Raine Kortet1 and Anssi Vainikka - UEF...regulation (Zapata and Cooper 1990; Zapata et al. 1992)....

In: New Research on Innate Immunity ISBN: 978-1-60456-549-2 Editors: M. Durand, C. V. Morel © 2008 Nova Science Publishers, Inc.

Chapter 1

SEASONALITY OF INNATE IMMUNITY; EVOLUTIONARY ASPECTS AND LATEST UPDATES

Raine Kortet1 and Anssi Vainikka2 Section of Ecology, Department of Biology, University of Oulu, PO Box 3000, FI-90014

University of Oulu, Finland Institute of Coastal Research, Swedish Board of Fisheries, Box 109, SE-742 22

Öregrund, Sweden

ABSTRACT

Innate immunity is the first line defense of all animals against novel pathogens and parasites. Exposure to many parasites and pathogens varies seasonally following the life-cycle of the parasite or due to intra-annual variation in the infectivity of pathogens. At the same time the reproductive cycle of the host co-varies with changes in the environment resulting in a seasonally varying fitness landscape. Organisms face these seasonal challenges by regulating their internal physiology, i.e. by secreting hormones. Melatonin and steroid hormones contribute to the seasonal redistribution of immunological activity including winter-time up-regulation of some immune defenses, and reproduction-related immunosuppression. Whereas ectotherm’s immune functions are directly exposed to seasonal variations in environmental temperature, seasonality drives immunity also in endotherms mainly through photoperiodicity. Further, innate immune functions have been demonstrated to involve condition and stress-dependent components, which link the seasonal fluctuations, for example, in the availability of food to the seasonal variation in immune functions. Therefore, seasonal regulation of the immune defense has likely adapted along evolutionary lines to meet the requirements arising both within and outside individuals. Recently, the importance of seasonal variation in immunity has been increasingly emphasized due to its underlying importance in ecology, behavior and mate choice. In this chapter, we review recent studies of seasonal variation in innate immunity in an evolutionary context among a wide range of animals but concentrating mainly on ectothermic vertebrates and invertebrates.

1 E-mail: [email protected] 2 E-mail: [email protected]

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Raine Kortet and Anssi Vainikka

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1. INTRODUCTION

In order to understand the significance of the immune system in ecology and evolution, it is necessary to realize that there is no single general measure of immune defense (Siva-Jothy and Skarstein 1998; Zuk and Johnsen 1998). Rather the immune system is a physiological complex having both adaptive and non-adaptive qualities that must meet the requirements of the pathogenic environment, stress, and the risk of autoimmune attacks (for example, the haploid gametes are high-risk-targets of autoimmune attack) (Ahmed et al. 1985; Braude et al. 1999). Immunocompetence can be then defined as the resulting effect of all immune systems and their capacity to function adaptively, meaning not necessary maximally, when facing pathogenic or parasitic challenges. Non-specific or innate immunity is a major component of immunocompetence. It includes all cell-mediated and humoral (chemical substances) mechanisms that recognize and respond to all non-self threats in a generic germline-coded way, without providing long-lasting immunological memory to previously encountered threats (Bruce et al. 2002; Charles et al. 2001). This traditional definition has been challenged by recent studies that demonstrate that even innate immune functions can be “vaccinated” and that some receptors and qualities of innate immune cells such as macrophages actually can be modified by immunological challenges (Bowdish et al. 2007). In general, innate immunity can be divided into two parts: 1) constitutive defenses including macrophages, granulocytes, natural killer cells, and complement, lysozyme, defensins, non-specific antibodies, and other humoral compounds, and 2) inducible defenses including cytokine-mediated inflammation (Lee 2006).

Temporal phenotypic plasticity and flexibility in physiology is a rather well described phenomenon (e.g. Piersma and Lindström 1997). It is not a surprise that temporal variations in immunity have received increasing interest, in particular, because they deal with the actual resistance against parasitism, which is the major aspect in individual’s survival (Martin et al. 2007a). The biological rhythms animals become adapted to depend on the average lifespan of the animal: circadian rhythms have evolved in organisms that typically live more than one day, and only animals that generally live more than a year show real annual seasonality in their physiology (Nelson et al. 2002). Seasonal variations in immunity and immunological responses are ultimately defined from a theoretical-evolutionary viewpoint. We propose that the mechanism of seasonal variations in all immune systems can be separated into two groups: 1) intrinsic, i.e. adjusted evolutionarily over a long period and 2) phenotypically plastic and environmentally triggered. Phenotypic expression of innate immunity is then a result of these two mechanisms in different proportions (e.g. Raffel et al. 2006). In certain cases, animal show seasonal variations in immune functions even when kept in constant environmental conditions, which indicates intrinsic endogenous mechanisms behind the regulation (Zapata and Cooper 1990; Zapata et al. 1992). For example, tortoise (Mauremys caspica) kept in room at constant temperature show seasonal variation in numbers of plaque-forming cells (Leceta and Zapata 1986).

Previously, it was considered difficult to formulate any integrative hypothesis concerning seasonal mechanism involved in the regulation of immune responsiveness, at least in ectothermic vertebrates (Zapata and Cooper 1990). However, currently there are two main hypotheses to explain seasonal variation in immunity, highlighting the role of trade-offs in intra-annual variation (Martin et al. 2007a). The first of the mechanistic hypotheses proposes

Seasonality of Innate Immunity

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that animals have adapted to enhance immune function in winter-time to maximize survival from the challenging time period (Nelson 2004). The second posits the costs of immunity that are a trade-off with other life-history traits such as reproduction (Martin et al. 2007a). Although the most recent consensus of the theory and empirical studies suggests that immune defense is related to reproduction, certain intra-annual seasonal variations are triggered by the environment, i.e. natural changes in temperature and photoperiodicity in the winter months (Hotchkiss and Nelson 2002; Nelson et al. 2002; Martin et al. 2007a). In an evolutionary context, it is clear, however, that annual seasonal changes in temperature and photoperiodic rhythm would be considered rather proximate exogenous cues to regulate immunity than ultimate explanations for seasonal variation in immunity of the seasonally reproducing species. On the other hand, challenging seasons such as winter likely lead to the cessation of reproduction (Nelson et al. 2002). Therefore, we think that environment should be considered to ultimately drive seasonal reproduction and thus all seasonality in immunity.

