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REVIEW ARTICLE
Resources, Stress, and Immunity: An Ecological Perspective on Human Psychoneuroimmunology
Suzanne C. Segerstrom, Ph.D.
Published online: 5 June 2010 # The Society of Behavioral Medicine 2010
Abstract Ecological immunology provides a broad theoret- ical perspective on phenotypic plasticity in immunity, that is, changes related to the value of immunity across different situations, including stressful situations. Costs of a maxi- mally efficient immune response may at times outweigh benefits, and some aspects of immunity may be adaptively suppressed. This review provides a basic overview of the tenets of ecological immunology and the energetic costs of immunity and relates them to the literature on stress and immunity. Sickness behavior preserves energy for use by the immune system, acute stress mobilizes “first-line” immune defenders while suppressing more costly responses, and chronic stress may suppress costly responses in order to conserve energy to counteract the resource loss associated with stress. Unexpected relationships between stress “buf- fers” and immune functions demonstrate phenotypic plastic- ity related to resource pursuit or preservation. In conclusion, ecological models may aid in understanding the relationship between stress and immunity.
Keywords Ecology. Optimism . Psychoneuroimmunology.
Sickness behavior. Social . Stress
Introduction
The days of belief that the immune system operates autonomously are over. Demonstrations that the immune system can be classically conditioned, that it is innervated by the sympathetic nervous system, that it responds to hormonal changes, that it has both circadian and circannual
rhythms, and that its changes correlate with changes in psychological states such as emotion have all led to the abandonment of the model of a “shielded” immune system and the development of the field of psychoneuroimmunol- ogy, the study of interrelationships among the mind, nervous system, and immune system [1].
Immune changes that accompany stressful events have perhaps garnered more scientific scrutiny than any other topic in human psychoneuroimmunology. Meta-analytic findings support the principle that psychologically stressful events lasting anywhere from minutes to years associate with changes in the immune system [2]. Ecological immunology provides a broad theoretical perspective on these changes. From the ecological perspective, the well- being of an organism is maintained by efficiently matching biological and behavioral priorities to the demands of the environment. Unlike some other organs, the immune system is necessary for survival mainly when an immuno- logical challenge such as infection is present. In fact, evidence suggests that too much tonic immunological activity can lead to poor long-term health outcomes such as the development of heart disease, Alzheimer’s disease, frailty, and some kinds of cancer [3–5]. Therefore, robust immune activity is undesirable except during immunolog- ical challenge, and prioritizing immune function across all situations may not be adaptive. Specifically, it may not always be the fittest response to prioritize the immune system’s demands for physiological resources1—which can
1 I will use the term “energy” to stand in for these physiological resources so as to avoid confusion with the psychosocial resources that are the focus of the latter half of this review. However, it should be understood that this is a broad use of the term that could encompass not only physiological resources that are literally understood as energy (e.g., glucose, fatty acids) but also other proposed mediators such as proteins that act as transporters for these forms of physiological fuel (e.g., apolipophorin III; [89]).
S. C. Segerstrom (*) Department of Psychology, University of Kentucky, 115 Kastle Hall, Lexington, KY 40506-0044, USA e-mail: [email protected]
ann. behav. med. (2010) 40:114–125 DOI 10.1007/s12160-010-9195-3
be considerable—above other potential demands. Under some circumstances, suppressing immune function below optimal levels in terms of protection against pathogens may actually be to the overall benefit of the organism [6]. An ecological perspective that places the functioning of the immune system in an array of potential uses of energy has the potential to explain the effects of immune activation on motivation and behavior as well as diverse effects of motivation and behavior on immune function in humans.
An ecological perspective is particularly useful in understanding cases in which individual differences that should act as buffers against stress sometimes act as vulnerabilities. For example, epidemiological evidence correlating smaller social networks with increased all- cause mortality supports the idea that social relationships buffer against stress and improve health [7]. There are, however, some unusual and perplexing findings with regard to the effects of social networks on immune function. Larger social networks have associated with poorer cellular immunity in healthy young adults and HIV patients [8, 9]. One study found that the increased risk of upper respiratory infection that accompanies severe life stressors increased further for those people with large social networks [10]. Social relationships are not the only “buffer” to predict worse immunity. Dispositional optimism, the tendency to expect more good events than bad in the future, often predicts better cellular immune function during stressors but almost equally often predicts worse function, usually when stressors are more difficult or severe [11].
The Immune System and Its Energetic Costs
A comprehensive review of the immune system is beyond the scope of this paper; the interested reader is referred to immunology sources (e.g., Refs. [12, 13]) for more detailed discussion of the immune components reviewed below. For the purposes of this paper, it is most important to understand the basic components of the immune system, their functions, and the relative costs associated with those functions [14].
