stress has been commonly considered as immunosuppressive. However, several studies show that acute, subacute or chronic stresses might suppress cellular immunity but boost humoral immunity. This effect is mediated by a differential effect of stress hormones (i.e. glucocorticoids and catecholamines) on T helper (Th)1/Th2 cells and the production of type 1/type 2 cytokines (i.e. IFN-gamma and IL-12; and IL-4, IL-5, IL-9 and IL-13, respectively for Th1 and Th2 cytokines) . While some cytokines, such as IL-1, TNF-alpha and IL-6 are involved in numerous inflammatory diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease, others are more specific to allergic inflammation. Moreover, Th2 cytokines may play an important role in the pathophysiology of allergic diseases, including asthma [58; 59].
The stress-induced Th2 shift in the Th1-Th2 balance results in the suppression of cellular immunity and the potentiation of humoral immunity. Thyroid autoimmunity offers an example of the relation between Th1-Th2 balance and psychosocial stress. Thyroid autoimmunity is clinically expressed as either Hashimoto’s thyroiditis (HT) or as Grave’s disease (GD). The different phenotypic expression of thyroid autoimmunity is largely dependent on the balance of Th1 versus Th2 immune response. Indeed, a predominantly Th1-mediated immune activity may promote apoptotic pathways on thyroid follicular cells leading to thyroid cell destruction and HT development. Conversely, prevalence of Th2-mediated immune response may induce antigen-specific B lymphocytes to produce anti-TSH receptor antibodies causing GD. As it has been recently emphasized , many lines of evidence from epidemiological and case-control studies suggest an association between stress and GD (Th2 prevalence). On the other hand, there is little information available on the effect of stress on HT (Th1 prevalence), but there is evidence for an increase in postpartum thyroiditis, following the cellular immune suppressive effect of pregnancy.
Whether stress has a causative effect on GD remains elusive. Circumstantial evidence supports the hypothesis that stress may influence the clinical expression of thyroid autoimmunity in susceptible individuals favoring the development of GD by shifting the Th1-Th2 balance away from Th1 and toward Th2. Conversely, recovery from stress may induce a reverse shift from Th2 to Th1, leading to sporadic autoimmune or postpartum thyroiditis, respectively . Furthermore, acute stress might induce pro-inflammatory activities in certain tissues through neural activation of the peripheral corticotropin-releasing hormone–mast cell–histamine axis. Through the above described mechanisms, stress might influence the onset and/or course of infectious, autoimmune/inflammatory, allergic and neoplastic diseases.
Therefore, emotion-immunity relationships appear quite complex, and call for further analyses. Some promising insights are provided from studies addressing the impact of psychosocial stress (and its physiological consequences) upon autoimmune disorders.
In a correlational study, the relation between stress and current disease activity in rheumatoid arthritis was investigated . After controlling for disease severity and stress level in patients, authors found that minor stress accounted for a significant amount of the variance in inflammation level (i.e. subject’s erythrocyte sedimentation rate). Such results suggest that the accumulation of minor stressful life-events would be associated with current disease activity in rheumatoid arthritis. However, data are lacking concerning the effects of a specialized social support on the course of such autoimmune disorders. Several lines of data are nevertheless available concerning the immune effects of emotions in healthy subjects . Indeed, an experimentally-induced emotion is followed, 20-min after its induction, by an increase in the proportion of T cells, whatever the valence of the elicited emotion (i.e. ‘positive’ or ‘negative’). However, positive emotions (e.g. elation, happiness) are rather followed by an increase in lymphocyte proliferative response to phytohemagglutinin, whereas negative emotions (e.g. fear, disgust) are rather marked by a decrease in this proliferative response. Other relevant studies suggest that issues in emotional expression (emotional upregulation) are associated with virus reactivation (herpes-type viruses) probably through a decrease in the T-cell cytotoxic activity .
Among autoimmune disorders, type 1 diabetes and its relations to stress and emotions have been extensively studied. Several studies suggest that psychological stress decreases insulin sensitivity and increases insulin resistance and may hence be important in the development/onset of type 1 diabetes. A recent review pointed out that nine retrospective case-control studies out of ten revealed a positive association between stress and the development/onset of type 1 diabetes in children, adolescents or adults .
