Seasonal Changes In Immune Function Research Articles

Circadian and circannual timescales interact to generate seasonal changes in immune function

Annual changes in day length enhance or suppress diverse aspects of immune function, giving rise to seasonal cycles of illness and mortality. The daily light–dark cycle also entrains circadian rhythms in immunity. Most published reports on immunological seasonality rely on measurements or interventions performed only at one point in the day. Because there can be no perfect matching of circadian phase across photoperiods of different duration, the manner in which these timescales interact to affect immunity is not understood. We examined whether photoperiodic changes in immune function reflect phenotypic changes that persist throughout the daily cycle, or merely reflect photoperiodic shifts in the circadian phase alignment of immunological rhythms. Diurnal rhythms in blood leukocyte trafficking, infection induced sickness responses, and delayed-type hypersensitivity skin inflammatory responses were examined at high-frequency sampling intervals (every 3 h) in Siberian hamsters (Phodopus sungorus) following immunological adaptation to summer or winter photoperiods. Photoperiod profoundly enhanced or suppressed immune function, in a trait-specific manner, and we were unable to identify a phase alignment of diurnal waveforms which eliminated these enhancing and suppressing effects of photoperiod. These results support the hypothesis that seasonal timescales affect immunity via mechanisms independent of circadian entrainment of the immunological circadian waveform.

Temperature-independent, seasonal fluctuations in immune function of the Mojave Desert Tortoise (Gopherusagassizii)

As long-lived reptiles, Mojave Desert Tortoises (Gopherus agassizii (Cooper, 1861)) are expected to make substantial energetic investments in immune defense. This species also has many adaptations to living in an arid environment characterized by seasonal extremes in temperature and resource availability. By housing G. agassizii at a controlled, constant ambient temperature, we quantified predominantly temperature-independent, seasonal fluctuations in innate immune function and circulating leukocytes in a reptile. We found a decrease in bacteriocidal activity of the blood plasma in winter, with reduced function lasting into the spring. Lymphocyte numbers were elevated in fall and winter, whereas eosinophil numbers increased in summer. Thus, properties of the immune system were up- or down-regulated in different directions across the seasons. We found a much higher level of variation of leukocyte profiles among individuals than has previously been reported for other chelonians. Heterophil:lymphocyte ratios (indicative of chronic glucocorticoid levels) were not associated with any measure of immune function, and thus glucocorticoid does not seem to mediate the observed seasonal changes. We propose a new hypothesis to explain seasonal changes in immune function, based on seasonal resource limitation in the Mojave Desert, including the availability of dietary protein, energy, and opportunities for thermal regulation.

Neuroendocrine control of photoperiodic changes in immune function.

Seasonal variation in immune function putatively maximizes survival and reproductive success. Day length (photoperiod) is the most potent signal for time of year. Animals typically organize breeding, growth, and behavior to adapt to spatial and temporal niches. Outside the tropics individuals monitor photoperiod to support adaptations favoring survival and reproductive success. Changes in day length allow anticipation of seasonal changes in temperature and food availability that are critical for reproductive success. Immune function is typically bolstered during winter, whereas reproduction and growth are favored during summer. We provide an overview of how photoperiod influences neuronal function and melatonin secretion, how melatonin acts directly and indirectly to govern seasonal changes in immune function, and the manner by which other neuroendocrine effectors such as glucocorticoids, prolactin, thyroid, and sex steroid hormones modulate seasonal variations in immune function. Potential future research avenues include commensal gut microbiota and light pollution influences on photoperiodic responses.

Photoperiod Alters Duration and Intensity of Non–Rapid Eye Movement Sleep Following Immune Challenge in Siberian Hamsters (Phodopus sungorus)

