Download Stress and immunity in wild vertebrates: Timing is everything

General and Comparative Endocrinology 163 (2009) 70–76
Contents lists available at ScienceDirect
General and Comparative Endocrinology
journal homepage: www.elsevier.com/locate/ygcen
Stress and immunity in wild vertebrates: Timing is everything
Lynn B. Martin *
University of South Florida, Department of Integrative Biology, Tampa, FL 33620, USA
a r t i c l e
i n f o
Article history:
Received 3 November 2008
Revised 5 March 2009
Accepted 17 March 2009
Available online 24 March 2009
Keywords:
Immunocompetence
Bird
Trade-off
Season
a b s t r a c t
Stress has profound effects on vertebrate immunity, but most studies have considered stress–immune
interactions in terms of wild animals enduring demanding, but predictable activities (e.g., immune alterations during breeding). A growing biomedical literature, however, indicates that stress may not be obligatorily immunosuppressive; in response to transient, unpredictable stressors, immune activity can be
enhanced, especially in body areas requiring immune protection. Also, immune sensitivity to stressors
is not fixed throughout life; oftentimes, glucocorticoid (GC) insensitivity can be induced. Further GC
sensitivity can be programmed early in life; greater exposure to stressors prior to maturity heightens
GC effects on immunity in adulthood. In the present paper, I review the cellular and molecular mechanisms that link stress responses to immune adjustments over short time scales in domesticated species
then I attempt to place stress–immune interactions in a naturalistic, organismal context. When, how and
why stressors affect immunity in wild animals remains practically unstudied.
Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction
Defining stressors (e.g., aversive conditions that would compromise fitness if not successfully endured or avoided) and stress responses (e.g., physiological and behavioral mechanisms that
allow individuals to survive or recover from the adverse conditions
belied by a stressor) has been much easier than defining stress.
Many definitions are tautological (Apanius, 1998). For instance,
when stress hormones are elevated, stress is often claimed even
if the activity engaged is typical (e.g., high stress hormones during
reproduction represent the ‘‘stress” of breeding). Stress hormones
may be important to such processes, but elevations do not alone
mean stress. Only when organisms experience unpredictable (or
uncontrollable) situations that threaten fitness should an emergency life history state be entered (Wingfield et al., 1998). If an
aversive stimulus is insignificant to fitness, individuals would do
best to ignore or tolerate them and invest instead in more important processes (McNamara and Buchanan, 2005). Thus, the definition of stress implied throughout this paper is: a physiological
and behavioral state (mediated by stress hormones) engaged to endure, avoid, or recover from an aversive stimulus or condition.
Although this definition is restrictive, it is conducive to understanding links between the endocrine and immune systems.
2. Stress and immune interactions in the wild: research
emphasis to date
The perspective that any demanding process that an organism
endures is a stressor represents the majority of work on stress–im* Fax: +1 813 974 3263.
E-mail address: [email protected]
0016-6480/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygcen.2009.03.008
mune interactions in wild animals. The best examples entail work
on trade-offs involving immune activity (Lochmiller and Deerenberg, 2000). Breeding and immune activity for example are expensive and thus incompatible, which can result in compromised
immunity, reproductive success and even survival (Ardia et al.,
2003; Hanssen et al., 2004). Fluctuations in environmental conditions, however, can also affect immunity. Cold temperatures (Dabbert et al., 1997; Hangalapura et al., 2003; Lifjeld et al., 2002) and
lack of food (Bourgeon et al., 2006; Hangalapura et al., 2005; Raberg et al., 2003) reduce immune activity in wild birds and domesticated fowl. Captivity too can reduce immune responses (Berzins
et al., 2008; Ewenson et al., 2003), although the magnitude of these
effects is species-specific (Matson et al., 2006). Artificial elevation
of stress hormones can dampen immune activity in eiders (Somateria sp. (Bourgeon and Raclot, 2006)) and zebra finches (Poephilia
guttata) (Roberts et al., 2007b). Intriguingly, GCs may also be indirectly responsible for the effects of testosterone on immunity
(Evans et al., 2000).
These findings demonstrate stress–immune linkages in wild
animals, but given the varied natures of the above stressors, it is
hard to make generalizations about stress–immune interactions.
If organisms can predict aversive conditions and preemptively
compensate for heightened demands, conditions may not represent true stressors. Animals use many environmental signals to
modify their phenotypes in preparation for recurrent environmental challenges. Photoperiod, or day-length, is an especially useful
cue (Martin et al., 2008). Seasonal adjustments of immunity to
photoperiod occur and may enable individuals to surmount conditions that at other times of year would indeed be stressful. Also, the
intensity or duration of stressors vary, which makes identifying
generalities about stress–immune interactions even more difficult.
