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.

On the winter enhancement of adaptive humoral immunity: hypothesis testing in desert hamsters (Phodopus roborovskii: Cricetidae, Rodentia) kept under long-day and short-day photoperiod.

We tested the winter immunity enhancement hypothesis (WIEH) on male desert hamsters (Phodopus roborovskii) kept under long-day (LD) and short-day (SD) photoperiods. We assumed that under SD in a laboratory, the adaptive humoral immune responsiveness to the antigenic challenge would be enhanced due to the lack of winter physical stressors and food shortages and/or because of the action of an endogenous winter bolstering mechanism, while under LD the immune responsiveness would be suppressed by the activity of the reproductive system. The results support the WIEH in part. We did not find a difference in antibody production in response to sheep erythrocytes between SD and LD hamsters, but SD males had the lower number of granulocytes and the higher number of lymphocytes in white blood cell counts. Reproductive activity was lower in SD males. These males demonstrated an increase in their mass-specific resting metabolic rate, their mass-specific maximal metabolic rate and their level of cortisol. The result of a generalized linear model analysis indicates the negative effect on secondary immunoresponsiveness to sheep erythrocytes of mid-ventral gland size, the organ characterizing individual reproductive quality, and designates a tradeoff between antibody production and reproductive effort. The mass-independent maximal metabolic rate also negatively affected antibody production, indicating a tradeoff between maximal aerobic performance and the adaptive immune function. The higher stress in SD males seems to be the most likely reason for the lack of the effect of daylight duration on antibody production.

Timing of Maternal Immunization Affects Immunological and Behavioral Outcomes of Adult Offspring in Siberian Hamsters (Phodopus sungorus).

Maternal influences are an important contributing factor to offspring survival, development, and behavior. Common environmental pathogens can induce maternal immune responses and affect subsequent development of offspring. There are likely sensitive periods during pregnancy when animals are particularly vulnerable to environmental disruption. Here we characterize the effects of maternal immunization across pregnancy and postpartum on offspring physiology and behavior in Siberian hamsters (Phodopus sungorus). Hamsters were injected with the antigen keyhole limpet hemocyanin (KLH) (1) prior to pairing with a male (premating), (2) at separation (postmating), (3) at midpregnancy, or (4) after birth (lactation). Maternal food intake, body mass, and immunity were monitored throughout gestation, and litters were measured weekly for growth until adulthood when social behavior, hormone concentrations, and immune responses were determined. We found that immunizations altered maternal immunity throughout pregnancy and lactation. The effects of maternal treatment differed between male and female offspring. Aggressive behavior was enhanced in offspring of both sexes born to mothers treated postmating and thus early in pregnancy relative to other stages. In contrast, maternal treatment and maternal stage differentially affected innate immunity in males and females. Offspring cortisol, however, was unaffected by maternal treatment. Collectively, these data demonstrate that maternal immunization affects offspring physiology and behavior in a time-dependent and sex-specific manner. More broadly, these findings contribute to our understanding of the effects of maternal immune activation, whether it be from environmental exposure or immunization, on immunological and behavioral responses of offspring.

Is allergic sensitization to Siberian Hamster preventable in high-risk individuals who are already sensitized or exposed to furry animals?

No disponible

Reply to Liccardi et al: Is allergic sensitization to Siberian Hamster preventable in high-risk individuals who are already sensitized or exposed to furry animals?

No disponible

Clinical characteristics of patients sensitized to Siberian Hamster

No disponible

Male-specific submaxillary gland protein, a lipocalin allergen of the golden hamster, differs from the lipocalin allergens of Siberian and Roborovski dwarf hamsters.