Sleep is regulated by circadian and homeostatic processes, but can be altered by infectious disease. During infection or exposure to inflammatory stimuli, such as bacterial lipopolysaccharide (LPS), the duration and intensity of non–rapid eye movement sleep (NREMS), as measured by electoencephalogram (EEG) delta waves (.5–4 Hz), increase. These sleep alterations are hypothesized to conserve or redirect energy for immune system activation. Many vertebrates exhibit seasonal changes in immune function and sleep-wake cycle, and photoperiod (day length) serves as a reliable environmental cue. For example, winter is energetically demanding for most animals, and Siberian hamsters (Phodopus sungorus) adapted to short winter day lengths display reduced fever after LPS administration to presumably conserve energy. We hypothesized that short days increase the duration and intensity of NREMS after LPS challenge to create additional energy savings, despite evidence to the contrary that high fever is associated with increased NREMS. Male hamsters were housed under long (16 h light (L):8 h dark (D)) or short (8L:16D) day lengths, and chronically implanted with transmitters that recorded EEG and electromyogram (EMG) biopotentials simultaneously or core body temperature. After >10 wks in photoperiod conditions, hamsters received an i.p. injection of LPS or saline (control), and vigilance states (duration and distribution of NREMS, rapid eye movement sleep (REMS), and wakefulness) and EEG delta power spectra (NREMS intensity) were assessed. As expected, LPS treatment increased the duration and intensity of NREMS compared to controls. Hamsters adapted to short photoperiods exhibited cumulatively larger increases in NREMS duration and EEG delta wave amplitude 0–8 h after LPS injection compared to long-day LPS-treated hamsters despite short-day attenuation of fever. These results suggest a seasonal decoupling of LPS-induced fever with sleep to promote energy conservation during predictable energy shortages. Ultimately, the combination of increased sleep and reduced fever could represent a suite of physiological adaptations that increase the probability of surviving winter. (Author correspondence: Noah.Ashley@osumc.edu)

Partial removal of brown adipose tissue enhances humoral immunity in warm-acclimated Mongolian gerbils ( Meriones unguiculatus)

Temperate rodent species experience marked seasonal fluctuations in environmental temperatures. High thermoregulatory demands during winter usually weaken immune function. Brown adipose tissue (BAT) plays a crucial role in adaptive thermoregulatory process. Thus, we proposed the hypothesis that BAT might participate in the regulation of seasonal changes in immune function. The present study examined the trade-off between thermoregulation and immune function and the potential role of BAT in regulating seasonal changes in immune function in Mongolian gerbils. Specifically, surgical removal of interscapular BAT (34% of total BAT) was performed in male gerbils, and subsequently acclimated to either warm (23 ± 1 °C) or cold (4 ± 1 °C) conditions. Gerbils were then challenged with innocuous antigens and the immune responses were measured. Resting metabolic rate (RMR) and nonshivering thermogenesis (NST) were increased under cold conditions. However, the cost of thermoregulation during cold acclimation did not suppress T-cell mediated immunity and humoral immunity or decrease spleen mass, thymus mass and white blood cells. Partial removal of BAT significantly enhanced humoral immunity in warm-acclimated, but not in cold-acclimated gerbils. T-cell mediated immunity, white blood cells and immune organs were not affected by BAT removal under both warm and cold conditions. Collectively, our results imply that BAT has a suppressive effect on humoral immunity in warm-acclimated gerbils and differential effects of BAT on humoral immunity under different temperatures (e.g., summer and winter) might be benefit to their survival.

Exogenous insulin enhances humoural immune responses in short-day, but not long-day, Siberian hamsters (Phodopus sungorus)

Many animals experience marked seasonal fluctuations in environmental conditions. In response, animals display adaptive alterations in physiology and behaviour, including seasonal changes in immune function. During winter, animals must reallocate finite energy stores from relatively costly, less exigent systems (e.g. reproduction and immunity) to systems critical for immediate survival (e.g. thermoregulation). Seasonal changes in immunity are probably mediated by neuroendocrine factors signalling current energetic state. One potential hormonal candidate is insulin, a metabolic hormone released in response to elevated blood glucose levels. The aim of the present study was to explore the potential role of insulin in signalling energy status to the immune system in a seasonally breeding animal, the Siberian hamster (Phodopus sungorus). Specifically, exogenous insulin was administered to male hamsters housed in either long 'summer-like' or short 'winter-like' days. Animals were then challenged with an innocuous antigen and immune responses were measured. Insulin treatment significantly enhanced humoural immune responses in short, but not long days. In addition, insulin treatment increased food intake and decreased blood glucose levels across photoperiodic treatments. Collectively, these data support the hypothesis that insulin acts as an endocrine signal integrating seasonal energetic changes and immune responses in seasonally breeding rodents.