71
L.B. Martin / General and Comparative Endocrinology 163 (2009) 70–76
In most studies, stress is portrayed or interpreted as obligatorily
immunosuppressive, but this generalization may be a consequence
of the types of studies yet conducted and the overreaching definitions of stress employed.
et al., 1998). Further, elimination of most leukocytes occurs
through apoptosis (Sapolsky et al., 2000), a process that requires
gene transcription and thus time. Energy savings via apoptosis is
unlikely to yield much resources, as apoptosis is itself expensive
(Sapolsky et al., 2000). Therefore, only over long periods (days/
weeks) would immune suppression provide resources; in the short
term, the costs of immune suppression would probably outweigh
the benefits. A limitation of the autoimmune avoidance hypothesis
is that it applies mostly to lymphocyte mediated immunity. Thus
alterations in innate immunity, a major component of immunity,
are not explained by this hypothesis.
Existing hypotheses for stress–immune interactions also ignore
the obvious: it makes little sense that organisms would suppress a
system that could be integral to recovery from stressors (Dhabhar
and McEwen, 1997). The main function of stress responses is to endure or recover from stressors (Wingfield et al., 1998), so why
would immunity not be enhanced in response to stressors if
enhancement promoted fitness? Some of the most significant
stressors for wild animals would be failed predation attempts, territorial conflicts escalating to physical aggression, and wounds induced or subsequently infected by pathogens. In these cases,
immune activity should be enhanced to ensure that survival of a
stressor was not for naught.
Hypotheses to explain stress–immune interactions thus require
refinement. All three implicitly or explicitly assume that stress
obligatorily suppresses immunity and thus seek to explain why.
An intriguing pattern emerges, however, when the duration of various stressors is juxtaposed with observed changes in immune
activity in studies of domesticated rodents (Fig. 1). In response to
stressors lasting minutes to days, immune activity tends to be elevated; over longer periods (days to months), it tends to be suppressed. Stressors that tend to occur over minutes to hours, such
as failed predation events and aggressive encounters, and slightly
longer term challenges that are often a consequence of the former
3. Why does stress affect immunity?
Before proposing another hypothesis for stress–immune interactions, it is important to discuss those that already exist. The most
popular is that immunity is diminished during stress responses to
redirect resources towards activities that are more immediately
valuable to survival (Sapolsky et al., 2000). Compared to increased
heart rate, lung ventilation, and other processes promoting of escape or aggression, immune activity is expendable. An extension
of this hypothesis posits that immune suppression may represent
a sacrifice to provide resources for more critical processes (Sapolsky et al., 2000). Thus, not only is immune activity suppressed, immune cells and tissues are actively catabolized to provide protein
and glucose. A third explanation is distinct from the first two and
involves minimization of autoimmune damage. Deployment of
stress hormones indirectly leads to the appearance of novel selfantigens due to degradation of tissues; immune activity must be
depressed to decrease collateral damage to self (Råberg et al.,
1998). Immune responses to antigens upon first encounter are typically polyclonal (Sapolsky et al., 2000), meaning that multiple B
and T cell lineages respond and proliferate as long as their respective receptors have an affinity for the antigen. Glucocorticoids are
integral to deletion of low affinity clonotypes (Sapolsky et al.,
2000).
These hypotheses have some support, but each also has shortcomings. For example, energy savings would be a viable explanation for immune suppression only if savings could be gained
rapidly. Down-regulation of the immune system cannot be rapid,
as the system is a diffuse network of cells and tissues (Råberg
Habitat modification
Invasive species
Pollution
Immune function
Immune
enhancement
basal immune function
Scope of baseline shift (or GC
insensitivity) contingent
on experience (#, timing
or intensity of prior stressors)
Infection
Injury
Aggressive interaction
Parasite detection
Predation
Minutes-hours
Inclement weather
Social status change
Immune
suppression
Food
restriction
Hours-days
Days-weeks
Weeks-months
Duration of stressor
Protective up-regulation
Protective down-regulation
Allostatic overload
Fig. 1. Juxtaposition of stressors that wild animals experience and known effects of similar duration stressors in domesticated rodents. Dashed line depicts changes in
immune function as a consequence of stressors of various durations. Shaded area depicts potential long-term increase or decrease in sensitivity to stressors driven by
experience. Plain text indicates variety of possible stressors. Italicized text below x-axis hypothesizes evolutionary relevance of changes in immunity as a function of stressor
duration.
72
L.B. Martin / General and Comparative Endocrinology 163 (2009) 70–76
stressors (infection/injury) overlap with enhancements in most
immune processes, particularly inflammatory ones. Longer duration stressors such as inclement weather (days/weeks) and habitat
modification (weeks/months) mirror reductions of most immune
processes. In these cases, suppression may represent adaptive
down-regulation for energy savings or a consequence of Type II
allostatic overload (McEwen and Wingfield, 2003). An important
avenue of research to pursue involves how stressors affect immune
processes during the period what are typically portrayed as acute
and chronic stressors. The duration and onset of this transition period is likely to vary among species, but little effort has gone to
investigating stress responses, much less their effects on immune
function, during this period in wild animals.
responses and stimulate release of vasoactive mediators (to cause
leaky membranes) that increase immune cell recruitment and amplify local clearance of the pathogen” (Sternberg, 2006).