The human immune system is made up of cells and organs that protect the body against foreign invaders as well as traitors within the ranks, that is, some types of cancerous cells. Its first line of defense is the innate immune system, a phylogenetically primitive subgroup of cells such as neutrophils and macrophages that respond to nonspecific signals of invasion such as tissue damage with an equally nonspecific defense, inflammation. Inflammation is pro- moted by proteins called cytokines, which are secreted by these cells. Proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1, and IL-6, promote local responses such as vasodilation and infiltration of
circulating immune cells into the affected tissue, as well as systemic responses such as fever.
Although the inflammatory response is important for early responses to infection, it is inadequate to control most infections to the point of clearing them. A second line of defense, the acquired2 immune system, is required. The acquired immune system comprises groups of cells that respond to specific antigenic stimulation, that is, specific and unique signatures—antigens—expressed or produced by invaders. For example, an antigen might be a viral protein, a component of bacterial cell wall, or a bacterial toxin. The antigen-specific lymphocytes that respond include helper T cells, which release cytokines such as IL- 2, IL-4, IL-5, and IL-10 to activate and direct other immune cells; cytotoxic T cells, which have the capacity to kill compromised cells such as an epithelial cell infected by a virus; and B cells, which produce antibody. Antibody can attach to an invader and either inactivate it or target it for killing by other cells.
Both innate and acquired immunities entail energetic costs. Perhaps the best-recognized cost of innate immunity is fever. It has been recognized for almost a century that increases in body temperature come at metabolic costs, estimated at 7–13% of daily metabolism per degree Celsius [15–17]. The daily metabolic cost for mild (i.e., 1°C) fever is comparable to the metabolic demands of the brain and the heart [16].
In addition to the well-known cost of fever, two other immune functions are particularly energetically costly: protein production and clonal proliferation [18]. Immune responses require cells to produce and secrete various proteins including cytokines, cytotoxic proteins that will effect the death of target cells, and antibody. In vitro, stimulated cells increase oxygen consumption, an index of metabolic rate, for the purpose of protein production by 70% [18]. In vivo, mice vaccinated with a benign antigen to produce antibody increased their metabolic rate by 20–30% in the absence of fever. In general, vaccination results in 15–30% increases in metabolic rate [15, 17]. Protein production therefore entails significant energetic costs.
The costs of clonal proliferation are also significant. The number of antigens for which a responsive T cell exists is estimated in the millions, but there are not enough cells with each antigen specificity present to effectively respond to a challenge. As a consequence, when an antigen is detected, the stimulated cell makes copies of itself, creating an expanded population of cells capable of responding. With regard to the costs of creating these cells, DNA
2 Also known as the adaptive branch of the immune system. The term “acquired” is used here to avoid confusion with the term “adaptive” as implied by evolutionary theory, that is, increasing fitness.
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replication alone increases in vitro oxygen consumption in stimulated immune cells by 17% [18].
In sum, almost every function of immune cells requires energy. As a consequence of the energetic demands of immunity, energy availability significantly impacts immune function. Although more work with humans is needed [19], in animal models, caloric restriction in the diet and reductions in body fat led to reduced expression of genes associated with antigen processing and presentation and antibody-mediated immune responses3, suppression of immune functions, and increased risk of infection (see Refs. [15, 17, 20] for reviews). Experimental surgical removal of body fat from rodents caused them to respond less effectively to vaccine than control animals. If they regained body fat, their response returned to normal [21].
Suppression of costly immune functions is likely to be an adaptive mechanism to preserve energy when it is at a premium. Although it is not ideal to gamble with immunity, it is possible for an organism to do so and survive, particularly if the risk for infection is low and if energy can be diverted to other systems or activities more important to survival. In fact, organisms that fail to gamble immunity may pay an even greater cost. One study activated bumblebee immune systems with a benign antigen, lipopolysaccharide (LPS). Under starvation con- ditions, immune activation significantly shortened survival time compared with control bumblebees. In short, energy used by an activated immune system accelerated time to death from starvation [22].
Ecological Immunology
An evolutionary, ecological perspective on behavior and immunity predicts trade-offs between the costs and benefits of immune activity. The basic principles are as follows (cf., Ref. [23]). Optimal immune responsiveness maximizes the cost/benefit ratio. Circumstances can, of course, change costs and benefits and therefore the optimum for immune activity. Immunity is therefore expected to show “pheno- typic plasticity” or “reaction norms”, that is, variability that occurs when “the value of a trait ... varies in relationship to one or more environmental variables” ([24], p. 1590). Phenotypic plasticity is provided by the organism’s if–then
reaction norms: genetically encoded reactions to the environment that can include changes in behavior and immunity [24]. Reaction norms provide the flexibility to respond to changing environmental circumstances and the reordering of the organism’s priorities.