Seasonal variations in onset of symptoms in Crohn's disease

Background Seasonal variations in onset of symptoms have been reported in ulcerative colitis but not in Crohn's disease. Aim. To investigate whether our inflammatory bowel diseases patients presented seasonal variations in onset of symptoms. Patients and methods Patients with a diagnosis of inflammatory bowel diseases established between 1995 and May 2004, and consecutively observed from June 2003 to May 2004, were included in the study. Onset of symptoms (year, season and month) was recorded. Expected onsets with a uniform distribution during the year were calculated and compared to observed onsets. Statistical analysis: chi-square test, odds ratio (95% confidence interval). Results Overall 425 inflammatory bowel diseases patients were enrolled. Onset of symptoms (year and season) was established in 353/425 patients (83%; 150 Crohn's disease; 203 ulcerative colitis). Onset of symptoms in inflammatory bowel diseases patients as a whole occurred more frequently in spring–summer compared to autumn–winter (odds ratio 1.39; 95% confidence interval 1.03–1.87; p < 0.03). This variation was observed in Crohn's disease (odds ratio 1.59; 95% confidence interval 1.00–2.51; p < 0.05) and a similar trend, although not significant, was observed in ulcerative colitis (odds ratio 1.27; 95% confidence interval 0.86–1.88; p = 0.27). Conclusions These data indicate that onset of Crohn's disease symptoms occurred more frequently during spring-summer. A similar trend was observed in ulcerative colitis. Environmental factors, such as associated infections, smoking, use of drugs and seasonal changes in immune function may be responsible for triggering the clinical onset of inflammatory bowel diseases.

Does neuroimmune dysfunction mediate seasonal mood changes in winter depression?

Background: Animal studies have demonstrated seasonal changes in immune function mediated by nocturnal melatonin duration as a biological signal for photoperiod. Recent research has highlighted the potential role of neuroimmune dysfunction in depressive disorders. The etiology of winter depression (seasonal affective disorder, or SAD) is not known, but a number of studies have provided support for both photoperiod and neurotransmitter hypotheses. Hypothesis: A new hypothesis is presented that links the SAD data on melatonin, photoperiod, and neurotransmitters by proposing that seasonal increases in proinflammatory cytokines are critical in the pathophysiology of winter SAD. Testing the hypothesis: In SAD patients, but not healthy subjects: proinflammatory cytokines will be increased and the Th1/Th2 balance will be shifted to the left in winter compared to summer; neuroimmune function will be correlated with nocturnal melatonin duration in SAD patients; and light treatment will correct neuroimmune dysfunction. Implications of the hypothesis: Diagnostic tests for SAD may be developed using cytokine assays; neuroimmune dysfunction may be predictors of response to treatments; new treatments for SAD (immune or anti-inflammatory treatment) may be developed.

Seasonal changes in immune response and parasite impact on hosts.

Seasonal changes in the impact of parasites on hosts should result in seasonal changes in immune function. Since both ectoparasites and endoparasites time their reproduction to that of their hosts, we can predict that hosts have been selected to show an annual peak in their ability to raise an immune response during the reproductive season. We found large seasonal changes in immune function between the breeding and the nonbreeding season for a sample of temperate bird species. These changes amounted to a decrease in spleen mass from the breeding to the nonbreeding season by on average 18% across 71 species and a seasonal decrease in T-cell-mediated immunity by on average 33% across 13 species. These seasonal changes in immune function differed significantly among species. The condition dependence of immune function also differed between the breeding and the nonbreeding season, with individuals in prime condition particularly having greater immune responses during breeding. Analyses of ecological factors associated with interspecific differences in seasonal change of immune function revealed that hole-nesting species had a larger increase in immune function during the breeding season than did open nesters. Since hole nesters suffer greater reduction in breeding success because of virulent parasites than do open nesters, this seasonal change in immune function is suggested to have arisen as a response to the increased virulence of parasites attacking hole-nesting birds.

Lack of immunological responsiveness to photoperiod in a tropical rodent, Peromyscus aztecus hylocetes.