Environmental factors cause selective pressures especially in highly seasonal areas where surviving harsh conditions requires allocating energy away from reproduction to maintain basal body functions and where immune function has to be upregulated to tolerate the fluctuating exposure to parasite and pathogen stress at certain periods of the cycle (Nelson et al. 2002; Hotchkiss and Nelson 2002; Martin et al. 2007a). Consequently, the benefits of the immune systems may also vary with the seasons. As a result of seasonal variation both in the exposure and susceptibility to parasites also parasite loads show seasonal fluctuations (e.g. Lamková et al. 2007). In addition, seasonal variation in parasitism could result from the natural life cycle of the parasite, by the fact that the host and parasite meet each other only during certain seasonal periods (e.g. Hotchkiss and Nelson 2002; Altizer et al. 2006). Seasonal variations in the infectivity and virulence of parasites and pathogens and in the parasite loads of hosts are known both in aquatic and terrestrial environments (e.g. Deviche et al. 2001; Pascual and Dobson 2005). Therefore, the host-parasite co-evolution likely operates on seasonal cycles in an infectivity – resistance arms race. We think that the seasonal resolution of the host-parasite co-evolution has been largely neglected by now, and needs to be incorporated both in the theories and experimental study designs. For example, parasite life-histories may evolve to match the reproductive cycle of the host because of the seasonal changes in host immunity or behavior (c.f. Sorci et al. 2003).

All investment in immunity is condition-dependent as ultimately the rate of resource use determines the amount of resources available for allocation between competing body functions (Nelson et al. 2002). Similarly, physiological stress per se experienced a) during a harsh time of year and b) during the reproductive season, proximately affects the seasonal variation in innate defenses. Therefore, to understand the intrinsic seasonal variations in innate immunity, an animal has to be removed from its environment or those ecological compounds that have a direct affect on its immunity need to be understood. Moreover, in some cases it may be possible, that exceptionally mild winters or other random events lead to the absence of the otherwise observed seasonal changes in immunity (Nelson et al. 2002).

Recently, seasonal variation in immunity has been increasingly emphasized due to its importance in ecology, behavior and mate choice (Nelson et al. 2002; Martin et al. 2007a). Temporal variation in immune systems and parasite resistance has been suggested to work as the main mechanism of seasonal regulation of host populations (Lochmiller 1995; Yang et al. 2007). Moreover, it is acknowledged that host-parasite-pathogen interactions function bi-directionally. Thus, temporal variation in host immune defense is likely reflected in the


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population dynamics of infectious diseases and parasites (Altizer et al. 2006). However, how evolution in host-parasite interactions affects the population dynamics in nature is still poorly known in most cases, and the most examples cover only ecological time scales (e.g. Dronen 1978; Müller-Graf et al. 2001, for an exception see e.g. Jaenike and Perlman 2002).

In behavioral evolutionary ecology, parasite resistance has been suggested to be centrally involved in host mate choice and sexual selection (Hamilton and Zuk 1982). Whether sexual displays actually signal parasite resistance or parasite loads have been intensively studied (e.g. Zuk 1996; Taskinen and Kortet 2002; Rantala et al. 2002; Rantala and Kortet 2003; Kortet and Taskinen 2004; Ahtiainen et al. 2006, reviewed by Viney et al. 2005; Lawniczak et al. 2006). However, seasonal fluctuations in immune functions may skew the results of studies into a parasite’s role in sexual selection. This is especially relevant if the interactions between different immune functions and the expression of sexual ornaments and other reproductive activities are measured only at the time of breeding. Indeed, such a confusing temporal interaction was found in jungle fowl by Zuk and Johnsen (1998), where variously ornamented males had different seasonal patterns in cell mediated immunity. A similar problem in the interpretation of results can occur in any correlative or experimental data that studied immunity in an ecological context but did not take seasonal variability into account. Thus, we feel that it is becoming increasingly evident that seasonal changes in immunity should be incorporated and acknowledged in the relatively young field of ecological immunology.

Zapata and Cooper (1990) reviewed the earlier work done on seasonal aspects of immune defense. Seasonal changes in immune systems of small mammals and birds were recently reviewed by Martin et al (2007a). A comprehensive general review was provided by Nelson et al. (2002), and a review of seasonal changes in immunity in fishes was recently published by Bowden et al. (2007). Consequently, we concentrate on evolutionary and physiological mechanisms affecting seasonal variation in innate immunity especially in ectothermic vertebrates and invertebrates. Seasonal changes in non-specific defenses play a major role in these animals that commonly lack specific immune functions at least at certain times of the year (Zapata et al. 1992). Often rather simple measures of innate immunity could have been linked to the survival of animals, and therefore demonstrated to have a link to fitness (Moller and Saino 2004). Therefore, we discuss the fitness value of the immune measures and their seasonal variation. Moreover, we discuss the importance of innate immune defense in different life-history strategies, and in taxa differing in their ability to exert specific immune responses. Finally, we propose directions for future research.

2. SEASONALITY IN THE DIFFERENT FACETS OF INNATE IMMUNITY

A) Vertebrates

Overview of the innate immune system in vertebrates Most vertebrates respond to an encounter by a non-self organism in a very similar way.