In retrospective studies, several disparate environmental factors (including experiences of serious life events) have been proposed as trigger mechanisms for type 1 diabetes or the autoimmune process behind the disease. Psychosocial stress in families may affect children negatively through a link with hormonal levels and nervous signals that in turn influences both the immune system and insulin sensitivity/need. In order to further investigate whether psychological stress (i.e. psychosocial constraints in families) is associated with diabetes-related autoimmunity during infancy, a large study was undertaken (over 4000 children) . Results revealed a very significant association between diabetes-related autoimmunity in children (assessed through type 1 diabetes-associated auto-antibodies toward tyrosine phosphatase and GAD) and several psychosocial factors like high parenting stress, experiences of a serious life event, foreign origin of the mother, and low paternal education, independently from family history of diabetes . Moreover, an association between stress and diabetes-related autoimmunity was found at 1 and 2- 3 years of age in a large epidemiological study of the general population . Hence, the hypothesis that psychological stress may contribute to the induction or development of diabetes-related autoimmunity, presumably through beta cell stress, has gained some strong initial support. It seems much clearer that stress can hurry, manifest type 1 diabetes, although the biological mechanisms are still unknown.
Psychological stress is commonly perceived to play a role in the etiology of cancer. However, the data available in this field of study are quite contradictory, with findings varying from no relations to strong associations .
The relationship between breast cancer and stress has received particular attention. Some studies in women with breast cancer have shown significantly higher rates of this disease among those women who experienced traumatic life events and losses within several years before their diagnosis . The biological explanation of this association might be that stress perturbs various arms of the immune system predisposing to neoplasia.
Although studies have shown that stress factors (such as death of a spouse, social isolation, and medical school examinations) alter the functioning of immune system, they have not provided clear scientific evidence of a direct cause-and-effect relationship between these immune system changes and the development of cancer. A major study suggests that there is no important association between stressful life events, such as the death of a loved one or divorce, and breast cancer risk . However, more recent studies have investigated the relationship between stress at initial cancer diagnosis and treatment and subsequent quality of life, and found that stress predicted both psychological and physical quality of life .
The role of stress in the etiology of breast cancer has been of considerable interest, partly because stress affects the hormonal system, and especially estrogen synthesis . The risk of breast cancer associated with acute stress has been well reported, however, less emphasis has been given to the effect of perceived daily stress . Prolonged low key stress of everyday life results in a persistent activation of stress hormones, which may impair estrogen synthesis, leading to a lower risk of breast cancer. A recent very large study in the Copenhagen City investigated the impact of everyday stress on the incidence of primary breast cancer among more than 6600 women followed up for a period of nearly twenty years . The women subjects were asked about their perceived level of stress at baseline in 1981-1983. These women were followed until 1999 in the Danish nationwide cancer registry, with < 0.1% loss to follow-up. Authors found that higher self-reported everyday stress was associated with lower risk of breast cancer . Indeed, during follow-up, 251 women were diagnosed with breast cancer.
After adjustment for confounders, women with high levels of stress had a hazard ratio of 0.60 for breast cancer compared with women with low levels of stress. Furthermore, for each increase in stress level on a six point stress scale an 8% lower risk of primary breast cancer was found. This association seemed to be stable over time and was particularly pronounced in women receiving hormone therapy. High endogenous concentrations of estrogen are a known risk factor for breast cancer, and impairment of estrogen synthesis induced by chronic stress may explain a lower incidence of breast cancer in women with high stress.
Impairment of normal body function should not, however, be considered a healthy response, and the cumulative health consequences of stress may be disadvantageous. If this large study is in agreement with other studies revealing an association between self-reported stress, or adapted coping strategies, and a lower incidence of breast cancer , these results are at odds with other studies [71, 74] in which psychosocial stress was associated with a higher incidence of breast cancer. The reasons for these discrepancies remain unclear. Psychological adjustment to stressful events (i.e. coping strategies) could account for these discrepancies. Moreover, it is also possible that HPA-axis dysregulation induced by prolonged stressful events would ultimately decrease estrogen synthesis . Consequently, it is hypothesized that this stress induced suppression of estrogen secretion could explain the reduced risk of breast cancer.
Finally, it has been shown that psychological stress alters the outcome of chemotherapy in cancer patients; the more the subjects are submitted to chronic stress, the less efficient is the chemotherapy . Experimentally, it has been shown that the anti-tumor effects of chemotherapeutic drugs are decreased in a murine tumor models when animals are submitted to repeated stressful stimulations [76, 77]. Further studies are needed to understand whether psychosocial stress impairs chemotherapy by acting either on the host’s anti-tumor processes or on the biology of cancer cells.