Non-tropical rodents undergo seasonal changes in immune function and disease. It has been hypothesized that seasonal fluctuations in immunity of non-tropical rodents are due to suppressed immune function during harsh winter conditions. A logical extension of this hypothesis is that seasonal changes in immunity should be reduced or absent in tropical rodents that do not experience marked seasonal fluctuations in environmental conditions; however this hypothesis remains to be tested. The present study tested the effects of photoperiod on humoral and cell-mediated immune function of male Aztec mice ( Peromyscus aztecus hylocetes). P. a. hylocetes were housed in long (L:D 16:8) or short days (L:D 8:16) for 10 weeks. Animals were then immunized with the antigen keyhole limpet hemocyanin (KLH). Serum anti-KLH immunoglobulin G (IgG) concentrations and splenocyte proliferation in response to the T-cell mitogen Concanavalin A were assessed. Short-day P. a. hylocetes did not display differences in reproductive or immune measures compared with long-day mice. Collectively, these results suggest that P. a. hylocetes are reproductively and immunologically non-responsive to photoperiod. This lack of immunological responsiveness is likely due to the relative seasonal stability of their environment compared with temperate zone species.

Melatonin and Immune Function: Hype or Hypothesis?

Outside of the tropics, the combined challenge of food shortage and low temperature makes winter a particularly difficult time for reproduction and survival. Traditionally, vertebrate physiologists interested in seasonal phenomena have focused on reproduction and largely ignored survival. Our goal is to emphasize a new dimension to the study of seasonality by shifting the focus from reproduction to immune function and survival. Our hypothesis is that mechanisms enhancing immune function have evolved that enable individuals to anticipate predictable seasonal challenges that may adversely affect immunity. Stated differently, we visualize seasonal variations in survival as the interaction between two factors: the suppression of immune response due to changing energetic conditions and an endogenous rhythm of enhancement of immune response that is dependent on photoperiod, clocks, and melatonin. In this article, we review evidence of photoperiod influences on seasonal changes in immune function within the context of energy allocation. Further, we also examine mounting evidence that the pattern of melatonin secretion, mediated by photoperiod, directly influences immune function.

Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist.

In addition to marked seasonal changes in reproductive, metabolic, and other physiological functions, many vertebrate species undergo seasonal changes in immune function. Despite growing evidence that photoperiod mediates seasonal changes in immune function, little is known regarding the neuroendocrine mechanisms underlying these changes. Increased immunity in short days is hypothesized to be due to the increase in the duration of nightly melatonin secretion, and recent studies indicate that melatonin acts directly on immune cells to enhance immune parameters. The present study examined the contribution of melatonin receptors in mediating the enhancement of splenocyte proliferation in response to the T cell mitogen Concanavalin A in mice. The administration of luzindole, a high-affinity melatonin receptor antagonist, either in vitro or in vivo significantly attenuated the ability of in vitro melatonin to enhance splenic lymphocyte proliferation during the day or night. In the absence of melatonin or luzindole, splenocyte proliferation was intrinsically higher during the night than during the day. In the absence of melatonin administration, luzindole reduced the ability of spleen cells to proliferate during the night, when endogenous melatonin concentrations are naturally high. This effect was not observed during the day, when melatonin concentrations are low. Taken together, these results suggest that melatonin enhancement of splenocyte proliferation is mediated directly by melatonin receptors on splenocytes and that there is diurnal variation in splenocyte proliferation in mice that is also mediated by splenic melatonin receptors.

Unraveling the enigma: the role of melatonin in seasonal processes in birds.