BACKGROUND: An increasing number of asthma cases upon exposure to hamsters and anaphylactic reactions following hamster bites are being reported, but the allergens responsible are still poorly characterized. In the Golden hamster, male-specific submaxillary gland protein (MSP), a lipocalin expressed in a sex- and tissue-specific manner in the submaxillary and lacrimal glands, is secreted in the saliva, tears and urine. The purpose of this study was to determine if MSP is an allergen, to identify IgE-reactive proteins of different hamster species and to analyse potential cross-reactivities. METHODS: Fur extracts were prepared from four hamster species. Hamster-allergic patients were selected based on a history of positive IgE-test to hamster epithelium. The IgE-reactivity of patients' sera was investigated by means of immunoblot and ELISA. IgE-reactive proteins in fur extracts and the submaxillary gland were identified using anti-MSP antibodies, Edman sequencing or mass spectrometry. MSP was purified from Golden hamster and recombinant MSP was expressed in E. coli. RESULTS: Four patients had IgE-antibodies against 20.5-kDa and 24-kDa proteins of Golden hamster fur extract, which were identified as MSP. IgE-reactive MSP-like proteins were detected in European hamster fur extract. Three patient sera showed IgE-reactive bands at 17-21 kDa in Siberian and Roborovski hamster fur extracts. These proteins were identified as two closely related lipocalins. Immunoblot inhibition experiments showed that they are cross-reactive and are different from MSP. CONCLUSION: MSP lipocalin of the Golden hamster was identified as an allergen, and it is different from the cross-reactive lipocalin allergens of Siberian and Roborovski hamsters. Our findings highlight the need for specific tools for the in vitro and in vivo diagnosis of allergy to different hamster species.

Metabolic stressors and signals differentially affect energy allocation between reproduction and immune function.

Most free-living animals have finite energy stores that they must allocate to different physiological and behavioral processes. In times of energetic stress, trade-offs in energy allocation among these processes may occur. The manifestation of trade-offs may depend on the source (e.g., glucose, lipids) and severity of energy limitation. In this study, we investigated energetic trade-offs between the reproductive and immune systems by experimentally limiting energy availability to female Siberian hamsters (Phodopus sungorus) with 2-deoxy-d-glucose, a compound that disrupts cellular utilization of glucose. We observed how glucoprivation at two levels of severity affected allocation to reproduction and immunity. Additionally, we treated a subset of these hamsters with leptin, an adipose hormone that provides a direct signal of available fat stores, in order to determine how increasing this signal of fat stores influences glucoprivation-induced trade-offs. We observed trade-offs between the reproductive and immune systems and that these trade-offs depended on the severity of energy limitation and exogenous leptin signaling. The majority of the animals experiencing mild glucoprivation entered anestrus, whereas leptin treatment restored estrous cycling in these animals. Surprisingly, virtually all animals experiencing more severe glucoprivation maintained normal estrous cycling throughout the experiment; however, exogenous leptin resulted in lower antibody production in this group. These data suggest that variation in these trade-offs may be mediated by shifts between glucose and fatty acid utilization. Collectively, the results of the present study highlight the context-dependent nature of these trade-offs, as trade-offs induced by the same metabolic stressor can manifest differently depending on its intensity.

[Resting metabolic rate, stress, testosterone, and induced immune response in "spring" and "fall" males of Campbell dwarf hamsters. Rearing under the long day conditions].

We have studied morphological and physiological traits of even-young males of Campbell dwarf hamsters (Phodopus campbelli Thomas, 1905) born at the end of summer ("fall males") and at the end of winter ("spring males") in a vivarium with constant 14-hour day length (14D:10N). After removal from parental cages at the age of one month, males were kept in isolation under the same light conditions. The results obained signify the statistical difference between "fall" and "spring" males in resting metabolic rate, morphological traits associated with sexual activity, some endocrine and immunologic characteristics. Spring males had higher resting metabolic rate, higher body mass in the middle of experiment, bigger testes, seminal vesicles, higher concentration of testosterone in blood and more intensive T-cell immune response to the intracutaneous injection of phytohemagglutinin. They did not differ significantly in basal level of blood cortisole and antibodies production in response to sheep red blood cells (SRBC) antigen challenge, but possessed lower adrenocortical response to the social stressor and adrenocorticotropic hormone. GLM analysis showed that cortisol level in blood after 10 min encounter of males in the open arena, and resting metabolic rate were the only factors significantly influenced humoral immune response to SRBC. When intensity of T-cell immune response was considered as dependent variable, season turned out to be the only factor in the final model that caused a significant effect.