When an infection is present, the benefit of immune activity increases, so optimal immune responsiveness should increase. Likewise, when the cost of immune activity increases, optimal immune responsiveness should decrease. What are the costs of immunity? One that plays an important role in ecological models is the opportunity cost of the energy used by immune activity, that is, other activities that could be pursued with the energy used by the immune system. For example, maintaining immune func- tion but failing to escape from a predator could impose a very steep opportunity cost. Optimal immune function could decrease in the presence of opportunities as well as threats. Behavioral goal pursuit both demands energy and improves reproductive opportunities, particularly when the goal involves gaining status and resources that could increase one’s value as a mate [25, 26]. When the opportunity to gain such resources presents itself, the opportunity costs of other energetic uses, such as immunity, increase and optimal immune function should decrease, particularly if both energy and resources are limited. The range of situations that fall under the rubric of “stress” may encompass more than one of these circumstances, so any understanding of immunological responses to “stress” needs to consider the potential priorities of the organism in each specific situation. This paper will consider three such situations: infection, acute or “fight or flight” stressors, and chronic stressors. In each case, immunolog- ical adaptations may maximize the cost/benefit ratio.
When Immunity is a Priority: Sickness Behavior
In the face of infection, the best chance of survival comes from making energy available to the immune system. In a practical sense, this means reducing other activities com- peting for that energy. When infection is not a threat, energy is well used by foraging for food, competing for and attracting mates, and forming social bonds, and animals (including humans) are motivated to engage in these activities. When an infection is present, however, motiva- tion and priorities should and do change.
A substantial body of evidence from nonhuman animals demonstrates that when proinflammatory cytokines are stimulated by the injection of LPS or are directly administered, a series of behavioral changes ensues. Affected animals reduce their activity levels and stop exploring their environments, reduce their food intake and grooming, lose interest in investigating new conspecifics in
3 The increases in longevity associated with long-term caloric restriction do not appear to be mediated by improved immunity; in fact, caloric restriction is associated with poorer immunity. Instead, increased expression of tumor suppressor genes points to decreased rates of cancer as the major mechanism by which caloric restriction increases longevity. Increased expression of genes protective against oxidative stress may also play a role in the decreased rates of neurodegenerative disorders and cardiovascular disease observed with caloric restriction [20].
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their environments, decrease sexual receptivity and behav- ior (particularly in females), and increase sleep (particularly non-rapid eye movement sleep) [27, 28]. One consequence of these behavioral changes is less energy expended in motivated behavior to acquire food, friends, and mates, and more energy available to the immune system. Although low motivation to eat may seem to work against the goal of providing energy to the immune system, the energetic costs of foraging may be more consequential during illness, food metabolism may compete with immune function [29], or some combination thereof. Therefore, it may be more efficient to rely on stored energy during illness.
Sickness behavior is observed in humans who have high levels of proinflammatory cytokines either from exogenous administration as medical treatment or endogenous produc- tion as a consequence of infection. Administration of chemotherapeutic cytokines such as interferon-α stimulates the release of endogenous proinflammatory cytokines. A substantial number of patients receiving interferon-α experience moderate to severe symptoms of sickness behavior such as anhedonia, appetite disturbance, sleep disturbance, and especially fatigue [30]. Acute, febrile infections that are characterized by proinflammatory cyto- kine production also produce sickness behavior. Patients infected with pathogens such as Ross River virus, Epstein– Barr virus, or Q fever reported even higher frequency of sickness behavior than patients receiving interferon-α, with over half reporting malaise, loss of appetite, and fatigue, and all reporting anhedonia. Cells from patients with severe symptoms also produced more proinflammatory cytokines in culture than those from patients with mild symptoms, consistent with the experimental evidence linking these cytokines to sickness behavior [31].
At a phenomenological level, these changes may be the consequence of anhedonia, so ordinarily rewarding activi- ties such as eating, socializing, and sex are no longer of interest to the sick individual. Anhedonia had the highest correlation with proinflammatory cytokine production by cells from pathogen-infected patients [31]. This and other studies (e.g., Ref. [32]) suggest that infection decreases appetitive motivations that might otherwise be priorities for the animal, promoting energy-conserving behavior such as sleep and withdrawal [33].
There is evidence that sickness behavior shows pheno- typic plasticity. In this case, the “trait” of sickness behavior varies in relationship to an evolutionarily important situation: threats to young. Mouse dams were injected with LPS. The resulting sickness behavior included deficits in nest-building and time to retrieve pups removed from the nest. However, these deficits were reversed by lowering the ambient temperature [34]. Because mouse pups depend on the nest to regulate their body temperature, their survival is threatened if they are outside the nest when temperatures
drop. Under those circumstances, the dam’s sickness behavior took a back seat to her motivation to protect her offspring (as reflected in renewed alacrity in nest-building and pup-retrieving).
When Survival is a Priority: Fight or Flight
When infection is present or the risk of infection is high, a physiological shift that prioritizes availability of energy for an immune response seems most adaptive. However, some circumstances that pose a high risk of infection also produce competing demands for energy. Such competition occurs during acute stress responses, commonly described as fight-or-flight responses.