However, the variety of biochemicals and immunological cells available depend clearly on the phylogeny of the taxon with the endothermic mammals having the most diverse immunological assortment. In order, the four major steps in an immunological challenge


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include: 1) Non-specific first-line humoral defenses present in mucus, saliva and blood which prevent the growth or cause the death of potential pathogens. Chemical substances include several enzymes and proteins such as lysozymes, haemolyzin, transferring, lectins, interferons, etc. 2) The second phase involves production of specific chemical substances called cytokines, such as interleukin-6, that recruit immune cells to sites of infection and trigger the inflammation response. As a response to cytokine-induced inflammation, acute phase proteins (APPs) including coagulating and fibrinolytic compounds, antiproteases, C-reactive protein, and different complement compounds are secreted in order to control inflammation (reviewed for humans by Gabay and Kushner 1999). The complement cascade is activated via classical or alternative pathways depending on whether the pathogen was detected by specific antibodies or directly. The activation of complement leads to lysis of the intruding cell or eventual phagocytosis of the intruder. 3) As a response to the production of cytokines specialized leukocytes arrive to the site of infection and start clearing away foreign substances present in organs, tissues, the blood and lymph. 4) In the last phase, specific immunity is activated through a process known as antigen presentation (Charles et al. 2001). However, some animals like invertebrates lack the strictly specific arm of immunity, and in the poikilothermic vertebrates the production of specific antibodies is often, as in fishes and amphibians, adversely affected by the cold ambient temperatures. Therefore, poikilothermic vertebrates must rely almost entirely on the innate immune system during cold periods of the year (Alcorn et al. 2002). This, indeed, can be a major source of seasonal variation in innate immunity in these animals.

Innate immunity in fishes

Fishes represent a group of animals, whose innate immune functions have been probably the most intensively studied due to the serious implications of pathogens in aquaculture (Whyte 2007). The main source of phagocytes, and therefore a major immunological organ in fish is the head kidney which is also involved in haematopoiesis, antibody production, and cortisol and catecholamine production (Weyts et al. 1999). Not surprisingly, several studies have focused on the ability of head kidney phagocytes to ingest and kill pathogens (e.g. Kortet et al. 2003a, Vainikka et al. 2005a, b; Lamková et al. 2007). Other main organs exhibiting immunological activity in fish are the thymus, spleen and mucosa-associated lymphoid tissues including the skin and gills (Manning 1994; Press and Evensen 1999). Nonspecific hydrolytic enzymes including lysozyme, alkaline phosphatase, and cathepsin B, and antibacterial proteases and enzymes are present in the mucus of several teleost fish species (Subramanian et al. 2007). Some enzymes such as lysozyme are present also in the peripheral blood leukocytes and in the head kidney for example in rainbow trout (Oncorhynchus mykiss) (Smith et al. 2000). In general, the innate immune system of fish undergoes remarkable seasonal changes in the types of leukocytes in blood, the size of immunological organs, and the activity of phagocytes (e.g. Nelson and Demas 1996, Álvarez et al. 1998, Scapigliati et al. 1999, Thomas et al. 1999, Kortet et al. 2003a, Lamková et al. 2007, for a recent review see Bowden et al. 2007). Here we review the major facets of innate immunity in fish and link their seasonal changes to other physiological processes.

Seasonal variations in humoral innate immune defenses in fishes

Serum lysozyme activity was found to follow the environmental temperature in dab (Limanda limanda), by being lowest in February-March, the time of coldest water with


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reduced breeding activity, and highest in September-October with the highest yearly water temperature recorded (Hutchinson and Manning 1996). Similar patterns were found in the lysozyme and myeloperoxidase activities in Indian major carp (Labeo rohita) (Swain et al. 2007). Additionally, lysozyme activity in sockeye salmon (Oncorhynchus nerka) was generally higher at 12°C than at 8°C independent of the season (Alcorn et al. 2002). In Atlantic halibut (Hippoglosus hippoglosus) serum lysozyme activity was higher in summer than in winter, but the levels could not be related to either photoperiodicity or water temperature (Bowden et al. 2004). Alternatively, anti-protease and haemolytic activities peaked in late autumn and in October-January in cod (Gadus morhua) (Magnadóttir et al. 2001). In Asian catfish (Clarias batrachus) lysozyme levels remained low during the summer in comparison to other seasons (Kumari et al. 2006).

The induction of the alternative complement pathway showed seasonal variation in tench (Tinca tinca); the ACH50 (ACH50 is an abbreviation for alternative complement hemolysis 50, i.e. causing 50% lysis of the substrate) values being highest in winter with little change during the spring-autumn, but also exhibiting some sex-differences (Collazos et al. 1994a). No seasonal variation but higher complement activity at 8°C than 12°C was observed also in O. nerka (Alcorn et al. 2002). In C. batrachus ACH50 values were highest in spring, and lowest in autumn (Kumari et al. 2006). However, the haemagglutination titre was high in spring, summer and autumn indicating no temperature effects in C. batrachus (Kumari et al. 2006).

Humoral innate immunity of fishes does not seem to follow any general seasonal trend across all taxa, but the responses do differ for example between cyprinids and gadoids. Therefore, the seasonal patterns observed in fishes likely reflect the optimal environment the species are adapted to, the cold-water species showing strong immune responses in cold water and vice versa. It is also likely, that the dependency of these measures of immunity on temperature is curvilinear, showing the peak at some intermediate or optimal temperature.

Cell-mediated innate immunity in fishes and reptiles

In many organisms phagocytes are the most important component of the non-specific cell-mediated immune system (Finco-Kent and Thune 1987; Secombes and Fletcher 1992; Neumann et al. 2001), as they play a major role in clearing foreign particles in tissues. Phagocytotic cells are present in the circulation, head kidney, posterior kidney, thymus, and even in the endothelial lining of the atrium of the heart and in the gill lamella of fish. Along with respiratory burst and nitric oxide responses, phagocytosis in fish display marked similarities to homologous responses in mammals (Neumann et al. 2001). Foreign particles are recognized by receptors on the cell surface. Alternatively, recognition may depend on deposition of opsonins such as antibodies or complement factors on the particle surface (Frøystad et al. 1998). Production of oxidative anions in response to phagocytosis, often measured as chemiluminescence using luminol as substrate (e.g. Vainikka et al. 2005a, b), represents a mechanism of how animals kill pathogens and parasites (Neumann et al. 2001).