An odorant-binding protein as a new allergen from Siberian hamster (Phodopus sungorus).

A case of anaphylaxis following a bite from a Siberian hamster (SH; Phodopus sungorus) is described. Skin prick tests with hair, urine and salivary gland extracts from SH were positive, while the tests were negative for hair extracts from other rodents. IgE immunoblotting with the patient serum revealed 3 IgE-binding bands of about 18, 21 and 23 kDa. When the patient's serum was preincubated with rabbit, mouse and gerbil hair extracts, no inhibition of the 3 SH IgE-binding bands was demonstrated. Proteins extracted from the 3 bands were analyzed by N-terminal sequencing and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry, and peptides were sequenced. IgE-binding bands were identified as being an odorant-binding protein belonging to the lipocalin family. Analysis of the 3 IgE-binding bands found in the hair, urine and salivary glands of SH showed a new allergenic protein lacking cross-reactivity with allergens from other rodents. The 3 bands likely correspond to isoforms of a single allergen.

Chronic exposure to dim light at night suppresses immune responses in Siberian hamsters.

Species have been adapted to specific niches optimizing survival and reproduction; however, urbanization by humans has dramatically altered natural habitats. Artificial light at night (LAN), termed 'light pollution', is an often overlooked, yet increasing disruptor of habitats, which perturbs physiological processes that rely on precise light information. For example, LAN alters the timing of reproduction and activity in some species, which decreases the odds of successful breeding and increases the threat of predation for these individuals, leading to reduced fitness. LAN also suppresses immune function, an important proxy for survival. To investigate the impact of LAN in a species naive to light pollution in its native habitat, immune function was examined in Siberian hamsters derived from wild-caught stock. After four weeks exposure to dim LAN, immune responses to three different challenges were assessed: (i) delayed-type hypersensitivity (DTH), (ii) lipopolysaccharide-induced fever, and (iii) bactericide activity of blood. LAN suppressed DTH response and reduced bactericide activity of blood after lipopolysaccharide treatment, in addition to altering daily patterns of locomotor activity, suggesting that human encroachment on habitats via night-time lighting may inadvertently compromise immune function and ultimately fitness.

Early life experiences affect adult delayed-type hypersensitivity in short and long photoperiods.

Environmental experiences during development provide animals with important information about future conditions. Siberian hamsters are photoperiodic rodents that dramatically adjust their physiology and behavior to adapt to seasonal changes. For example, during short winter-like days, hamsters enhance some components of immune function putatively to cope with increasing environmental challenges. Furthermore, early life stress alters the developmental course of the immune system. Overall, immune function is typically suppressed in response to chronic stress, but responses vary depending on the type of stress and components of immune function assessed. This led us to hypothesize that delayed-type hypersensitivity (DTH), an antigen-specific, cell-mediated immune response, would be differentially modulated in hamsters that underwent early life maternal separation (MS) in either short or long photoperiods. At birth, hamsters were assigned to either short (SD; 8 h light/day) or long (LD; 16 h light/day) photoperiods and either daily 3 h MS, daily 15-min brief maternal separation (BMS), or no manipulation from postnatal day 2 through 14. In adulthood DTH was assessed. Hamsters reared in short days enhanced DTH responses. MS and BMS attenuated DTH responses in both short and long days. However, BMS long-day female hamsters did not suppress pinna swelling, suggesting a protective effect of female sex steroids on immune function. As is typical in short days, reproductive tissue was regressed. Reproductive tissue mass was also decreased in long-day MS female hamsters. Furthermore, MS altered photoperiod-induced changes in body mass. Taken together, these findings suggest that manipulations of early life mother-pup interactions in Siberian hamsters result in physiological changes and suppressed cell-mediated immunity.

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.

Photoperiod-related changes in hormonal and immune status of male Siberian hamsters, Phodopus sungorus.