Birds, unlike mammals, do not use the annual profile of pineal melatonin secretion to coordinate their reproductive efforts with a favorable time of year. Melatonin in birds mediates the entrainment of circadian activity rhythms, and thus helps to time hatching of eggs and facilitate migration. However, the role of melatonin as a reliable indicator of day length for seasonal processes has remained equivocal for many years. Recently, the influence of melatonin on two physiological processes involved in aspects of seasonal reproduction has been identified in European starlings: 1) the regulation of seasonal changes in immune function, and 2) neuroplasticity in the song control system. Melatonin can enhance cell-mediated immune function and acts as an inhibitory hormone on the song control system. Melatonin receptor (MelR) density in a forebrain song control nucleus, Area X, is regulated as a function of reproductive state; there is marked downregulation of MelR in Area X during the breeding season in starlings. Seasonal regulation of immune function and neural plasticity within the song control system, and the efficacy of the action of melatonin on these two processes, appears to be modified by the same central, thyroid-dependent mechanism that controls the reproductive state of birds. These data indicate that the interaction of day length and hormones of different classes affects the ability of melatonin to affect seasonal processes in birds. The downstream consequences of MelR regulation within the song control system are discussed with regard to the cellular action of melatonin and its possible interaction with immediate-early genes and transcription factors.

Endocrine-immune interaction: alteractions in immune function resulting from neonatal treatment with a GnRH antagonist and seasonality in male primates.

The effect of neonatal gonadotropin releasing hormone (GnRH) antagonist (Ant) treatment and seasonality on immune system development and function was investigated in male primates. Neonatal male rhesus monkeys and marmosets were treated with Ant, and its effect on immune system morphology, circulating lymphocyte subsets, and cell- and humorally-mediated immune responses was assessed during development. In adult rhesus monkeys, we correlated seasonal changes in immune function with circannual fluctuations in immunoactive hormones. In neonatal marmosets, Ant reduced the number of B cells and T cells in the thymic medulla and T cells in the periarterial lymphatic sheaths (PALS) of the spleen. Ant also altered the development of, but did not permanently impair, the proliferative index (PI) of blood lymphocytes to mitogens. In vitro treatment of control lymphocytes with GnRH analogues altered their response to these proliferative agents. In neonatal rhesus monkeys, Ant treatment increased the frequency of clinical problems, lowered circulating levels of lymphocytes, total T cells, CD8+ T cells and B cells, and altered the PI of lymphocytes to mitogens. As adults, the cell- and humorally-mediated immune responses remained impaired. We also documented seasonal fluctuations in the prevalence of diseases, circulating immune cells and immune function in rhesus monkeys. The number of cases of campylobacteriosis and shigellosis was lowest in the winter and highest in the spring. Circulating numbers of white blood cells (WBC) and neutrophils and the PI of lymphocytes to mitogens were higher in the winter than in the summer. Natural killer cell activity also varied with season. Cortisol and leptin secretion exhibited circannual rhythms, rising in concert with decreasing photoperiod and increasing testicular activity in the fall. Conversely, prolactin levels declined with decreasing photoperiod and then rose in the spring. Neonatal exposure of male primates to Ant appears to alter early postnatal programming of immune function. In the rhesus monkey, immune function shows seasonal fluctuations that may be driven by circannual changes in the secretion of immunoactive hormones.

Melatonin mediates seasonal changes in immune function.

Field studies indicate that immune function is compromised and the prevalence of many diseases are elevated during winter when energetic stressors are extensive. Presumably, individuals would enjoy a survival advantage if seasonally recurring stressors could be anticipated and countered by shunting energy reserves to bolster immune function. The primary environmental cue that permits physiological anticipation of season is daily photoperiod, a cue that is mediated by melatonin. However, other environmental factors, including low food availability and ambient temperatures, may interact with photoperiod to affect immune function and disease processes. This paper will review laboratory studies that consistently report enhanced immune function in short day lengths. Prolonged melatonin treatment mimics short days, and both in vitro and in vivo melatonin treatment enhances various aspects of immune function, especially cell-mediated immune function, in nontropical rodents. Reproductive responsiveness to melatonin appears to affect immune function. In sum, melatonin may be part of an integrative system to coordinate reproductive, immunologic, and other physiological processes to cope successfully with energetic stressors during winter.

Melatonin mediates seasonal adjustments in immune function.