In general, high temperatures enhance specific immune responses whereas low temperatures adversely affect their expression (Le Morvan et al. 1997). Therefore, for the fish to be able to survive in temperate waters non-specific functions have to function regardless of changes in environmental temperature. Both the number of phagocytotic cells and phagocytotic activity may vary with temperature with or within seasons. For example, combined measurements of blood and head kidney phagocytotic activities showed a


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relationship with environmental temperature within the breeding season in T. tinca (Vainikka et al. 2005b). The proportion of phagocytotic cells extracted in kidney has been observed to be higher in cold than in warm water in salmonid fish such as in O. nerka (Alcorn et al. 2002). Also the leukocrit (proportion of white blood cells of total blood volume) of salmonid fish has been observed to be higher in colder environments (Alcorn et al. 2002). In contrast, in the cyprinid chub (Leuciscus cephalus), white blood cells were most numerous in the circulation during warm periods of the year, and decreased to low levels in November (Lamková et al. 2007). An analogical pattern was observed in cyprinid T. tinca (Collazos et al. 1998) suggesting that the responses in the number of white blood cells differ between fishes adapted to cold (salmonids) or warm water (cyprinids).

In another wild cyprinid, roach (Rutilus rutilus), the proportion of lymphocytes in blood has been observed to increase towards late autumn, and then decrease again in winter, whereas the number of neutrophilic granulocytes was highest during the spring and summer (Vainikka et al. 2004a). In L. cephalus, the proportion of lymphocytes remained somewhat constant through the seasons, but neutrophilic granulocytes were most numerous in spring before spawning while the developmental stages of the neutrophils showed variation between seasons (Lamková et al. 2007). Contrary, Swain et al. (2007) did not find statistically significant seasonal variations in the proportions of different leukocyte types in circulation in L. rohita. In general, an increase in the proportion of phagocytic cells in circulation may be indicative of immunological challenges, which may also link these measures of immunity to exposure to parasites (Anderson 1990). Seasonal patterns in differential counts of white blood cells may therefore be indicative of immuno-redistribution rather than a sign of an overall change in innate immunocompetence.

In vivo experiments by Le Morvan et al. (1997) showed that head kidney macrophages of carp (Cyprinus carpio) displayed better phagocytotic capacity in normal (long-term acclimatization) temperature (12 °C) than in higher temperatures (20 or 28 °C). A similar pattern was observed in vitro in T. tinca, where the blood granulocytes showed higher capacity to phagocytose latex beads and to produce oxidative anions in 12°C than in 22 °C (Collazos et al. 1994b). Also, further studies by Collazos et al. (1995) support the conclusion that phagocytosis in fish is resistant to cold temperatures: the mobility rate, phagocytic index and microbiocidal (ability to kill Candida albicans) activity all showed highest response during the winter in tench. This pattern was also observed in C. batrachus, where superoxide production was highest at a lower temperature of 19 °C during winter than at higher temperatures of 28–31 °C during rainy and autumn seasons (Kumari et al. 2006). In L. cephalus, peak respiratory burst of phagocytes was observed in August, and the lowest values were observed in November (Lamková 2007). However, values climbed again in April which was the coldest time period studied (Lamková et al. 2007), suggesting that respiratory burst response of phagocytes may be acutely reduced in early winter but recovers by the spring. Kortet et al. (2003a) found that seasonal patterns of certain immune parameters including white cell counts, chemotaxis and respiratory burst of head kidney phagocytes and spleen size differed between populations and sex in roach R. rutilus. The total number of white blood cells peaked clearly in early summer in a warm water population, but later in summer in a normal temperate lake. Both chemotaxis and respiratory burst showed peak in October and a transient decrease until minimum levels in late summer. The results in roach support the general pattern: white blood cells counts are high in early summer when the fish condition is


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low but the functionality of head kidney phagocytes increases with fish condition in autumn (Kortet et al. 2003a).

In general, these results support the idea of winter-time upregulation of cellular immune defenses in fish, although the term winter means very different environments at different latitudes (~ 20°C in C. batrachus and ~1°C in R. rutilus). The winter-time of upregulation of cellular innate defenses seems not to be limited to fishes. In a turtle, M. caspica, chemotaxis and proliferation of lymphocytes, and the activity of natural killer (NK) cells showed high winter-time levels, likely not due to the temperature effect but depressed sex and stress hormone levels (Muñoz et al. 2000). However, various functions of splenic leukocytes in M. caspica showed different patterns during the seasonal cycle, for example the adherence to substratum being low but the cytotoxic capacity high in winter (Muñoz and De la Fuente 2001). Together with the often observed increase in the number of phagocytotic cells in spring time this suggest that there might be internal trade-offs in the cellular innate immune functions. For example, the spring-time increase in the number of phagocytotic cells may be a response to warming-caused decrease in the activity of the available cells. However, in this type of the studies it is very important to control for the difference between the temperature animal have been living and the actual assay temperature. It is also important to realize that the type and level of actual immune response likely depends on the type of the immune challenge, and laboratory experiments providing information on some single aspects of immunity (or health) may not reveal the true capacity of individual to cope with the biological challenges.