4.1. Sympathetic nervous system effects on immunity
Most stress induced changes in immune function are orchestrated either by the sympathetic nervous system (SNS) (Sternberg,
2006) or glucocorticoid hormones and other components of the
hypothalamic–pituitary–adrenal axis (Sapolsky et al., 2000). Primary and secondary lymphoid organs (e.g., bone marrow, thymus,
splenic white pulp, and lymph nodes) are innervated with SNS fibers, and many nerve endings terminate adjacent to pro-inflammatory T cells and macrophages. In these and other resident cells,
peripheral neuropeptides induce the release of several pro-inflammatory substances including corticotrophin-releasing hormone
(CRH), substance P, and calcitonin gene-related protein (CGRP;
(Sternberg, 2006)). These molecules (and noradrenaline directly)
induce expression of adhesion molecules (e.g., CXCL8 and CCL2),
especially from macrophages. Increased adhesion molecule receptors in epithelial and vascular cells and ligands for these receptors
on macrophages (monocytes) promote infiltration of leukocytes
into appropriate areas. CCR2+ macrophages are particularly
sensitive, and when they are exposed to pathogen-associated molecules or certain pro-inflammatory molecules (e.g., IFNc, IL-4 and
IL-10), their antibacterial and wound healing capacities are
elevated (Gordon and Taylor, 2005). Lymphocytes also are differentially sensitive to SNS-derived molecules. Naïve and Th1 (proinflammatory), but not Th2 (B-cell promoting), CD4+ T cells
express beta-adrenergic receptors (b2AR) and thus respond more
strongly to norepinephrine (Kin and Sanders, 2006).
The intimate connectivity between the SNS and immune system
probably often allows local resolution of stressor-induced damage.
If local control of the challenge that induced a stress response is
achieved (i.e., an infection is controlled or eliminated), local pro-
4. Stress-induced immune alterations in vertebrates
The pattern in Fig. 1 emerges from studies of domesticated rodents. Different duration/intensity stressors alter immune function
distinctly. Further, some immune components are strongly sensitive to stressors whereas others less so if at all. Stress hormones
tend to elevate processes involved in inflammation early (hours),
followed by elevation of T cell activity (especially Th1) and finally
B cell activity (Fig. 2). Persistent stimulation by these same hormones suppresses all three systems (although inflammatory defenses are oftentimes exacerbated in response to chronically
elevated stress hormones, an underlying cause for many autoimmune disorders (Medzhitov, 2008)). It is not surprising, given the
types of stressors animals experience, that innate and particularly
inflammatory defenses tend be engaged first and most rapidly in
response to stressors. The purpose of an inflammatory response
is ‘‘to remove or sequester the source of the disturbance, to allow
the host to adapt to the abnormal conditions and, ultimately, to restore functionality and homeostasis to the tissue” (Medzhitov,
2008). For this reason, ‘‘activation of the peripheral nervous system
at local inflammatory sites (may) serve to enhance innate immune
Th1
Th2
Immune function
innate
Minutes-hours
Hours-days
Days-weeks
Weeks-months
Time to effectiveness
Neuropeptides dominate
Glucocorticoids dominate
Fig. 2. Progression of changes in various immune functions with duration of stressors in domesticated rodents. Dashed line depicts innate immunity, small dotted line depicts
Th1 (pro-inflammatory T cell) defenses, and large dotted line depicts Th2 (antibody-response promoting T cell) defenses. Note (i) the higher start-point for innate immune
mediators, as these defense are constitutively present in (wounded) tissue, and (ii) the positive inflection for innate immunity in response to long-term stressors, a
hypothesized driver of many inflammatory autoimmune disorders. Boxes below x-axis depict main mediators of immune alterations: SNS-derived peptides or GCs.
L.B. Martin / General and Comparative Endocrinology 163 (2009) 70–76
duction of anti-inflammatory molecules attenuates the inflammatory response and the immune system reassumes its initial unperturbed state (Sternberg, 2006). If not, neutrophils instead of
macrophages infiltrate the inflamed areas, T cells are recruited,
and a systemic response is engaged (Medzhitov, 2008). This state
can be achieved via cellular and hormonal mediators entering circulation or via the vagus nerve directly. The vagus nerve is highly
sensitive to inflammatory stimuli, allowing systemic or regional
inflammatory states to be relayed quickly to the brain (via IL-1
receptors; Sternberg, 2006). When systemic pro-inflammatory
states occur, effects on phenotype can extend beyond the immune
system. The adrenal glands can release IL6, and TNFa in response
to pathogen-associated molecular pattern (PAMPs) molecules,
and chromaffin cells begin releasing antimicrobial peptides (Sternberg, 2006). Additionally, muscle sensitivity to insulin decreases
(Medzhitov, 2008), a process that may promote redistribution of
glucose from one of its major consumers to the cells that will be
integral to fight infection and repair tissue. Ultimately, all of these
adjustment are resolved (i.e., returned to their prior condition) by
vagus nerve activity and SNS or glucocorticoid pathways (e.g., release of acetylcholine; Kin and Sanders, 2006).