So far, hundreds of studies over the past thirty years have established strong link between stress, emotions and immune system, even if discrepancies remain between results.
Immune and emotional/stress responses constitute evolved adaptive defensive processes that share common mechanisms. However, further (comparative) studies are needed to understand not only the evolutionary roots of these defensive processes, but also the detailed two-way communication between emotion and immunity.
On the physiopathological side, it has been shown that stress can contribute, in varying extents, to many illnesses and diseases. Additionally, numerous animal studies have clearly shown that a vast array of stressors can alter many aspects of the immune response, much of which is mediated via the hypothalamic–pituitary–adrenal or sympathetic adrenal-medullary axes.
Although some conflicting data exist, the general findings depict that chronic stress contributes to the onset, severity and/or progression of many infectious (e.g. immune response to HIV or viral vaccines), cancer and autoimmune (e.g. diabetes, rheumatoid arthritis) diseases. Recent findings about the crosstalk between neuroendocrine and immune systems, involving catecholamines and steroids, but also cytokines (e.g. IL-1, IL-6, TNF-alpha, IL-2, IFN-gamma) offer new insights to further study and understand the mechanisms underlying such deleterious effects.
Finally, as the role of Th2 cytokines (IL-4, IL-5, IL-9 and IL-13) has been emphasized in several inflammatory and autoimmune disorders, and other cytokines are regularly identified as key-factors for some of them (e.g. IL-21 in cancer), future research should examine the potential relation between these molecules (either direct or indirect) and brain activity. Such findings could constitute valuable discoveries to better understand (and regulate) the influence of stress and emotions on many inflammatory and autoimmune disorders.
A Aubert – INRA URH, 63122 Saint Genès Champanelle, France
Dobzhansky, T. 1964. Biology, Molecular and Organismic. American Zoologist, 4, 443-452.
Hart, BL 1988. Biological basis of the behaviour of sick animals. Neuroscience and Biobehavioral Reviews, 12, 123-137.
Hart, BL. 1990. Behavioral adaptations to pathogens and parasites: five strategies. Neuroscience and Biobehavioral Reviews, 14, 273-294.
Dantzer, R., Bluthé, RM., Aubert, A., Goodall, G., Bret-Dibat, JL., Kent, S., Goujon, E., Layé, S., Parnet, P., Kelley, KW. Cytokines actions on behaviour. In: Rothwell NJ, editor. Cytokines in the nervous system. Austin: Landes; 1996
Maier, SF., Watkins, LR. 1999. Bidirectional communication between the brain and the immune system: implications for behaviour. Animal Behaviour, 57, 751-751.
Aubert, A. 1999. Sickness and behaviour in animals: a motivational perspective. Neuroscience and Biobehavioral Reviews, 23, 1029-1036.
Anderson, RM., May, RM. 1979. Regulation and stability of host parasite population interactions. Journal of Animal Ecology, 47, 219-247.
Dawkins, R., Krebs, JR. 1979. Arms race between and within species. Proceedings of the Royal Society B, 205, 489-511.
Ewald, EW. 1980. Evolutionary biology and the treatment of signs and symptoms of infectious disease. Journal of Theoretical Biology, 86, 169-176.
Templeton, JW., Smith, R., Adams, LG. 1988. Natural disease resistance in domestic animals. Journal of American Veterinary Medicine Association, 1992, 1306-1315.
Brown, GR., Rundell, JR., McManis, SE., Kendall, SN., Zachary, R., Temoshok, L. 1992. Prevalence of psychiatric disorders in early stages of HIV. Psychosomatic Medicine, 54, 588-601.
Greenwood, R. Residual mental disorders after herpes virus infections. In: Kurstak E, Lipowski ZJ, Morozov PV, editors. Viruses, immunity and mental disorders. New York: Plenum Press, 1987, 65-80.
Hendler, N. Infectious mononucleosis and psychiatric disorders. In: Kurstak E, Lipowski ZJ, Morozov PV, editors. Viruses, immunity and mental disorders. New York: Plenum Press, 1987, 81-94.
Meijer, A., Zakay-Rones, Z., Morag, A. 1988. Post-influenzal psychiatric disorders in adolescents. Acta Psychiatrica Scandinavia, 78, 176-181.
Marshal, PS. 1993. Allergy and depression: a neurochemical threshold model of the relation between the illnesses. Psychological Bulletin, 113, 23-43.
Parry, BL. Mood disorders linked to the reproductive cycle in woman. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press, 1995, 1029-1042.