Seasonal changes in innate immunity in birds and mammals

Most studies of ecological immunity in birds have concentrated on specific immune function using data collected during the breeding season. However, the importance of efficient immune function may increase even within the breeding season, as demonstrated by Merino et al. (2000) who showed that the nestlings of late-breeding barn swallow (Hirundo rustica) individuals exposed to largest number of parasites had stronger T cell mediated immune responses than nestlings from earlier broods. In contrast, Wilk et al. (2006) detected exactly the opposite pattern in the nestlings of collared flycatchers (Ficedula albicollis) using a phytohaemagglutinin induced wing swelling test. Indirect assays of the total lytic activity of complement revealed that barn swallows in general, exhibited the highest seasonal values during breeding (Møller and Haussy 2007).

Indeed, birds have been hypothesized to show the greatest immune response during the breeding season, when the threat of parasitism, especially by ectoparasites, is strongest (Møller et al. 2003). Møller et al. (2003) found indirect evidence concluding that individuals in good condition are more likely to elicit a strong immune response at the time of breeding. However, birds often breed in nests and the seasonal pattern of exposure to parasites may differ greatly from other animals that do not build nests or live in locations vulnerable to parasitic invasions. This, again, underlines the significance of the ecology of the species in order to better understand the evolutionary forces that drive the evolution of seasonality in innate immune defenses. Another hypothesis that could explain heightened immune response during reproduction is the fact that resistant parents are less likely to transmit diseases to immunologically naïve newborns (c.f. Hosseini et al. 2004).

We leave out the mammalian literature on seasonal changes in innate immunity except for the extreme ways of over wintering in some mammalian species. Hibernation is a specific


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and at times extreme method of over wintering in some mammals like hedgehogs, bats, ground squirrels and bears, that however, rather “winter sleep” as they arouse from hibernation occasionally. During hibernation some immune functions (e.g. discernable febrile response to lipopolysaccharides (LPS)) may be down-regulated in ground squirrels (Prendergast et al. 2002). Black bears (Ursus americanus canus) did not show immunosuppression but up-regulation of some humoral components during the experimentally induced hibernation (Tsiouris et al. 2004). Also immune functions in the intestine of ground squirrels (Spermophilus tridecemlineatus) were up-regulated during the hibernation likely as a response to preserve gut integrity throughout the winter fast (Kurtz and Carey 2007). The results obtained from hibernating animals in general support the view that innate immune functions are upregulated during the extreme harsh periods of the year to maintain survival. However, the number of studies conducted by far is limited and further studies that test for example, how the hibernating animals cope with immunological challenges just after arousal, are warranted.

B) Invertebrates

Overview of the innate immune system in invertebrates In recent years invertebrates, such as insects, have become popular model organisms for

immunological studies in both ecological and evolutionary contexts (Lavine and Strand 2002; Rolff and Siva-Jothy 2003; Schmid-Hempel 2005). Generally, it is predictable that animals with short life span rely more on non-specific immune defenses (Klasing 2004; Lee 2006). This is also true with invertebrates, although the phylogeny of insects more likely explains the lack of a clearly defined arm of immunity. Though the immune system in invertebrates may be somewhat less complex than that of the vertebrates, many components are functionally homologous (Vilmos and Kurucz 1998; Little and Kraaijeveld 2004; Hancock et al. 2006). Further, some components analogous to an adaptive immune system have been found in insects (Kurtz and Armitage 2006) indicating that evolutionary pressure in general may favor adaptive qualities over costly innate immune functions.

The defense repertoire in invertebrates consists of different kinds of immune responses - constitutive and induced, general and specific – involving immunological memory and lasting protection (Little and Kraaijeveld 2004; Schmid-Hempel 2005). For example, mealworm beetle (Tenebrio molitor) show ‘immunological priming’, which means that an insect’s past experience with a pathogen might increase its chance for survival when encountering the same pathogen in the future (Moret and Siva-Jothy 2003; Little and Kraaijeveld 2004). The humoral system of insect immune defenses includes various peptides, used in the cascades of which regulate coagulation and melanization of haemolymph (Lavine and Strand 2002; Hancock et al. 2006). Melanin is a key component in invertebrate humoral immune response and is produced in the cuticle as a result of activation of the phenoloxidase (PO) enzyme cascade (Söderhäll and Cerenius 1998). For example, in T. molitor, cuticular melanin (dark colour) is associated with haemocyte density and pre-immune challenge activity of PO (Armitage and Siva-Jothy 2005). It is known, that certain antimicrobial peptides, like tachycitin in horseshoe crabs, synergistically with other humoral immune compounds enhance the invertebrate immune response (Hancock et al. 2006). Cellular defences in insects


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rely on phagocytosis and encapsulation of foreign particles by a range of haemocyte types (Lavine and Strand 2002). Haemocytes can produce reactive oxygen and nitrogen intermediates which have the ability to kill pathogens (Lavine and Strand 2002).

The most commonly assayed aspects of invertebrate immunity in ecological studies are haemocyte counts (haemocyte numbers/density), encapsulation of novel standard ‘pathogen’ (like nylon implant), concentration and activity of antibacterial enzymes such as lysozyme in haemolymph and concentration and activity of PO and its zymogen, pro-phenoloxidase (proPO) (e.g. Armitage and Siva-Jothy 2005; Kortet et al. 2007). These aspects of immunity likely reflect also to a high fitness value.

Seasonality of innate immunity in invertebrates

During the last ten years it has been demonstrated that aspects of invertebrate immune response can be affected by or correlated with several factors, including genotype (Kraaijeveld and Godfray 1997; Webster and Woolhouse 1999; Cotter and Wilson 2002; Armitage and Siva-Jothy 2005; Lazzaro et al. 2006), sex (Zuk and McKean 1996; but see Rantala and Roff 2007), temperature (Fellowes et al. 1999) number of predators and parasites in the environment (Rigby and Jokela 2000; Kortet et al. 2007), previous exposure to pathogens (Moret and Siva-Jothy 2003), quality and quantity of food (Vass and Nappi 1998; Rantala et al. 2003a; Siva-Jothy and Thompson 2002; Yang et al. 2007), developmental time and age (Adamo et al. 2001; Rolff 2001; Rantala and Roff 2005), population density (Reeson et al. 1998; Barnes and Siva-Jothy 2000; Wilson et al. 2002), social dominance status (Rantala and Kortet 2004; Väänänen et al. 2006) and physical activity (Ahtiainen et al. 2006). Most of the environmental and/or innate factors mentioned above affect animals at levels that show intra-annual and inter-seasonal variation, but the detailed studies on the seasonal associations between immunity and the factors above are missing. Since invertebrates like insects usually have very short life spans (from days to a few months) with long inactive dormant stages during the winter, temporal investigations in these species require modified time scales (usually intra-seasonal). However, for long living invertebrates such as certain mollusks, dragonflies, crayfishes, and other aquatic invertebrates, environmental seasonal variation should be considered as a natural source of variation in immunity.