4.2. Glucocorticoids effects on immunity
Glucocorticoids also have pervasive enhancive effects on immune processes. In fact, it is only since the Nobel Prize was
awarded for treatment of rheumatoid arthritis with GCs that the
immunosuppressive effects of GCs have been emphasized. Research prior to 1950 advocated the use of GCs for protection
against infectious disease (Jefferies, 1991). The strongest examples
of GCs as promoters of immune function come from the work of
Dhabhar et al. (1996). In response to an acute stressor (i.e., restraint) both innate and adaptive immune responses can be enhanced in mice (Dhabhar, 2002). Moreover, adrenalectomy
eliminated stress-induced enhancement whereas artificial GC
and/or epinephrine administrations restore it. Elevated immune
activity in response to GCs is especially obvious in areas where
wounding has occurred. Cell-mediated immune responses in skin
are greatly enhanced if restraint stress is imposed for a few hours
prior to induction of the immune response (Dhabhar and McEwen,
1997). This enhancement is coordinated by IFNc and increased
neutrophil, macrophage and T cell activity at the site (Dhabhar
et al., 2000). Enhancement of immunity via acute stressors is not
limited to T cell responses though. Antigen presentation and
phagocytosis by macrophages are increased by GCs, and artificial
administration of GCs alone can elevate acute phase protein secretion from the liver (Dhabhar, 2002).
GCs can of course have down-regulating effects on immune
parameters (Sapolsky et al., 2000). GCs can suppress maturation,
differentiation and proliferation of all immune cells (Sternberg,
2006), and trigger apoptosis in immature T and B cells and mature
T cells (Sapolsky et al., 2000). GCs also suppress IL-1 transcription,
translation, and secretion and destabilize mRNA in leukocytes
(Dhabhar and McEwen, 1997), rapidly reduce lymphocyte, monocyte, and granulocyte chemotaxis (Sapolsky et al., 2000) and
reduce numbers of circulating lymphocytes (T cells > B cells
and CD4+ > CD8+) as well as eosinophils, basophils, macrophages,
and monocytes. The prime role of GCs in inflammation is to
reign-in of defenses once infections are controlled.
4.3. Immunoredistribution
Chronic stressors decreases circulating leukocyte numbers
(Dhabhar, 2002) and often these changes are due to GCs. In response to acute stressors, however, leukocytes also decrease in circulation, but what seems to happen in these cases is not immune
73
suppression, but redistribution. When animals experience a transient stressor, leukocytes exit circulation and infiltrate sites of
wounding and lymphoid tissues (Dhabhar and McEwen, 1999).
This result was demonstrated elegantly when surgical sponges
were implanted subcutaneously in mice, mice restrained for a
short period, and sponges (into which leukocytes invaded)
explanted hours later (Viswanathan and Dhabhar, 2005). Neutrophils, macrophages, NK cells, and T cells were 200–300% higher
in animals restrained prior to explant; in stressed and unstressed
mice, innate cells infiltrated earlier than adaptive (T) cells. A second study determined that infiltration could be further elevated
for most cell types if TNFa (a pro-inflammatory cytokine) or lymphotactin (LTN; a lymphocyte-specific chemoattractant) was applied prior to implantation. Stress responses at the time of
wounding (surgery) thus enhance immune activity at the compromised site. These effects are partly mediated by GCs, but intravenous administration of adrenaline can also reduce numbers of
circulating monocytes, lymphocytes and NK cells (Sternberg,
2006), perhaps also because of redistribution.
The ecological relevance of redistribution has yet to be determined, but it has been proposed (Braude et al., 1999) as an alternative explanation for the immunocompetence handicap hypothesis
(Folstad and Karter, 1992). According to that idea, testosterone
(T) dampens immune activity but enhances ornaments and other
sexually selected traits indicative of quality. Traits are thus honest
indicators of mate quality because only high quality individuals
can endure disease and produce elaborate traits (i.e., handicaps).
If T induces redistribution, leukocyte reductions in circulation
may be revealed as reallocations to the skin and peripheral organs.
A better supported role for immunoredistribution in wild animals
entails responses to obvious stressors, particularly failed predation
events. Living within the territory of a predator (Scheuerlein et al.,
2001) or just the sight of a predator can induce GC elevations (Cockrem and Silverin, 2002). Although untested, redistribution in large
part may serve to help animals heal wounds or prevent infections
when they are able to escape predation (Dhabhar and McEwen,
1997).
This hypothesis alone leads to several predictions. In species in
which males defend territories, redistribution should be greater in
males than females. These effects should be increased further in
harem-breeding species or any other social system in which conflicts are common. On the other hand, sex differences may reverse
contingent on time of year. When females are breeding, they may
require a heightened capacity to redistribute immune resources to
areas that would be susceptible to infection during copulations. As
sexually-transmitted diseases tend to be virulent, one would predict strong seasonal up-regulation of immune protection in reproductive organs during the breeding season. Seasonal variability in
redistribution is known for some mammals (Bilbo et al., 2002),
but in the single species studied, up-regulation occurs in the opposite direction.
4.4. Glucocorticoid insensitivity
When mice are exposed repeatedly to an aggressive intruder,
some of their leukocytes cease responding to GCs (Avitsur et al.,
2001). In other words, multiple transient stressors desensitize
the immune system to the hormones that otherwise would modulate it. The decreased responsiveness of macrophages may reflect a
general up-regulation of immune activity in a threatening environment; indeed, mice with the greatest GC insensitivity also have the
most bite wounds (Stark et al., 2001).