The label “fight or flight” describes the behavioral responses available when confronting situations such as predation, storms, fires, or hostile peers, to name a few likely stressors for early humans as well as other animals. Both fighting and fleeing entail significant energetic demand. In order to support this behavior, well-described metabolic and physiological changes occur that support the important actors in fight or flight: the muscles. Sympathetic nervous system activation increases respiratory and heart rates and directs blood to the heart and large muscles. With increasing exertion, blood flow in the muscles increases from 1,200 to 22,000 mm/min. Blood flow in the viscera, however, decreases markedly. Blood flow to the kidney, for example, decreases from 1,100 to 250 mm/min [35]. Sympathetic activation also provides increased fuel to working muscles. Catecholamines mobilize stores of glycogen and triacylglycerol to glucose and fatty acids that can be used by muscles. Activation of the HPA axis and secretion of cortisol also promotes conversion of glycogen to glucose, although cortisol also inhibits the uptake of glucose by muscle [36].
Along with changes in blood flow and metabolism come changes in the immune system. The energetic costs of fighting and fleeing would seem to dictate the opposite pattern from that seen in sickness behavior: energy should be directed away from the immune system and made available to the heart and muscles. On the other hand, this might not be the most ecologically adaptive response because the circumstances that dictate fighting or fleeing also increase risk of infection [2, 37]. Targets of predators or human enemies, if they survive, would be likely to incur scratches, punctures, or bites. Headlong flight from a storm or flood might also involve injury such as scrapes from tree branches. Any wound that breaks the barrier of the skin or allows pathogens entry into the bloodstream is a candidate for infection. Bacteria, for example, are omnipresent in the environment, and most wounds are therefore contaminated by definition [38]. Infections of wounds acquired during
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fight or flight were a common cause of death in ancestral environments [39].
Acute stressors therefore pose a conundrum for the organism. Provide too little energy to the muscles and risk the possibility of death by predation, attack, or natural disaster, or provide too little energy to the immune system and risk the possibility of death by infection. Examination of the kind of immune changes that occur during acute stressors illustrates how this conundrum is solved. A meta- analysis of studies of human participants challenged with acute stressors indicated that there are a number of reliable changes in the immune system during such tasks [2]. These changes are energetically conservative but could provide increased short-term protection against infection incurred during fight or flight.
First, cells and proteins are redistributed. In particular, there is a dramatic increase in the number of neutrophils and natural killer cells in the blood. Neutrophils and natural killer cells have in common their roles as innate first-line defenders. Neutrophils are the first cells to respond to injury or infection in the tissues and initiate further inflammatory responses; natural killer cells contain viral infections until antigen-specific T cell-mediated responses are possible. Therefore, during acute stress, the blood becomes more highly populated with cells that provide first-line defense. It is important to note that there is little evidence that these cells individually become more potent. For example, natural killer cell cytotoxicity on the level of an individual cell does not increase with acute stress [2].
Another potentially important redistribution involves the release of antibody into secretions, particularly saliva. Although the time frame of acute stressors is often too short to permit the de novo synthesis of antibody, preformed antibody is secreted at a faster rate, increasing the density of potentially protective antibody in saliva. Redistribution is perhaps the least energetically costly of immune functions; by loading blood and saliva with first responders, the immune system prepares itself for challenge in an energetically conservative way.
Second, lymphocyte proliferation, particularly among T cells, reliably decreases. Because proliferation is a costly response of antigen-specific cells, it is not relevant to the short-term, nonspecific responses that would be most critical during acute threat of infection. Decreased prolifer- ation during acute stressors could also be due to redistri- bution, since not all T cells have equal proliferative capacity. T cells are capable of a finite number of replications; once that number has been reached, the cells maintain their cytotoxic and cytokine-producing capabili- ties but lose co-stimulatory molecules and the ability to proliferate [40]. One possibility to explain the decrease in T-cell proliferation during acute stress is that these cells are distributed into the blood because they offer potential for
protection without the cost of proliferation. Supporting this possibility, acute exercise differentially mobilized T cells with restricted proliferative ability [41]. This redistribution means that proliferative capabilities in other immune compartments such as lymph nodes might be preserved or even enhanced (as cells with low proliferative ability are distributed out of the lymph nodes into the blood). Compared with blanket suppression of T-cell proliferation, a redistribution of T cells would be more adaptive insofar as it preserves capacity for later antigen-specific responses in immune compartments other than the blood.
Typical “fight or flight” stressors such as predation, storms, fires, or fights, carry with them both the energetic demand of fighting or fleeing (or both) and an increased risk for infection. In this case, humans appear to have adapted by associating acute stressors with immune changes that could potentially provide better first-line defense against infection at a low cost.
When Resources are a Priority: Sacrificing Immunity?
Unlike acute stressors, chronic stressors—those that last from days to years—are not associated with changes in the immune system that could lead to more robust immune responses. Instead, these changes mostly involve decre- ments in immune cell functions including proliferation, cytotoxicity, cytokine production and secretion, and anti- body production. These changes are seen during stressors ranging in both severity and duration from academic examinations to caring for a loved one with dementia. The longer the stressor, the broader the changes, so that stressors that last only a few days are more likely to affect cellular (i.e., killer cell-mediated or Th1 functions), whereas those that last months or years appear to affect both cellular and humoral (i.e., antibody-mediated or Th2) functions [2]. Although acquired immunity appears to decrease during chronic stress, innate immunity—particularly the produc- tion of proinflammatory cytokines—may be increased [42]. One possibility is that innate immunity is being mustered to provide a potentially less costly compensation for decreased acquired immunity; another possibility, considered in more detail later, is that the process of containing acquired immunity results in innate immunity “escaping” from that containment.