Previously we have demonstrated that in Siberian hamsters some immune measures, especially the development of experimentally evoked peritonitis, varied in a photoperiod- and gender-dependent manner. The aim of the present study was to investigate whether the photoperiod-related differences in the activity of inflammation-involved immune cells are in this species attributed to the changes in the pineal gland function and/or hormonal status. Male hamsters housed in short day (SD), compared with those from long day (LD) conditions, exhibited significantly reduced plasma testosterone concentration and elevated cortisol and melatonin levels, the latter resulting from increased activity of hydroxyindole-O-methyltransferase (HIOMT). In LD hamsters but not in those from SD, an intraperitoneal (i.p.) injection of zymosan evoked a well-pronounced peritonitis expressed by increased free radical (ROS) production by peritoneal leukocytes (PTLs) stimulated in vitro with PMA. ROS production by these cells was additionally stimulated by both in vivo and in vitro treatment with melatonin and the latter was partially reversed by melatonin receptor antagonist luzindole. To conclude, in Siberian hamsters melatonin seems to exert rather immunostimulatory than anti-inflammatory effect, therefore other mechanisms, e.g. immunosuppressive effect of glucocorticoids, may underlay the compromised immune status observed in SD in this species.

Sex-specific effects of glucose deprivation on cell-mediated immunity and reproduction in Siberian hamsters (Phodopus sungorus).

In most species, sexes differ in levels of parasitism. These differences have traditionally been believed to be static, but a capacity for adjusting anti-parasite investments would allow sexes to allocate resources adaptively contingent on environmental conditions. During stressful periods, such as a food shortage, allocation decisions would be mandated in males and females, but the biasing of resources may differ depending on the value of various physiological alternatives to the fitness of each sex. To determine whether sexes sacrifice immune or reproductive capacity when stressed, male and female Siberian hamsters (Phodopus sungorus) were pharmacologically deprived of glucose. Glucose deprivation was expected to compromise immune activity (delayed-type hypersensitivity) more than reproductive capacity in males because male fitness is limited by reproductive opportunities. The opposite was predicted for females because of the greater value of surviving to breed in favorable conditions. Contrary to expectations, glucoprivation compromised immune activity in female, but not male, hamsters. Conversely, glucoprivation reduced male, but not female, reproductive organ masses. These results may reflect the adjustments made by wild hamsters during food shortages, or they may be influenced by the study design; neither sex was permitted to incur other behavioral and physiological costs, such as lactation and parental care. Regardless, our results indicate that sex differences in parasitism are likely to be plastic in many circumstances, but further work in free-living animals is critical to ascertain whether results of the present study are naturally representative.

Melatonin mediates photoperiod control of endocrine adaptations and humoral immunity in male Siberian hamsters.

Effects of photoperiod are mediated by the pineal gland in male Siberian hamsters. The hypothesis that the pineal hormone melatonin mediates the effects of short days (SD) to blunt select humoral and endocrine functions was tested. In the first study, regressed testes were found in pineal-intact controls transferred from long days (LD) to SDs (16 hr to 8 hr light/day); the rise in antigen-induced serum immunoglobulin (Ig) M was blunted and serum cortisol concentrations elevated compared with long-day controls. These effects of short-day were blocked in pinealectomized males moved from long to SDs, but restored by melatonin treatments. In a second study, males in LD were exposed to constant light (LL) to abolish the nighttime melatonin rhythm. In hamsters in LL, melatonin induced testicular regression as in males in SDs. Large testes were present in vehicle-treated controls in LL and in males that remained in LDs. Antigen-induced increases in serum IgM in vehicle and melatonin treatment males in LL were intermediate between concentrations in long- or short-day controls and not significantly different from each other. However, serum cortisol was again elevated in hamsters in SDs or in LL when treated with melatonin compared with males in LL or LDs. These findings indicate that melatonin treatments mimicked the effects of SDs to regulate adaptive physiologic functions in hamsters lacking the nocturnal melatonin rhythm. Thus, the photoneuroendocrine mechanism regulating reproductive responses to photoperiod also mediates short-day effects on T cell-dependent B-cell antibody production and processes that regulate cortisol in circulation.

Photoperiod alters macrophage responsiveness, but not expression of Toll-like receptors in Siberian hamsters.