GC insensitivity has some parallels in free-living animals. Tropical house sparrows, for example, do not respond to artificial elevation of GCs whereas temperate sparrows dampen immune activity
(Martin et al., 2005). This pattern was proposed as a protective
74
L.B. Martin / General and Comparative Endocrinology 163 (2009) 70–76
mechanism to ensure individuals living in areas of greatest disease
threat would maintain competent immune function at all times.
Similar insensitivity occurs for different types of immune function.
Some antigen responses in chickens are affected by stressors
whereas others are not (El-Lethey et al., 2003). In the rodent model
above, GC insensitivity was pronounced in macrophages but nonexistent in B cells (Stark et al., 2001).
4.5. Immune priming via GCs
Immune processes can become insensitive to GCs, but they can
also be primed if GC exposure happens early in life. Exposure of
neonatal rats to endotoxin (a component of gram-negative bacteria) elevated basal GCs and increased the sensitivity of leukocytes
to GCs in adulthood (Shanks et al., 2000). Thus, timing of exposure
to GCs determines GC effects on immunity in later life. If animals
experience many stressors during development, they may become
more sensitive to GCs later. Sensitization may have profound effects on fitness prospects. Not only are leukocytes more sensitive
to GCs, hypothalamic regulation of lutenizing hormone (LH) pulsatility, which regulates reproductive capacity, is altered by endotoxin exposure early in life (Li et al., 2007). Endotoxin exposure
in adulthood to individuals exposed to endotoxin as adults causes
much greater depression of LH pulsatility than individuals not having been exposed to endotoxin at all.
Programming of immune activity via GCs (and the reverse) is
probably significant in many natural systems. Exposure to GCs
(or cytokines) during development may alter the magnitude of
investment in immune defenses in adulthood. This mechanism
could ensure that individuals living in areas where stressors are
common would be prepared for stressors throughout their lives.
Indeed, because GCs can be transferred to offspring in ovo or in utero, mothers could prepare their offspring prior to birth for the challenges they will face later. It is also important to address a recent
(re)discovery that may have programming implications for GC-immune interactions: production of GCs by immune organs during
development (Schmidt and Soma, 2008). GCs may often influence
the development of immunity in growing animals, perhaps by
driving expression of proteins responsible for lymphocyte receptor
diversity (e.g., RAGI and II).
5. Ecological implications of stress–immune interactions
A variety of factors may influence when and how stress affects
immunity in wild animals. Group-living species experience
different sorts of stressors than individual or pair-living species.
Predominantly monogamous species may experience mate separation as a greater stressor than promiscuous species. In species with
mate-fidelity, mate separation induces GC elevations and compromises wound healing; no immune effects are seen in promiscuous
species (Glasper and Devries, 2005). In group living species, stressor effects on immune activity may be more affected by conflicts
than mate loss. Experimental increases in competition compromised humoral immunity in house finches (Carpdodacus mexicanus), although these effects were not mediated directly by GCs
(Hawley et al., 2006). In zebra finches, pair-housing induces subordinate but not dominant individuals to reduce immune function
(Gleeson, 2006). The significance of stress hormones was not determined. Environmental conditions may further influence how
group-living species adjust their immune systems in response to
stressors. In cooperative-breeders, alleviation of reproductive
responsibilities can have positive effects (Valencia et al., 2006),
but when environmental conditions are demanding, help during
breeding may not offset stress-induced immune suppression
(Rubenstein et al., 2008).
Environmental conditions generally may have broad effects on
stress–immune interactions. Incidence of Mycoplasma gallisepticum
infections and GC responses to stressors in house finches vary
among populations and years, but not in an obviously intelligible
way (Lindström et al., 2005). Even on small spatial scales, GCs
may have distinct effects on immune function. GC release by birds
varies along urbanization gradients (Bonier et al., 2007; Partecke
et al., 2006), and songbird populations in urban areas tend to have
higher disease prevalence than rural ones (Bradley et al., 2008).
More study in these contexts is needed though, as different species
harbor different pathogens depending on habitat (Fokidis et al.,
2008).
Finally, a recurrent theme regarding stress–immune interactions involves coping styles (Koolhaas, 2008). Proactive coping
styles tend to be coupled with efforts to prevent or manipulate
stressors, high SNS activity, and a Th1 biased immune system.
Reactive coping styles entail passive acceptance of stressors, high
HPA reactivity, and a Th2 biased immune responses. Th1-dominated (inflammatory) immune responses of proactive individuals
(Hawks) and Th2-dominated (humoral) immune responses of reactive individuals (Doves) are biologically sensible because hawks
are at greater risk of wounds and infections during fighting
whereas doves with their exploratory nature and greater intake
of new resources are more likely to be contaminated with parasites
(Korte et al., 2005). However, the hyper-inflammatory state of
Hawks together with a blunted HPA axis may impose greater risk
autoimmune disease, and Doves’ higher motivation to explore
may put them at greater risk of parasite exposure (i.e., via novel
food consumption). Evidence from wild species supports the generalizations above based on domesticated ones. Zebra finches and
other species can be selected for strong or weak GC responses to
stressors (Roberts et al., 2007a), although the implications of these
genetic underpinnings are unknown for immunity. Moreover, GC
responses to stressors tend to be repeatable within individuals
and similar irrespective of the stressor imposed (Wada, 2008). Still,
little work has yet considered the evolutionary implication of coping styles in wild animals; potential differential effects of stress on
immunity are likewise unstudied.