Hall, S., Smith, A. 1996. Investigation of the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance. Physiology and Behavior, 59, 569-577.
Malek-Ahmadi, P. 1996. Neuropsychiatric aspects of cytokines research: an overview. Neuroscience and Biobehavioral Reviews, 20, 359-365.
Yirmiya, R. 1996. Endotoxin produces a depressive-like episode in rats. Brain Research, 711, 163-174.
Kelley, KW, Aubert, A., Dantzer, R. Inflammation and behavior. In: Eco-Immunology. Gregory E. Demas & Randy J. Nelson (eds.) Oxford University Press, 2011.
Maes, M., Sharpé, S., Bosmans, E., Vanderwoude, M., Suy, E., Calabrese, J., Cosnys, P. 1993. Relationships between inteleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Research, 49, 11-27.
Sluzewska, A., Rybakowski, J., Bosmans, E., Sobieska, M., Berghmans, R., Maes, M., Wiktorrowicz, K. 1996. Indicators of immune activation in major depression. Psychiatry Research, 64, 161-167.
Linkowski, P., Mendelwicz, J., LeClerq, R., Brasseur, M., Hubain, P., Golstein, J., Copinschi, G., VanCauter, E. 1985. The 24-hour profile of adrenocorticotropin and cortisol in major depressive illness. Journal of Clinical Endocrinology and Metabolism, 61, 429-438.
Anisman, H., Kokkinidis, L., Borowski, T., Merali, Z. 1998. Differential effects of interleukin (IL)-1b, IL-2 and IL-6 on responding for rewarding lateral hypothalamic stimulation. Brain Research, 779, 177-187.
Dunn, AJ., Swiergiel, AH. 2001. The reductions in sweetened milk intake induced by interleukin-1 and endotoxin are not prevented by chronic antidepressant treatment. Neuroimmunomodulation, 9, 163-169.
Aubert, A., Dantzer, R., 2005. The taste of sickness: Lipopolysaccharide-induced finickiness in rats. Physiology and Behavior, 84, 437-444.
Cross-Mellor, SK., Kent, WD., Ossenkopp, KP., Kavaliers, M. 1999. Differential effects of lipopolysaccharide and cholecystokinin on sucrose intake and palatability. American Journal of Physiology, 277, R705-R715.
Aubert, A. 1998. Cytokines and anhedonia: evidence from animal studies. Eur. Neuropsychopharmacology, 8, S103.
Aubert, A., Dantzer, R. 1998. Effects of lipopolysaccharide on taste reactivity in rats. Neuroimmunomodulation, 5:63.
Dess, NK. 1993. Saccharin’s aversive taste in rats: evidence and implications. Neuroscience and Biobehavioral Reviews, 17, 359-372.
Cabanac, M. 1979. Sensory pleasure. Quarterly Review of Biology, 54, 1-29.
Porsolt, RD., Le Pichon, M., Jalfre, M. 1977. Depression: a new animal model sensitive to antidepressant treatments. Nature, 266, 730-732.
Dunn, A.J., Swiergiel, AH., de Beaurepaire, R. 2005. Cytokines as mediators of depression: what can we learn from animal studies? Neuroscience and Biobehavioral Reviews, 29, 891-909.
Deak, T., Bellamy, C., D’Agostino, L.G., Rosanoff, M., McElderly, N.K., Bordner, K.A. 2005. Behavioral responses during the forced swim test are not affected by anti-inflammatory agents or acute illness induced by lypopolysaccharide. Behavioral Brain Research, 160, 125-134.
Makino, M., Kitano, Y., Hirohashi, M. & Takasuna, K. 1998. Enhancement of immobility in mouse forced swimming test by treatment with human interferon. European Journal of Pharmacology, 356, 1-7.
Renault, J., Aubert, A. 2006. Immunity and emotions: Lipopolysaccharide increases defensive behaviours and potentiates despair in mice. Brain, Behavior, and Immunity, 20, 517-526.
Zillman D. Transfer of excitation in emotional behaviour. In T.J. Cacciopo & R.E. Petty (Eds.) Social psychophysiology: A sourcebook. New-York: Guilford Press. 1983, 215-240.
Berkowitz, L. The experience of anger as a parallel process in the display of impulsive, “angry” aggression. In: Aggression: Theoretical and empirical reviews. Academic Press: Orlando, 1993.