To our knowledge, recent studies in seasonality of innate immune defenses in invertebrates are relatively few. Most of the work completed has been on aquatic invertebrates with fewer studies on terrestrial invertebrates. The results of these studies seem ambiguous. The giant freshwater prawn (Macrobrachium rosenbergii), displayed the highest and lowest total haemocyte count in autumn and winter respectively, with no significant difference between the sexes (Cheng and Chen 2001). Novas et al. (2007) demonstrated that basal nitric oxide production by haemocytes in a mollusc (Mytilus galloprovincialis), was higher during summer than in winter. In the flat oyster (Ostrea edulis), low levels of lysozyme were detected in haemolymph during the summer months with similar patterns found also in other oysters (Cronin et al. 2001). However, there was variation between study sites and study strains in the lysozyme levels (Cronin et al. 2001). In Pacific oyster, (Crassostrea gigas), phagocytosis index was low during spawning (early summertime) before reaching a maximum in autumn (Duchemin et al. 2007). In Manila clam (Venerupis philippinarum), high haemocyte counts and general protein content were observed in spring–summer and low values recorded in autumn–winter. In contrast, average haemocyte size was greater in autumn–winter than in spring–summer. The observed haemocyte size – total haemocyte count


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relationship was explained based on variation of cell division rate. During cell division the size of resulting haemocyte cells was assumed to be smaller than the size of mature cells (Soudant et al. 2004). Cao et al. (2007) studied seasonal variations in haemocyte response to LPS and interleukin-2 (IL-2) in Mytilus galloprovincialis and found that haemocytes are less sensitive to LPS in summer with half the maximum activity as that observed in winter. The response of haemocytes to IL-2 was higher in summer than in winter. However their activation level was much lower than that obtained with LPS in winter.

In invertebrates, there may be intra-season variation in innate immunity as observed in birds (Merino et al. 2000; Wilk et al. 2006). Yourth et al. (2002) demonstrated that adult damselfly (Lestes forcipatus) hosts sampled later in the mating season displayed more probable and stronger melanotic encapsulation of endoparasitic mite feeding tubes resulting in mites dying without engorging. However, this result can be explained by the higher temperatures experienced by the emergent adults later in the summer suggesting rather temperature-dependent effects that true seasonality (Robb and Forbes 2005). Further, as in the case of damselflies the juvenile aquatic environment in insects may differ totally from the adult terrestrial environment. Therefore, the general level of invertebrate immunity in adult phase may already be determined during ontogeny (c.f. Jacot et al. 2005), and observing seasonal changes in adult individuals becomes difficult because of the different background and time of emergence among adults.

Most studies agree that reproductive effort is the major cause of seasonal alterations in invertebrate immune response, relying on the idea of a trade-off operating between reproduction and immunity (e.g. Taskinen and Saarinen 1999; Ahtiainen et al. 2006; Duchemin et al. 2007). Mating has been shown to suppress and in some aspects induce invertebrate immunity (Rolff and Siva-Jothy 2002; Shoemaker et al. 2006; Lawniczak et al. 2006). Microarray analyses have shown that mating may regulate the expression of many immune-related genes (Lawniczak et al. 2006). For example, in fruit fly (Drosophila melanogaster) there was differential expression in 38 genes between virgin and recently mated females and immune related genes were overrepresented among these mating influenced gene candidates (Lawniczak and Begun 2004). However, not all studies have been able to demonstrate that the cost of immunity would be reflected by sexual signaling or longevity (Vainikka et al. 2007), suggesting that in some invertebrates the cost of immunity might be moderate and therefore only marginally adjusted by season.

3. MECHANISMS OF SEASONAL REGULATION OF IMMUNE DEFENCE

Role of reproduction in regulation of innate immune defenses

Reproduction and the resources required play a central role in life-history evolution, as they are traded-off against survival-related traits such as growth and immunity (Roff 1992; Stearns 1992; Schmid-Hempel and Ebert 2003). To increase reproductive success individuals may be forced to divert resources from traits such as immunity (Sheldon and Verhulst 1996; Nordling et al. 1998; Lochmiller and Deerenberg 2000; Norris and Evans 2000; Harshman and Zera 2006). In addition, gametes may be susceptible to autoimmunity which may require


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further down-regulation of the immune system during the reproductive season (Folstad and Skarstein 1997; Skau and Folstad 2004; Kortet et al. 2004a).