6. Conclusion
In spite of the insight provided by the above studies, it is impossible to know their natural relevance. Many have been conducted
in vitro only, and many in vivo studies involve pharmacological or
supra-physiological doses of hormones to induce effects (Dhabhar,
2002). More troublesome, almost all whole-organism studies involve species bred for reproductive proclivity and docility and thus
likely damped stress responsiveness, and most have been conducted in artificial conditions with contrived stressors. What
would be stressful to organisms that have lived for generations
in conditions where resources are plentiful, predators are nonexistent, climate is benign and predictable, and disease threats
are minimal? Undoubtedly, some factors are such as loud noises,
novelty, and social insubordination still induce stress responses.
Nonetheless, given the decoupling of stress responses from fitness,
are stress responses in lab rodents of the same magnitude and consequence as wild animals?
Animals engage stress responses to maximize fitness prospects
in the environments in which they live (Wingfield et al., 1998).
Although stress oftentimes affects immunity, suppression is not
obligate; in many contexts, enhancements in immunity may occur
that similarly help animals to survive or recover from stressors.
This modified perspective of stress and immunity should lead to
new insight into how animals endure challenging conditions in
their environment. The most rapid progress is likely to be gained
by considering the identity of stressors, as the intensity and/or
L.B. Martin / General and Comparative Endocrinology 163 (2009) 70–76
duration of environmental challenges are likely pivotal to determining when and how immune adjustments are made.
Acknowledgments
L.B. Martin thanks J.R. Kuhlman for discussions of ideas presented in this manuscript, the conveners of the 9th ISAE conference
for the opportunity to present my ideas at the conference and in
this special issue, Dr. Peter Sharp for the opportunity to contribute
to this issue, two anonymous reviewers for constructive criticism,
and The University of South Florida for financial support.
References
Apanius, V., 1998. Stress and immune defense. Advances in the Study of Behavior
27, 133–153.
Ardia, D.R., Schat, K.A., Winkler, D.W., 2003. Reproductive effort reduces long-term
immune function in breeding tree swallows (Tachycineta bicolor). Proceedings
of the Royal Society of London Series B-Biological Sciences 270, 1679–1683.
Avitsur, R., Stark, J.L., Sheridan, J.F., 2001. Social stress induces glucocorticoid
resistance in subordinate animals. Hormones and Behavior 39, 247–257.
Berzins, L.L., Tilman-Schindel, E., Burness, G., 2008. Sex-specific effects of handling
time on an index of immune activity in zebra finches. Physiological and
Biochemical Zoology 81, 383–387.
Bilbo, S.D., Dhabhar, F.S., Viswanathan, K., Saul, A., Yellon, S.M., Nelson, R.J., 2002.
Short day lengths augment stress-induced leukocyte trafficking and stressinduced enhancement of skin immune function. Proceedings of the National
Academy of Sciences of the United States of America 99, 4067–4072.
Bonier, F., Martin, P.R., Sheldon, K.S., Jensen, J.P., Foltz, S.L., Wingfield, J.C., 2007. Sexspecific consequences of life in the city. Behavioral Ecology 18, 121–129.
Bourgeon, S., Martinez, J., Criscuolo, F., Le Maho, Y., Raclot, T., 2006. Fasting-induced
changes of immunological and stress indicators in breeding female eiders.
General and Comparative Endocrinology 147, 336–342.
Bourgeon, S., Raclot, T., 2006. Corticosterone selectively decreases humoral
immunity in female eiders during incubation. Journal of Experimental Biology
209, 4957–4965.
Bradley, C.A., Gibbs, S.E.J., Altizer, S., 2008. Urban land use predicts West Nile Virus
exposure in songbirds. Ecological Applications 18, 1083–1092.
Braude, S., Tang-Martinez, Z., Taylor, G.T., 1999. Stress, testosterone, and the
immunoredistribution hypothesis. Behavioral Ecology 10, 345–350.
Cockrem, J.F., Silverin, B., 2002. Sight of a predator can stimulate a corticosterone
response in the great tit (Parus major). General and Comparative Endocrinology
125, 248–255.
Dabbert, C.B., Lochmiller, R.L., Teeter, R.G., 1997. Effects of acute thermal stress on
the immune system of the Northern Bobwhite (Colinus virginianus). Auk 114,
103–109.
Dhabhar, F.S., 2002. Stress-induced augmentation of immune function—the role of
stress hormones, leukocyte trafficking, and cytokines. Brain Behavior and
Immunity 16, 785–798.