In addition to seasonal changes in reproductive function, seasonal changes in immune function are mediated by the pineal hormone, melatonin. Melatonin affects immune function both indirectly, acting through other hormones, and directly by acting on components of the immune system. Melatonin also affects tumorigenesis and tumor development. We hypothesize that many of the indirect effects of melatonin on immune function are mediated through glucocorticoids, and appear to be part of an integrated series of adaptations to manage energy. Direct effects of melatonin on immune function appear to be mediated by melatonin receptors on lymphatic tissue or on immune cells in circulation. Winter is energetically demanding and stressful; thermoregulatory demands typically increase when food availability decreases. Individuals would enjoy a survival advantage if seasonally recurring stressors could be anticipated and countered by bolstering immune function. To summarize, melatonin may be part of an integrative system to coordinate reproductive, immunologic and other physiological processes to cope successfully with energetic stressors during winter.

Exogenous melatonin enhances cell-mediated, but not humoral, immune function in adult male deer mice (Peromyscus maniculatus).

Many nontropical rodent species display seasonal changes in reproductive physiology and metabolism, as well as in immune function. Field studies of seasonal changes in immune function typically report decreased immune function in the short days of winter compared to summer; presumably, reduced immunity in winter reflects increased glucocorticoid secretion in response to environmental stressors. In contrast, laboratory studies of photoperiodic changes in immunity invariably demonstrate increased immune function in short compared to long days. Although the precise mechanisms regulating short-day enhancement of immune function are not known, it is hypothesized that increased immunity is due to the increased duration of melatonin secretion in short compared to long days. However, melatonin can act both directly (i.e, via melatonin receptors located on lymphatic tissue) and indirectly (i.e., via alterations in gonadal steroids) to affect immune function. The present study examined the effects of exogenous melatonin administration on both cell-mediated and humoral immune function in adult male deer mice (Peromyscus maniculatus), as well as the role of gonadal steroid hormones in mediating these effects. Mice either were castrated to remove circulating androgens or received sham operations and were implanted with empty capsules or capsules containing melatonin. Individual mice implanted with melatonin underwent reproductive regression and displayed enhanced splenocyte proliferation to the T-cell mitogen concanavalin A; antigen-specific serum immunoglobulin M production was unaffected by melatonin treatment. Castration had no effect on either cell-mediated or humoral immune function. Taken together, these results suggest that exogenous melatonin enhances cell-mediated, but not humoral, immune function in adult male deer mice and that this effect is independent of gonadal steroid hormones. These results are consistent with a direct effect of melatonin on immunity.

Photoperiodic Mediation of Seasonal Breeding and Immune Function In Rodents: A Multi-Factorial Approach

SYNOPSIS. Winter is energetically-demanding; thermoregulatory demands increase when food availability usually decreases. Physiological and behavioral adaptations, including termination of breeding, have evolved among nontropical animals to cope with winter energy shortages. Presumably, selection for mechanisms that permit physiological and behavioral anticipation of seasonal ambient changes have led to current seasonal breeding patterns for many populations. Energetically—challenging winter conditions can directly induce death via hypothermia, starvation, or shock; surviving these demanding conditions likely evokes significant stress responses. The stress of coping with energetically-demanding conditions may increase adrenocortical steroid levels to the extent that immune function is compromised. Individuals would enjoy a survival advantage if seasonally-recurring stressors could be anticipated and countered by shunting energy reserves to bolster immune function. The primary environmental cue that permits physiological anticipation of season is daily photoperiod, a cue that is mediated by melatonin. However, other environmental factors, such as low food availability and ambient temperatures, may interact with photoperiod to affect immune function and disease processes. Laboratory studies of seasonal changes in mammalian immune function consistently report that immune function is enhanced in short day lengths. Prolonged melatonin treatment mimics short days, and also enhances immune function in rodents. In sum, melatonin may be part of an integrative system to coordinate reproductive, immunologic, and other physiological processes to cope successfully with energetic stressors during winter. Social factors influence immune function and changes in social interactions may also contribute to seasonal changes in immune function. The mechanisms by which social factors are transduced into immune responses are largely unspecified. In order to understand the optimization of immune function it is necessary to understand the interaction of factors, on both mechanistic and functional levels, that affect immunity.