Defense against pathogens is a critical component of comparative and ecological biology. However, pathogen recognition, a process necessary for the facilitation of systemic immune response, remains understudied in a comparative context, yet could provide insight into how the immune system interacts with pathogens in variable environments. We examined pathogen recognition by macrophages in relation to an ecological variable, day length, in Siberian hamsters (Phodopus sungorus). Because peritoneal macrophages collected in long, summer-like day lengths are more responsive to a lipopolysaccharide (LPS) challenge compared to macrophages collected during short, winter-like day lengths, we hypothesized that these functional differences are mediated by variation in pathogen recognition, which occurs through binding to Toll-like receptors (TLRs). We predicted that expression of TLR2 and 4, the receptors that bind and respond specifically to LPS, would be upregulated in long vs. short days, and that expression of these receptors would reflect macrophage responsiveness to LPS. Macrophages collected during long days were again more responsive to LPS challenge compared to short-day macrophages; however, TLR2 and TLR4 expression was similar between photoperiods and were unrelated to our measure of macrophage responsiveness suggesting that other downstream intracellular mechanisms may be responsible for photoperiod-based variation in macrophage responsiveness in this species.

Pineal-dependent and -independent effects of photoperiod on immune function in Siberian hamsters (Phodopus sungorus).

Siberian hamsters (Phodopus sungorus) exhibit reproductive and immunological responses to photoperiod. Short (<10-h light/day) days induce gonadal atrophy, increase leukocyte concentrations, and attenuate thermoregulatory and behavioral responses to infection. Whereas hamster reproductive responses to photoperiod are dependent on pineal melatonin secretion, the role of the pineal in short-day induced changes in immune function is not fully understood. To examine this, adult hamsters were pinealectomized (PINx) or sham-PINx, and transferred to short days (9-h light/day; SD) or kept in their natal long-day (15-h light/day; LD) photoperiod. Intact and PINx hamsters housed in LD maintained large testes over the next 12 weeks; sham-PINx hamsters exhibited gonadal regression in SD, and PINx abolished this effect. Among pineal-intact hamsters, blood samples revealed increases in leukocyte, lymphocyte, CD62L+ lymphocyte, and T cell counts in SD relative to LD; PINx did not affect leukocyte numbers in LD hamsters, but abolished the SD increase in these measures. Hamsters were then treated with bacterial lipopolysaccharide (LPS), which induced thermoregulatory (fever), behavioral (anorexia, reductions in nest building), and somatic (weight loss) sickness responses in all groups. Among pineal-intact hamsters, febrile and behavioral responses to LPS were attenuated in SD relative to LD. PINx did not affect sickness responses to LPS in LD hamsters, but abolished the ameliorating effects of SD on behavioral responses to LPS. Surprisingly, PINx failed to abolish the effect of SD on fever. In common with the reproductive system, PINx induces the LD phenotype in most aspects of the immune system. The pineal gland is required for photoperiodic regulation of circulating leukocytes and neural-immune interactions that mediate select aspects of sickness behaviors.

Metabolic stress suppresses humoral immune function in long-day, but not short-day, Siberian hamsters (Phodopus sungorus).

Individuals of many species experience marked seasonal variation in environmental conditions and must adapt to potentially large fluctuations in energy availability and expenditure. Seasonal changes in immunity have likely evolved as an adaptive mechanism to cope with seasonal stressors. In addition, these changes may be constrained by seasonal fluctuations in energy availability. The goal of this study was to assess the role of energetic trade-offs associated with seasonal variation in immunity. In addition to body fat stores, metabolic fuels (e.g., glucose) may affect immune function in seasonally breeding rodents. In this study we experimentally reduced energy availability via injections of the metabolic inhibitor 2-deoxy-D-glucose (2-DG) in long- and short-day housed Siberian hamsters (Phodopus sungorus) and then examined antigen-specific antibody production. Metabolic stress decreased antibody response compared with control animals in long days. In contrast, no difference was observed between treatment groups in short days. These data suggest that reductions in energy availability suppress immunity and short days buffer organisms against glucoprivation-induced immunosuppression.