The dominant perspective on these changes is that chronic stress perturbs homeostatic mechanisms in the body and results in poorer immune functions in the cellular arm, the humoral arm, or both. When the fight-or-flight response, which was designed to meet short-term energetic demands, is prolonged, undesirable consequences ensue [43]. Changes in the immune system under chronic stress therefore reflect maladaptive, chronic use of a system
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adapted to respond to acute threat and distress. This is a reasonable and useful perspective as evidenced by its influence and longevity in psychoneuroimmunology re- search. However, it is not the only potential explanation and, in fact, more than one mechanism may be acting at once to influence the immune system during chronic stress. From an ecological perspective, immunological changes during chronic stress may reflect a change in priorities in which the pursuit, protection, or restoration of resources becomes more important, and optimal immunity becomes less important.
An Ecological Perspective on Chronic Stress and Immunity
An ecological perspective does not assume that immuno- logical responses to chronic stressors are necessarily maladaptations. Instead, there may be a range of optima in terms of immunocompetence depending on the circum- stances. From this perspective, suppression of costly immune functions such as decreased cytotoxicity or antibody production can be adaptive because immunity is located in an array of potential uses of energy, some of which may be more important to the organism’s long-term well-being, survival, or reproductive capacity. In fact, from an evolutionary perspective, the ultimate measure of an organism’s adaptive quality is not how well it fights infection but how well it transmits genes to the next generation. Fighting infection is important, but not at the cost of reproductive opportunities or protection of off- spring. As an example, Bateman’s principle of life-history strategies states that longevity is more important to females’ fitness, whereas increasing mating rates are more important to males’ fitness. This principle may explain the finding in many species that females have stronger immune responses than males [44].
Resources other than mating opportunities may “trump” immunity. In murine models, pursuing as well as protecting ecologically important social and environmental resources were associated with poorer immunity against experimental parasite exposure. Scent exposure that signaled upcoming competition or a mating opportunity with another mouse increased infection severity and duration [45]. Importantly, olfactory signals of both the need to protect an existing resource (in this case, social dominance protected from another male mouse) and the opportunity to gain a new resource (in this case, mating opportunity gained with a female mouse) were associated with worse immunity against the parasite. Another study randomly assigned group-housed male mice to cages that were or were not equipped with shelves and nestboxes, examining the effects of providing “defendable resources” ([46], p. 1224). Greater parasitic burden and longer infection occurred in mice provided with these environmental resources. There-
fore, phenotypic plasticity in immunity against parasites appears to occur in response to the need to both pursue and protect social and environmental resources.
Decreases in costly immune responses in the service of protecting threatened resources does not necessarily con- tradict usual models of stress, since the “threat” of losing resources could be appraised as stressful and result in immune changes. Such decreases in the service of pursuing possible new resources, however, provoke a broader perspective in which this change takes place as “part of an adaptive mechanism of physiological and behavioural decision-making, rather than as simply an unwelcome incidental cost” ([46], p. 1223).
Human Resources and Ecology
Important human resources overlap significantly with important mouse resources. On the most basic level, humans and mice share with many other organisms their needs for physical energy, the means to replenish that energy (e.g., food), and the ability to protect their physical integrity (e.g., shelter). Among social species, acceptance into a social group can mean sharing food and shelter, as well as providing mutual protection from predators, so social resources facilitate access to basic resources. Finally, within a social group, status can provide more access to food, shelter, and protection. Basic resources, social resources, and status resources all contribute to the ultimate outcome from an evolutionary perspective: representation of one’s genes in subsequent generations.
Resource loss either implicitly or explicitly plays a role in most theories of stress. Stress appraisal models accord a lesser role to resources, predicting that stress occurs only when demands tax or exceed available resources [47]. If one has enough resources to “spend” in compensating for a stressful event, these models propose that it is possible to counteract the demands of stress. However, resource- focused models are more expansive than appraisal models in that they propose that any net resource loss is stressful [48, 49]. Even if resources can be mustered to address the stressor itself, the process of that mustering also creates stress. Such loss may be felt acutely if resources in that domain are already scarce; that is, loss is felt proportion- ately to available resources [48, 50]. This model accounts for some phenomena related to stress, resources, and health.
First, in the realm of status resources, there is a continuous gradient between SES and health [51]. If the protective value of income arose from having enough money available to meet the demands of stressors, there should be a nonlinear relationship between income and health in which the greatest benefit comes with having enough income to counteract common stressors (such as parking tickets) or meet basic needs (such as living in a safe
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neighborhood). Living in a safe, luxurious neighborhood should not provide much benefit above and beyond living in a safe, middle-class neighborhood. The resource model, however, predicts that stressors are felt—albeit differentially—across the income spectrum. At the lower end, a ticket that costs 10% of one’s monthly income is more stressful than one that costs 5%, but likewise, at the upper end, one that costs 0.05% is more stressful than one that costs 0.01%.