Dhabhar, F.S., McEwen, B.S., 1997. Acute stress enhances while chronic stress
suppresses cell-mediated immunity in vivo: a potential role for leukocyte
trafficking. Brain Behavior and Immunity 11, 286–306.
Dhabhar, F.S., McEwen, B.S., 1999. Enhancing versus suppressive effects of stress
hormones on skin immune function. Proceedings of the National Academy of
Sciences of the United States of America 96, 1059–1064.
Dhabhar, F.S., Miller, A.H., McEwen, B.S., Spencer, R.L., 1996. Stress-induced changes
in blood leukocyte distribution—Role of adrenal steroid hormones. Journal of
Immunology 157, 1638–1644.
Dhabhar, F.S., Satoskar, A.R., Bluethmann, H., David, J.R., McEwen, B.S., 2000. Stressinduced enhancement of skin immune function: a role for y interferon.
Proceedings of the National Academy of Sciences of the United States of
America 97, 2846–2851.
El-Lethey, H., Huber-Eicher, B., Jungi, T.W., 2003. Exploration of stress-induced
immunosuppression in chickens reveals both stress-resistant and stresssusceptible antigen responses. Veterinary Immunology and Immunopathology
95, 91–101.
Evans, M.R., Goldsmith, A.R., Norris, S.R.A., 2000. The effects of testosterone on
antibody production and plumage coloration in male house sparrows (Passer
domesticus). Behavioral Ecology and Sociobiology 47, 156–163.
Ewenson, E., Zann, R., Flannery, G., 2003. PHA immune response assay in captive
zebra finches is modulated by activity prior to testing. Animal Behaviour 66,
797–800.
Fokidis, H.B., Greiner, E.C., Deviche, P., 2008. Interspecific variation in avian blood
parasites and haematology associated with urbanization in a desert habitat.
Journal of Avian Biology 39, 300–310.
Folstad, I., Karter, A.J., 1992. Parasites, bright males, and the immunocompetence
handicap. American Naturalist 139, 603–622.
Gordon, S., Taylor, P.R., 2005. Monocyte and macrophage heterogeneity. Nature
Reviews Immunology 5, 953–964.
Glasper, E.R., Devries, A.C., 2005. Social structure influences effects of pair-housing
on wound healing. Brain Behavior and Immunity 19, 61–68.
75
Gleeson, D.J., 2006. Context-dependent effect of social environment on immune
response and sexual signalling in male zebra finches. Australian Journal of
Zoology 54, 375–379.
Hangalapura, B.N., Nieuwland, M.G.B., Reilingh, G.D., Buyse, J., Van Den Brand, H.,
Kemp, B., Parmentier, H.K., 2005. Severe feed restriction enhances innate
immunity but suppresses cellular immunity in chicken lines divergently
selected for antibody responses. Poultry Science 84, 1520–1529.
Hangalapura, B.N., Nieuwland, M.G.B., Reilingh, G.D., Heetkamp, M.J.W., van den
Brand, H., Kemp, B., Parmentier, H.K., 2003. Effects of cold stress on immune
responses and body weight of chicken lines divergently selected for antibody
responses to sheep red blood cells. Poultry Science 82, 1692–1700.
Hanssen, S.A., Hasselquist, D., Folstad, I., Erikstad, K.E., 2004. Costs of immunity:
immune responsiveness reduces survival in a vertebrate. Proceedings of the
Royal Society of London Series B-Biological Sciences 271, 925–930.
Hawley, D.M., Lindstrom, K., Wikelski, M., 2006. Experimentally increased social
competition compromises humoral immune responses in house finches.
Hormones and Behavior 49, 417–424.
Jefferies, W.M., 1991. Cortisol and Immunity. Medical Hypotheses 34, 198–208.
Koolhaas, A., 2008. Coping style and immunity in animals: making sense of
individual variation. Brain Behavior and Immunity 22, 662–667.
Korte, S.M., Koolhaas, J.M., Wingfield, J.C., McEwen, B.S., 2005. The Darwinian
concept of stress: benefits of allostasis and costs of allostatic load and the tradeoffs in health and disease. Neuroscience and Biobehavioral Reviews 29, 3–38.
Li, X.F., Kinsey-Jones, J.S., Knox, A.M.I., Wu, X.Q., Tahsinsoy, D., Brain, S.D., Lightman,
S.L., O’Byrne, K.T., 2007. Neonatal lipopolysaccharide exposure exacerbates
stress-induced suppression of luteinizing hormone pulse frequency in
adulthood. Endocrinology 148, 5984–5990.
Lifjeld, J.T., Dunn, P.O., Whittingham, L.A., 2002. Short-term fluctuations in cellular
immunity of tree swallows feeding nestlings. Oecologia 130, 185–190.
Lindström, K.M., Hawley, D.M., Davis, A.K., Wikelski, M., 2005. Stress responses and
disease in three wintering house finch (Carpodacus mexicanus) populations
along a latitudinal gradient. General and Comparative Endocrinology 143, 231–
239.
Lochmiller, R.L., Deerenberg, C., 2000. Trade-offs in evolutionary immunology: just
what is the cost of immunity? Oikos 88, 87–98.