Stress affects corticosteroid and immunoglobulin concentrations in male house mice ( Mus musculus) and prairie voles ( Microtus ochrogaster)

Glucocorticoids, secreted in response to perceived stress, can suppress immunoglobulin (Ig) levels and compromise immune function in mice and rats. Prairie voles ( Microtus ochrogaster) have been reported to exhibit basal corticosterone concentrations that would cause pathological changes in the immune function of most other rodents. The goals of the present study were to verify that serum corticosterone concentration are high in prairie voles, as compared with house mice ( Mus musculus), by measuring serum corticosterone with the same RIA; to examine the effects of mild stressors on corticosterone response in both species and to examine the effects of elevated corticosterone levels on IgM and IgG levels in prairie voles and house mice. After 2 weeks of randomly timed 15-min daily restraint or cold-water swim sessions, animals were injected with sheep red blood cells. The data confirmed that basal blood concentrations of corticosterone were higher in prairie voles than house mice, but these high levels doubled after the first swim session in prairie voles, indicating that the adrenals can respond to stressors by producing increased corticosterone. After stress, antibody production (both IgM and IgG) was reduced in house mice but not in prairie voles, despite higher blood concentrations of glucocorticoids in prairie voles. Although body mass was statistically equivalent between species, prairie voles and mice differed dramatically in adrenal and splenic masses. Average adrenal mass of prairie voles was approximately three times the average mass of these organs in house mice; in contrast, the average splenic mass of house mice was approximately three times that of prairie voles. These data may be relevant to seasonal changes in immune function and survival.

Seasonal changes in immune function.

Winter is energetically demanding. Physiological and behavioral adaptations have evolved among nontropical animals to cope with winter because thermoregulatory demands increase when food availability decreases. Seasonal breeding is central within the suite of winter adaptations among small animals. Presumably, reproductive inhibition during winter conserves energy at a time when the adds of producing viable young are low. In addition to the well-studied seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among many populations of mammals and birds in the field. Challenging winter conditions, such as low ambient temperatures and decreased food availability, can directly induce death via hypothermia, starvation or shock. In some cases, survival in demanding winter conditions puts individuals under great physiological stress, defined here as an adaptive process that results in elevated blood levels of glucocorticoids. The stress of coping with energetically demanding conditions can also indirectly cause illness and death by compromising immune function. Presumably, the increased blood concentrations of adrenocortical steroids in response to winter stressors compromise immune function and accelerate catabolic mechanisms in the field, although the physiological effects of elevated glucocorticoids induced by artificial stressors have been investigated primarily in the laboratory. However, recurrent environmental stressors could reduce survival if they evoke persistent glucocorticoid secretion. The working hypothesis of this article is that mechanisms have evolved in some animals to combat seasonal stress-induced immunocompromise as a temporal adaptation to promote survival. Furthermore, we hypothesize that mechanisms have evolved that allow individuals to anticipate periods of immunologically challenging conditions, and to cope with these seasonal health-threatening conditions. The primary environmental cue that permits physiological anticipation of season is the daily photoperiod; however, other environmental factors may interact with photoperiod to affect immune function and disease processes. The evidence for seasonal fluctuations in lymphatic organ size, structure, immune function, and disease processes, and their possible interactions with recurrent environmental stressors, is reviewed. Seasonal peaks of lymphatic organ size and structure generally occur in late autumn or early winter and seasonal minima are observed prior to the onset of breeding. Although many of the field data suggest that immune function and disease processes are also enhanced during the winter, the opposite seasonal pattern is also observed in some studies. We propose that compromised immune function may be observed in some populations during particularly harsh winters when stressors override the enhancement of immune function evoked by short day lengths. Because so many factors covary in field studies, assessment of our proposal that photoperiod mediates seasonal changes in immune function requires laboratory studies in which only photoperiod is varied. A review of the effects of photoperiod on immune function in laboratory studies reveals that exposure to short day lengths enhances immune function in every species examined. Short day exposure in small mammals causes reproductive inhibition and concomitant reduction in plasma levels of prolactin and steroid hormones, as well as alterations in the temporal pattern of pineal melatonin secretion. These hormones affect immune function, and influence the development of opportunistic diseases, including cancer: however, it appears that either prolactin or melatonin secretion is responsible for mediating the effects of photoperiod on immune function. Taken together, day length appears to affect immune function in many species, including animals that typically do not exhibit reproductive responsiveness to day length.