Second, in the realm of social relationships, using social resources does not buffer stress as well as having social resources. Available social support is a better predictor of health than received social support [52]; receiving social support alleviates distress only to the extent that the recipient is unaware of it [53]; and providing support to others may be healthier than receiving support from others [54]. One case in which receiving social support does seem to be protective is when the recipient has a high level of available resources [55]; as in the parking ticket example, spending resources is healthier when doing so depletes a smaller proportion of the resource pool. Social resources seem to counteract stress and protect health to the extent that individuals have them rather than spend them. This is consistent with a resource model that proposes that building resources rather than spending them buffers against stressors.
In order to minimize stress, then, humans must expend energy to maintain and pursue their resources. From the perspective of ecological immunology, pursuit of goals and resources reasonably and rationally changes optimum immune function. If chronic stress can be effectively defined as resource loss, immunosuppression under these circumstances might be a mechanism that makes energy available to preserve and renew lost resources.
Resources and Immunity: Evidence That More is Sometimes Less
The basic premise of ecological immunology is that immunity can be reduced in the service of other beneficial uses of energy. In many vertebrates, chronic stressors involve increased energy expenditure, decreased energy sources, or both. During migration, drought, or famine, animals may travel long distances to find scarce food or water sources. Even chronic social conflict may compro- mise an animal’s ability to acquire food, as when a subordinate animal has food taken from it by a dominant animal. These chronically stressful situations involve energy imbalance arising from decreased energy availabil- ity coupled with increased energy demand in trying to find (and keep) food. Under such circumstances, it would be adaptive to cut back on nonessential spending, especially on costly projects such as immunity and reproduction.
Therefore, costly aspects of human immunity might be adaptively suppressed during chronic stressors as a con- served response to ancestral chronic stressors, which usually and explicitly involved energy shortages.
If one also considers chronic stress to involve the scarcity or loss of resources other than food and water, human immunity might also be adaptively suppressed during chronic stressors in order to protect, maintain, and pursue those resources. For many vertebrates, these activities might involve physical acts such as retrieving offspring, competing for mates, and acquiring and defend- ing territory such as a nestbox [34, 45, 46]. For humans, these activities might involve the pursuit of maintaining and acquiring resources such as socioeconomic status or social integration. When resources are lost or threatened through social conflict, bereavement, unemployment, and the like, an adaptive response would be to redirect energy toward rebuilding or compensating for those resources. This response could account for some of the decreases in immune function (e.g., in proliferation, protein production, and cytotoxicity) observed during stressors such as marital conflict, bereavement, and unemployment [2]. It might also create empirical relationships that are unexpected: people making stronger efforts to maintain or accumulate resources might have poorer immune function than those making weaker efforts, particularly if they are facing multiple demands on their energy. In fact, several examples of just such relationships exist. The largest number of examples examines the relationships among stressors, social net- works, and immune function, but there is also evidence that personality factors associated with persistent goal pursuit can yield similar findings.
Social Networks, Energy, and Immunity
Large and diverse social networks generally associate with better immunity and longevity [7, 56]. They also take time and energy to maintain. The number of social contacts received and available social support are directly related to efforts to initiate social contacts and provide social support [57, 58]. Social resources, like other resources, are actively built and maintained.
These building and maintenance activities, when com- bined with other demands, may come at an energetic and immunological cost. In a review of the literature on social relationships and HIV infection, perceived availability of social support was often associated with higher number of CD4+ T cells (the cells selectively infected and destroyed by the HIV virus), higher natural killer cell cytotoxicity, later symptom onset, and longer survival [8]. This is consistent with the finding that perceived social support is the most salubrious kind [52]. Other social parameters, such as social network size, were either unrelated to immunity
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and health or had negative consequences, particularly in prospective studies. More anticipated social activity, greater affinity with social networks, larger social networks, and less loneliness were associated with faster CD4+ T-cell decline, earlier symptom onset, and greater mortality [8]. The energetic costs of maintaining or even interacting with large social networks may be detrimental to immunity and, therefore, health in the context of chronic infection.
Paradoxical effects of social network size on immunity have also been observed in healthy, young adults. For first- year law students, one of the major challenges is balancing curricular demands with extracurricular interests and activ- ities, and finding time and energy to interact with significant others such as friends and family is a significant concern. Among first-year law students, relocation to attend law school and attendant separation from established social networks was associated with better cellular immunity as measured by delayed-type hypersensitivity (DTH) testing. Within-person changes in social network size across the first six months of law school paralleled this between- person finding: at those assessment points when a student had more social contacts, he or she also had poorer cellular immunity [9]. Although there might be a psychological benefit to tonic and phasic engagement with one’s social network, there also appears to be an immunological cost associated with maintaining network contacts while also meeting the demands of law school.