Investment in mating partly explains reproduction-related immunosuppression since the production and maintenance of elaborated mating displays may negatively affect the immune system because of the female’s interest to acquire good genes for their offspring (Folstad and Karter 1992) or because the energy requirements of the production of sexual traits in males are energetically traded-off against immunity (Wedekind and Folstad 1994). In line with this “immunocompetence handicap hypothesis”, several studies suggest that reproduction-related traits can impair immune function in males (e.g. Skarstein et al. 2001; Rolff and Siva-Jothy 2002; Kortet et al 2003a; Kilpimaa et al. 2003; Ahtiainen et al. 2005; Martin et al. 2007a). Further, Bilbo et al. (2003) showed female-favoured sex-differences in leukocyte counts (total white blood cells, total lymphocytes, T and B cells) in a uni-parental hamster species (Phodopus sungorus) only during breeding and not at any other time of the year nor in monogamous species (P. campbelli). Activation of the immune system reduces reproductive output indicating that reproduction and immunity compete for common resources (Ilmonen et al. 2000; Ots et al. 2001; Colditz 2002; Bonneaud et al. 2003; Kilpimaa et al. 2003; Jacot et al. 2004; reviewed by Lochmiller and Deerenberg 2000). However, reproduction induces immunosuppression in females as well suggesting that the production of mating displays is not facultative for reproduction-related costs in immunity and reallocation of resources to reproduction from other life-history processes is adaptive independent of the mating system.

Reproduction-induced immunosuppression, however, is not always observed, and the fitness cost of disruption in immune defenses (death or serious damage) would likely be even higher than the cost of protective immune defense (Westneat and Birkhead 1998). In birds, indirect measures of immunity may be even higher in the breeding season than at other times of the year as a consequence of exposure to nest parasites (Møller et al. 2003). In fishes, the adaptive immune system may account for the immunity at the time of reproduction and steroid-induced decrease in the cell-mediated innate immune defenses as observed in the common carp C. carpio (Saha et al. 2002, Saha et al. 2003). Also study by Kortet et al. (2003a) on R. rutilus support the view that reproduction-related immunosuppression may occur only in some particular immune functions while animals are still able to sustain a substantial level of immunological defense (c.f. Braude et al. 1999).

Usually however, animals show high parasite loads during or after the breeding season. For example, in fish (Barbatula barbatula) parasite loads showed parallel seasonal changes with investment in gonads (Šimková et al. 2004). Similar pattern was found in R. rutilus, where the prevalence and abundance of gyrodactylid monogenean parasites also peaked in the spring during the spawning period (Koskivaara et al. 1991). In roach, also epidermal papillomatosis, a viral skin disease, peaks during spawning (Kortet et al. 2002). High parasite loads during breeding periods have been observed among birds, for example, dark-eyed juncos (Junco hyemalis) (Deviche et al. 2001).

Some correlative studies have reported that breeding individuals have higher measures of immunity than non-breeding individuals (Møller and Haussy 2007). Therefore, the cost of immunity may not always be detectable at population level especially not without taking into account the current parasitic load of the host (Harshman and Zera 2006). The individuals that are in best condition may be best to tolerate parasites and put most effort into reproduction hiding the hypothesized trade-off at population level.


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Reproduction-related variation in immunity is mediated through physiological trade-offs (review in Martin et al. 2007a). During the past 30 years involvement of the endocrine system in the regulation of immune defenses has received increasing interest including the interactions between the immune system and the hypothalamus-pituitary-interrenal axis (HPI) (Weyts et al. 1999). Reproduction-related seasonal trade-offs in immunity are likely mediated by endocrinological mechanisms either directly or indirectly (Nelson et al. 2002; Martin et al. 2007a). In vertebrates breeding-related immunosuppression is commonly thought to result from high breeding-time concentration of androgens or corticosteroids (Aida 1988; Zapata et al. 1992; Folstad and Karter 1992; Suzuki et al. 1997; Hou et al. 1999a, b; Muñoz et al. 2000; Martin et al. 2007a). Further, high levels of testosterone have been associated with the occurrence of epidermal papillomatosis, a viral disease, in cyprinids (Premdas et al. 2001; Kortet et al. 2003b). The main female sex hormone, estradiol has been found to increase susceptibility of goldfish (Carassius auratus) to Trypanosoma danilewskyi parasites (Wang and Belosevic 1994), and to a decrease in phagocytosis of C. carpio macrophages (Yamaguchi et al. 2001). Most steroid hormones interact with macrophages in vertebrates (Miller and Hunt 1996). Steroid hormone - immune system interactions also contribute to the general sex-difference in immunological capacity; females are often more immunocompetent but simultaneously more prone to suffer from autoimmunological diseases than males (Gaillard and Spinedi 1998). Generally, there are often clear sex differences in parasitism and parasite resistance supporting the essential role of sex hormones in the regulation of the immune defenses (e.g. Grossman 1985; but see Reimchen and Nosil 2001). Immunomodulatory effects of sex and stress hormones

Steroids including stress and sex hormones are potent immunomodulators in fish (Harris and Bird 2000) and their effects in mammalian species have been well known for decades (Grossman 1985). The major stress hormone in teleost fish, cortisol, has mostly suppressive effects on the immune defense (Yamaguchi et al. 2001; Padgett and Glaser 2003) as it for example directly causes programmed cell death, apoptosis in leukocytes (Saha et al. 2003), and in long-term exposure it can cause susceptibility to parasites and diseases (Davis et al. 2003). When injected experimentally in grass carp (Ctenopharyngodon idella), cortisol decreased phagocytosis activity of head kidney macrophages, relative mass of the spleen, lysozyme activity in serum and resistance against Aeromonas hydrophila bacteria (Wang et al. 2005). In birds, cortisol may be involved in the seasonal regulation of immune functions, as cortisol was found to suppress phytohemagglutin (PHA) induced inflammation in temperate populations but not in tropical populations of house sparrows (Passer domesticus) (Martin et al. 2005). Cortisol has also been linked to the occurrence of some diseases, for example viral epidermal papillomatosis in fish (Vainikka et al. 2004b) further illustrating that stress and stress hormones clearly have a link to parasitism. Therefore, stressful seasonal events such as migrations, leks or other behavioral events may contribute to the observed seasonal patterns in innate immunity. Stress and its effect on immunity are likely linked to behaviors and other signals related to mating (Buchanan et al. 2000). To some extent the effects of starvation and changes in environmental temperature on innate immunity may be


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mediated via stress responses. However, hardly anything is known about physiological levels of stress in wild animals (Vainikka et al. 2004b).