Martin, L.B., Gilliam, J., Han, P., Lee, K., Wikelski, M., 2005. Corticosterone suppresses
cutaneous immune function in temperate but not tropical house sparrows,
Passer domesticus. General and Comparative Endocrinology 140, 126–135.
Martin, L.B., Weil, Z.M., Nelson, R.J., 2008. Seasonal changes in vertebrate immune
activity: mediation by physiological trade-offs. Philosophical Transactions of
the Royal Society of London B-Biological Sciences 363, 321–339.
Matson, K.D., Tieleman, B.I., Klasing, K.C., 2006. Capture stress and the bactericidal
competence of blood and plasma in five species of tropical birds. Physiological
and Biochemical Zoology 79, 556–564.
McEwen, B.S., Wingfield, J.C., 2003. The concept of allostasis in biology and
biomedicine. Hormones and Behavior 43, 2–15.
McNamara, J.M., Buchanan, K.L., 2005. Stress, resource allocation, and mortality.
Behavioral Ecology 16, 1008–1017.
Medzhitov, R., 2008. Origin and physiological roles of inflammation. Nature 454,
428–435.
Partecke, J., Schwabl, I., Gwinner, E., 2006. Stress and the city: urbanization and its
effects on the stress physiology in European Blackbirds. Ecology 87, 1945–1952.
Råberg, L., Grahn, M., Hasselquist, D., Svensson, E., 1998. On the adaptive
significance of stress-induced immunosuppression. Proceedings of the Royal
Society of London Series B-Biological Sciences 265, 1637–1641.
Raberg, L., Stjernman, M., Hasselquist, D., 2003. Immune responsiveness in adult
blue tits: heritability and effects of nutritional status during ontogeny.
Oecologia 136, 360–364.
Roberts, M.L., Buchanan, K.L., Hasselquist, D., Bennett, A.T.D., Evans, M.R., 2007a.
Physiological, morphological and behavioural effects of selecting zebra finches
for divergent levels of corticosterone. Journal of Experimental Biology 210,
4368–4378.
Roberts, M.L., Buchanan, K.L., Hasselquist, D., Evans, M.R., 2007b. Effects of
testosterone and corticosterone on immunocompetence in the zebra finch.
Hormones and Behavior 51, 126–134.
Rubenstein, D.R., Parlow, A.F., Hutch, C.R., Martin, L.B., 2008. Environmental and
hormonal correlates of immune activity in a cooperatively breeding tropical
bird. General and Comparative Endocrinology 159, 10-15.
Sapolsky, R.M., Romero, L.M., Munck, A.U., 2000. How do glucocorticoids influence
stress responses? Integrating permissive, suppressive, stimulatory, and
preparative actions. Endocrine Reviews 21, 55–89.
Scheuerlein, A., Van’t Hof, T.J., Gwinner, E., 2001. Predators as stressors?
Physiological and reproductive consequences of predation risk in tropical
stonechats (Saxicola torquata axillaris). Proceedings of the Royal Society of
London Series B-Biological Sciences 268, 1575–1582.
Schmidt, K.L., Soma, K.K., 2008. Cortisol and corticosterone in the songbird immune
and nervous systems: local vs. systemic levels during development. American
Journal of Physiology-Regulatory Integrative and Comparative Physiology 295,
R103–R110.
Shanks, N., Windle, R.J., Perks, P.A., Harbuz, M.S., Jessop, D.S., Ingram, C.D., Lightman,
S.L., 2000. Early-life exposure to endotoxin alters hypothalamic–pituitary–
adrenal function and predisposition to inflammation. Proceedings of the
National Academy of Sciences of the United States of America 97, 5645–5650.
Stark, J.L., Avitsur, R., Padgett, D.A., Campbell, K.A., Beck, F.M., Sheridan, J.F., 2001.
Social stress induces glucocorticoid resistance in macrophages. American
76
L.B. Martin / General and Comparative Endocrinology 163 (2009) 70–76
Journal of Physiology-Regulatory Integrative and Comparative Physiology 280,
R1799–R1805.
Sternberg, 2006. Neural regulation of innate immunity: a coordinated
nonspecific host response to pathogens. Nature Reviews Immunology 6,
318–328.
Valencia, J., Solis, E., Sorci, G., de la Cruz, C., 2006. Positive correlation between
helpers at nest and nestling immune response in a cooperative breeding bird.
Behavioral Ecology and Sociobiology 60, 399–404.
Viswanathan, K., Dhabhar, F.S., 2005. Stress-induced enhancement of leukocyte
trafficking into sites of surgery or immune activation. Proceedings of the
National Academy of Sciences of the United States of America 102, 5808–5813.
Wada, H., 2008. Glucocorticoids: mediators of vertebrate ontogenetic transitions.
General and Comparative Endocrinology 156, 441–453.
Wingfield, J.C., Maney, D.L., Breuner, C.W., Jacobs, J.D., Lynn, S., Ramenofsky, M.,
Richardson, R.D., 1998. Ecological bases of hormone-behavior interactions: the
‘‘emergency life history stage”. American Zoologist 38, 191–206.