Finally, ecologically motivated changes in immunity may have health consequences. A diary study of students found that life events were associated with higher numbers of clinically verified upper respiratory infections only among students with large social networks [10]. One potential explanation for this interaction among social networks, stress, and infectious disease is that social networks provide more opportunities for infection. Howev- er, this explanation cannot suffice to explain differences in response to DTH testing or studies of HIV infection in which controls for potential reexposure were included (e.g., Ref. [59]).
Optimism, Energy, and Immunity
The potential energetic and immunological costs of social networks are also evident in a series of studies focusing on the consequences of stress and dispositional optimism. Dispositional optimism reflects generalized expectations for a positive future [60]. In turn, positive expectations result in more goal-directed motivation and persistence both in and out of the lab [61–64]. In law students, more optimistic students should be expected to engage conflicts between academic and social demands while their pessimistic counterparts reduce their effort to meet curricular demands, extracurricular demands, or both [63].
In three separate samples, optimism was negatively correlated with cellular immunity (again, as measured by DTH testing) in students who did not move away to attend law school and positively correlated with cellular immunity in students who did [65, 66]. These results reflect phenotypic plasticity in response to energetic cost of goal pursuit under demanding circumstances. In this case, the cost is observed among individuals in the most demanding context and with the greatest propensity to pursue and protect goals and resources (i.e., optimists). A similar effect has been observed in community-dwelling women. In this sample, during short-term stressors (i.e., less demanding circumstances), dispositional optimism correlated with higher numbers of T cells. During long-term stressors (i.e., more demanding circumstances), however, dispositional optimism correlated with lower numbers of T cells [67]. Similarly, in laboratory studies, dispositional optimism predicted higher immune parameters (such as natural killer cell cytotoxicity or skin test response) after less demanding stressors or rest, but lower immune parameters after more demanding stressors [68, 69]. In demanding circumstances, optimists’ energetic efforts to overcome or master difficulties and stressors appear to result in lower cellular immune function than the withdrawal more typical of their pessimis- tic counterparts.
These effects are, however, potentially interpretable in another light. Specifically, it has been suggested that when positive expectations are not borne out, optimism can result in disappointment and distress and thereby compromise immunity [67, 69, 70]. However, there is little evidence to support this mechanism. Explicit tests of the effects of disappointing situations do not show that optimists are vulnerable relative to pessimists [66, 71, 72] or that affective pathways mediate between optimism and DTH responses [66].
Further Considerations
Can Traditional and Ecological Models Coexist?
Ecological effects do not eliminate the need for traditional views of stress and stress buffers, and vice versa. For example, the interaction between dispositional optimism and social demands (as indexed by relocation) predicted number of T cells and the immune response to DTH testing in a manner consistent with the ecological model [65, 66], but in the same samples, appraisals of law school as more stressful correlated with lower natural killer cell cytotox- icity and poorer response to DTH testing, more negative daily mood correlated with poorer immune responses to DTH testing, and more positive daily mood correlated with more robust responses [66, 73, 74].
ann. behav. med. (2010) 40:114–125 121
Ideally, psychoneuroimmunology research should begin to combine these perspectives to best understand changes in the immune system that accompany stressors. Many investigations into the relationship between stressors and immunity have assessed stress appraisals or negative moods directly, but the assessment of resources is rare. Resource assessments for PNI studies could be standardized, as in the Conservation of Resources Evaluation [50]; idiosyncratic to situation, as in loss of possessions after an earthquake [75]; or idiographic, as in self-nominated resources pertinent to current goals [76]. In any case, combining assessments of resources and distress may yield fruitful insights into the relationship between stress and immunity. These effects may be additive: among hospital workers who experienced the Northridge earthquake, both distress and resource loss were independently associated with number of T cells [75].
It may also be important to examine the construct of stress through an evolutionary or ecological lens in order to determine what kind of response is demanded by the stressor and what the adaptive response might be. One principle of evolutionary science is that adaptations emerge in response to specific challenges in the environment. The nonspecificity of the term “stress” disguises the variety of environmental challenges. Equating stress with threat and the “fight or flight” response supposes that stressors should invariably result in increased energy directed to the periphery (through autonomic and neuroendocrine mecha- nisms described above), particularly the muscles. Behavior is the prioritized response. However, stress can also result from an internal threat such as infection, in which case the “protein production and proliferation” response of the immune system should result and behavior will be inhibited. Immunity is the prioritized response. Finally, stress may also result from opportunities to acquire resources that require self-regulatory responses. In this case, the needs of the brain to “pause and plan” may take priority, with energy directed away from the periphery [77]. Definitions of stress as equivalent to threat may not be broad enough to encompass all important situations in human ecology.