Haddad, J.J., Saadé, N.E., Safieh-Garabedian, B. 2002. Cytokines and neuro-immuno-endocrine interactions: a role for the hypothalamic-pituitary-adrenal revolving axis. Journal of Neuroimmunology, 133, 1-19.
Besedovsky, H.O., Del Rey, A., Klusman, I., Furukawa, H., Monge Arditi, G., Kabiersch, A. 1991. Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. Journal of Steroids Biochemistry and Molecular Biology, 40, 613-618.
Maier SF, Watkins LR. 1998. The role of the vagus nerve in cytokine-to-brain communication. Annals of NY Academy of Science, 840, 1004-1017.
Schmidt, E.D., Aguilera, G., Binnekade, R., Tilders, F.J. 2003. Single administration of interleukin-1 increased corticotropin releasing hormone and corticotropin releasing hormone-receptor mRNA in the hypothalamic paraventricular nucleus which paralleled long-lasting (weeks) sensitization to emotional stressors. Neuroscience, 116, 275-283.
Castanon, N., Konsman, J.P., Médina, C., Chauvet, N., Dantzer, R. 2003. Chronic treatment with the antidepressant tianeptine attenuates lipopolysaccharide-induced Fos expression in the rat paraventricular nucleus and HPA axis activation. Psychoneuroendocrinology, 28, 19-34.
Kavaliers, M., Choleris, E. 1997. Sex differences in N-methyl-D-aspartate involvement in kappa opioid and non-opioid predator-induced analgesia in mice. Brain Research, 768, 30-36.
Blanchard, D.C., Griebel, G., Blanchard, R.J., 2003. The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic. European Journal of Pharmacology, 463, 97-116.
Blanchard, R.J., Yudko, E.B., Rodgers, R.J., Blanchard, D.C., 1993. Defense system psychopharmacology: An ethological approach to the pharmacology of fear and anxiety. Behavioral Brain Research, 58, 155-165.
Renault J., Aubert A. Sickness-induced predatory-risk assessment in mice (Mus musculus domesticus). 29th International Ethological Conference, Budapest, Hungary, 21-27 august 2005.
Coulston, S., Stoddart, D.M., Crump, D.R., 1993. Use of predator odors to protect chick-peas from predation by laboratory and wild mice. Journal of Chemical Ecology, 19, 607-612.
Perrot-Sinal, T.S., Ossenkopp, K.P., Kavaliers, M. 1999. Brief predator odour exposure activates the HPA axis independent of locomotor changes. Neuroreport, 10, 775-780.
Zhang, J.-X., Cao, C., Gao, H., Yang, Z.-S., Sun, L., Zhang, Z.-B., Wang, Z.-W. 2003. Effects of weasel odor on behavior and physiology of two hamster species. Physiology and Behavior, 79, 549-552.
Pinel, J.P.J., Mana, M.J. Adaptative interactions of rats with dangerous inanimate objects: support for a cognitive theory of defensive behavior. In: R.J. Blanchard, P.F.B., D.C. Blanchard and S. Parmigiani (Ed.), Ethoexperimental approaches to the study of behavior. Kluwer Academic Publishers, Dordrecht, 1989, 137-150.
McNaughton, N., Corr, P.J. 2004. A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neuroscience and Biobehavioral Reviews, 28, 285-305.
Blanchard, R.J., Griebel, G., Henrie, J.A., Blanchard, D.C. 1997. Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries. Neuroscience and Biobehavioral Reviews, 21, 783-789.
Kemeny, ME., Schedlowski, M. 2007. Understanding the interaction between psychosocial stress and immune-related diseases: A stepwise progression. Brain, Behavior, and Immunity, 21, 1009-1018.
Coe, C., Laudenslager, ML. 2007. Psychosocial influences on immunity, including effects on immune maturation and senescence. Brain, Behavior, and Immunity, 21, 1000-1008.
Aubert, A. 2008. Psychosocial Stress, Emotions and Cytokine-Related Disorders. Recent Patents in Inflammation & Allergy Drug Discovery, 2, 139-148.
Elenkov, IJ., Chrousos, GP. 1999. Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease. Trends in Endocrinology and Metabolism, 10, 359-368.
Barnes, P. 2001. Th2 cytokines and asthma: an introduction. Respiratory Research, 2, 64-65.
Chen, E., Miller, GE. 2007. Stress and inflammation in exacerbations of asthma. Brain, Behavior, and Immunity, 21, 993-999.