Chronic Stress and Proinflammatory Cytokines
Although stressors typically associate with decrements in immunity in the cellular and humoral compartments, recent evidence demonstrates that stressors, both acute and chronic, are associated with higher levels of proinflamma- tory cytokines [42, 78]. How does a potentially energy- conserving mechanism (ecologically driven suppression of immune functions such as cell proliferation and antibody production during chronic stress) account for increased levels of proinflammatory cytokines? One possibility is that the mechanism by which acquired immunity is contained eventually allows innate immunity to escape this contain-
ment. Tonic and phasic control over immune activity is likely to be achieved via immunosuppressive mechanisms such as corticosteroids. In animal models, withdrawing corticosteroids via adrenalectomy results in a pathological level of immune activity that can result in mortality from autoimmunity or septic shock [79, 80]. Humans with insufficient endogenous production of cortisol are also at higher risk for death from septic shock, a risk that can be ameliorated by administration of exogenous corticosteroids [81]. Titration of immune activity to meet optimal levels is likely to be achieved by greater or lesser degrees of suppression, not by immune enhancement—the effects of a merely unrestricted immune system are potent enough.
Prolonged exposure to elevated cortisol can alter the sensitivity of receptors on immune cells and blunt its anti- inflammatory potential [82]. These findings suggest that after some time, ecologically titrated containment of the immune system may fail. A similar failure as a consequence of frequent or prolonged “fight or flight” responses has been implied in the development of allostatic load (i.e., “the wear and tear that results from chronic overactivity” of stress response systems; [83], p. 171). The time course of the progress from ecological allostasis to pathological allostatic load will be an important area of further investigation. The clinical implications of this failure are not trivial, insofar as inflammatory escape can increase health risk associated with proinflammatory cytokines such as IL-6 [3–5], the energetic costs of this escape may reduce availability of energetic resources for other systems (cf. Ref. [22]), or both.
The Ecological Model and Long-term Implications for Health
The basic premise of the ecological model is that costs (e.g., increased risk of infection) can be traded for benefits (e.g., resources or reproduction). Empirical tests of this proposition in humans are needed, although the factors that are associated with phasic reductions in immunity in healthy adults (i.e., social network size and dispositional optimism) in small-scale psychoneuroimmunology studies also tend to be associated with better long-term health outcomes in epidemiological and meta-analytic studies (e.g., Refs. [7, 84]). Therefore, the long-term health evidence suggests that the immunological cost associated with protecting or building resources may be more than offset by the longer- term health advantage of having those resources.
Adamo [85] lists major problems in interpreting immune function in light of disease resistance and health:
(1) correlations between assays of immunity and disease resistance are typically pathogen specific, (2) correlations between assays of immunity and disease
122 ann. behav. med. (2010) 40:114–125
resistance are sometimes weak or nonexistent, (3) research suggests that some immune components have a threshold value such that changes above that threshold value may have no biological significance (p. 1443).
These problems raise interesting questions about eco- logical effects on immunity and their consequences for health. For example, life history of pathogen exposure, as a signal of what kinds of infectious threats exist in the environment, might affect which immune components are more or less susceptible to ecological effects. Immune components that have been called into use may be less susceptible. As another example, different populations may differ in their “threshold value”, such that ecological effects have health consequences for some populations (e.g., HIV patients or the elderly) but not others (e.g., healthy children or young adults).
Mechanisms of Ecological Effects on Immunity
Further investigations into the role of energy in stress- related immune change and especially the mechanisms involved are needed. Schmid-Hempel [86] noted that in the ecological immunology literature, survival costs or reduc- tion in physical condition during immune responses become apparent only when additional energy challenge is present (e.g., starvation), possibly because up to a point it is possible to compensate for energetic demands (e.g., through additional food intake). Hormonal pathways directly related to energy and energy mobilization (e.g., cortisol) are therefore obvious potential mediators between ecological demands and immunological responses. However, others have been proposed. Lessells [24] points out that energy starvation per se may act as a mediator of ecologically motivated immunosuppression, but it is “better to shut [the immune system] down in an orderly fashion that allows remaining resources to be used to maximum effect than to starve it into inactivity” (p. 1593). The neuroendocrine system is likely to provide signals about resources that mediate ecological trade-offs with immunity. Testosterone may account for immunological differences between the sexes that conform to the Bateman principle, although such sex differences also exist in invertebrates that lack testosterone [44]. Leptin, a hormone secreted by adipose tissue (i.e., body fat), has been suggested as a signal to the immune system about the amount of energy available to the organism [15]. Melatonin has been proposed to signal energetic trade-offs related to the seasons, including immunological trade-offs [87]. Finally, others (e.g., Refs. [88]) have argued that lack of energy may not entirely mediate the negative effects of stress on the immune system. Rather, an increase in energy turnover or metabolic
rate during stress could increase the production of free radicals that damage the immune system and prevent it from functioning effectively.
Conclusion
An ecological approach to the relationship between stress and immune function specifies that immune function may be sacrificed to meet other goals, a process that does not necessary imply threat but incorporates the idea of limited energetic resources. This approach can account for immune responses to both acute and chronic stressors, as well as seemingly paradoxical effects of stress buffers such as social network size and optimism on immune function.
Acknowledgements The author thanks David Westneat and Gregory E. Miller for their helpful comments on an earlier version of the manuscript.
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