Tsatsoulis, A. 2006. The role of stress in the clinical expression of thyroid autoimmunity. Annals of the NY Academy of Science, 1088, 382-395.
Thomason, BT., Brantley, PJ., Jones, GN., Dyer, HR., Morris, JL. 1992. The relation between stress and disease activity in rheumatoid arthritis. Journal of Behavioral Medicine, 15, 215-220.
Futterman, AD., Kemeny, ME., Shapiro, D. et al. 1994. Immunological and physiological changes associated with induced positive and negative mood. Psychosomatic Medicine, 56, 499-511.
Esterling, BA., Antoni, MH., Kumar, M. et al. 1990. Emotional repression, stress disclosure responses, and Epstein-Barr vital capsid antigen titers. Psychosomatic Medicine, 52, 397-410.
Sepa, A., Ludvigsson, J. 2006. Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation, 13, 301-308.
Sepa, A., Wahlberg, J., Vaarala, O., Frodi, A., Ludvigsson, J. 2005. Psychological stress may induce diabetes-related autoimmunity in infancy. Diabetes Care, 28, 290-295.
Young, CR., Welsh, CJ. 2005. Stress, health and disease. Cell Science Review, 2, 132-159.
Ollonen, P., Lehtonen, J., Eskelinen, M. 2005. Stressful and adverse life experiences in patients with breast symptoms; a prospective case-control study in Kuopio, Finland. Anticancer Research, 25, 531-536.
Roberts, FD., Newcomb, PA., Trentham-Dietz, A., Storer, BE. 1996. Self-Reported Stress and Risk of Breast Cancer. Cancer, 77, 1089-1093.
Golden-Kreutz, DM., Thornton, LM., Wells-Di, GS. et al. 2005. Traumatic stress perceived global stress and life events: Prospectively predicting quality of life in breast cancer patients. Health Psychology, 24, 288-300.
Rivier, C. 1995. Luteinizing-hormone-releasing hormone, gonadotropins, and gonadal steroids in stress. Annals of the NY Academy of Science, 771, 187-191.
Lillber, K., Verkasalo, PK., Kaprio, J., Teppo, L., Helenius, H., Koskevuo, M. 2001. Stress of daily activites and risk of breast cancer: a prospective cohort study in Finland. International Journal of Cancer, 91, 888-893.
Nielsen, NR., Zhang, ZF., Kristensen, TS., Netterstrom, B., Schnohr, P., Gronbaek, M. 2005. Self-reported stress and risk of breast cancer: prospective cohort study. British Medical Journal, 331, 548.
Kroneke, CH., Hankinson, SE., Schernhammer, ES., Colditz ,GA., Kawachi, I., Holmes, MD. 2004. Caregiving stress, endogenous sex steroid hormone levels, and breast cancer incidence. American Journal of Epidemiology, 159, 1019-1027.
Helgesson, O., Cabrera, C., Lapidus, L., Bengtsson, C., Lissner, L. 2003. Self-reported stress levels predict subsequent breast cancer in a cohort of Swedish women. European Journal of Cancer Prevention, 12, 377-381.
Ferin, M. 1999. Clinical review 105: stress and the reproductive cycle. Journal of Clinical Endocrinology and Metabolism, 81, 1768-1774.
Strange, KS., Kerr, LR., Andrews, HN., Emerman, JT., Weinber, J. 2000. Psychosocial stressors and mammary tumor growth: An animal model. Neurotoxicology and Teratology, 22, 89-102.
Zorzet, S., Perissin, L., Rapozzi, V., Giraldi, T. 1998. Restraint stress reduces the antitumor efficacy of cyclophosphamide in tumor-bearing mice. Brain, Behavior, and Immunity, 12, 23-33.
Cover Image Credit: Image by <a href=”https://pixabay.com/users/victoria_borodinova-6314823/?utm_source=link-attribution&utm_medium=referral&utm_campaign=image&utm_content=5336965″>press 👍 and ⭐</a> from <a href=”https://pixabay.com/?utm_source=link-attribution&utm_medium=referral&utm_campaign=image&utm_content=5336965″>Pixabay</a>
Before you go…
Please consider helping us secure the growth of BrainImmune – the only resource that delivers up to date information into the broad interdisciplinary area of neuroendocrine-immunology and stress-immune interactions – and their impact on health and disease. See the list of colleagues & readers that have supported us. Ilia Elenkov, MD, PhD, The Editors, BrainImmune.
We accept donations – via the PayPal button shown below. THANK YOU!