Slater et al. (1995) characterized receptor response to testosterone in O. mykiss, leukocytes and suggested that they are an important link in testosterone-mediated immunosuppression. Since then, several studies have confirmed that testosterone has suppressive effects both on innate and specific immune defences in salmonids (Buchmann 1997; Slater and Schreck 1997; Slater et al. 1995; Hou et al. 1999a, b). However, studies in cyprinids suggest that testosterone, common to both sexes, does not affect innate immune functions (Law et al. 2001; Saha et al. 2003; Vainikka et al. 2005a, Vainikka et al. 2005b) but may decrease the production of specific antibodies (Saha et al. 2004). Interestingly, testosterone concentration correlated positively with innate immune functions and the proportion of killed parasites in roach (Vainikka et al. 2004a) which suggests that testosterone concentration in cyprinids is related more to the condition than to direct immunomodulation. In salmonids, testosterone can mediate seasonal changes in immunity partly via changes in the number and affinity of leucocyte androgen receptors (Slater and Schreck 1998). In cyprinids, the effects of testosterone may be mediated via its effects on specific immune system (Saha et al. 2004), since for example epidermal papillomatosis shows a positive relationship with testosterone level at the time of spawning (Kortet et al. 2003b; Kortet et al. 2004a, 2004b) but the disease disappear rapidly after spawning when the water temperature rises and specific immunity is activated (Kortet et al. 2002).

The main androgen in teleost fishes is 11-ketotestosterone (Borg 1994), which in a recent study by Kurtz et al. (2007) was found to both suppress immune functions and increase oxidative stress in three-spined sticklebacks (Gasterosteus aculeatus). Similar results were obtained in C. carpio, where 11-ketotestosterone among other steroids suppressed phagocytosis, superoxide anion and nitric oxide production of kidney macrophages (Watanuki et al. 2002).

Results from other taxa are mixed (Roberts et al. 2004) but suggest that androgens are immunomodulatory in several species. Testosterone is the major reproduction-related regulator of the seasonality of innate immunity in lizards (Saad et al. 1990, 1991, Veiga et al. 1998). Experimental manipulations show that testosterone concentration also translates to the parasite loads in lizards (Veiga et al. 1998). The effects of androgens and estrogens, in concert with stress hormones, likely mediate most of the reproduction-related changes in innate immunity in most of the vertebrate species. Some of the strongest evidence for this comes from white-footed mice (Peromyscus leucopus) where the injection of testosterone increased reproductive effort at the cost of humoral immune responses and even more so when exposed to an artificial immune challenge (Derting and Virk 2005).

Recent research has revealed that hormones other than sex and stress steroids have potential immunomodulatory effects. For example, prolactin, a peptide hormone released from the anterior pituitary, has an important role in the regulation of life-history trade-offs between reproduction and other functions (reviewed by Martin et al. 2007a). It has not been shown to have a “seasonal effect”, but however, it has been suggested to act synergistically with glucocorticoids, and in high doses, suppress several cell-mediated immune functions in small mammals (Martin et al. 2007a). Leptin is a potentially important hormone with seasonal variations in concentration that has been reported to have direct effects on immunity, and immunity vs. reproduction interplay (Martin et al. 2007a). These two hormones are both


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potentially important in evolutionary context and should be studied as potential candidates to contribute to reproduction-related immunosuppression and immunocompetence-handicaps.

As in vertebrates, trade-offs in invertebrates are likely mediated through hormones (Rolff and Siva-Jothy 2003). For example, juvenile hormones (JH) are key insect hormones that play important roles in various aspects of insect ontogeny, longevity and reproduction (Herman and Tatar 2001; Rolff and Siva-Jothy 2003; Rantala et al. 2003b). In T. molitor, JH type III injection suppressed phenoloxidase activity and encapsulation, but simultaneously increased the attractiveness of male pheromones (Rantala et al. 2003b). Also, the role of JH in the adjustment of mating related suppression in immunity was indicated in allograft experiments, where the main JH secreting organ, corpora allata from either mated or virgin beetles was transplanted into virgin recipients (Rolff and Siva-Jothy 2002). Further studies are needed to explore if JH shows seasonal changes in long-lived invertebrates and whether it mediates seasonal changes in immunity, and immunity vs. reproduction trade-offs.

Environmental cues affecting seasonal variation in innate immunity

There are two major abiotic mechanisms synchronizing seasonal variations in the environment to internal physiology: photoperiodicity and temperature (Zapata 1992). Short day-length has been found to elevate cell-mediated hypersensitivity reactions in arvicoline rodents such as collared lemmings (Dicrostonyx groenlandicus) (Weil et al. 2006a). Humoral components of immunity, including complement, lysozymes and peroxidase activities were shown to exhibit changes along circadian rhythm in seabream (Sparus aurata) and seabass (Dicentrachus labrax), which suggest that these components of immunity could be affected by photoperiodism between seasons (Esteban et al. 2006). Exposure to shorter periods of daylight increased the survival rate of Siberian hamsters (Phodopus sungorus), to experimental endotoxemia as a result of a decrease in the production of proinflammatory cytokine TNFα in macrophages (Prendergast et al. 2003).

Most mammalian cells have been found to have components of a functional biological oscillator. These peripheral clocks are controlled by the major circadian pacemaker found within the suprachiasmatic nuclei of the hypothalamus that has the ability to control the production and release of the indole hormone melatonin from the pineal gland (Bowden et al. 2007). Nelson and Demas (2004) suggested that day-length mediates the winter-time enhancement of immunity by melatonin in order to increase survival during harsh times of the year. Therefore, melatonin plays a main role in regulating the trade-off between reproductive success and survival (Nelson 2004). Majewski et al. (2005) linked the endogenous activity of N-acetyltransferase (NAT), a key enzyme in melatonin biosynthesis, to the development of peritonitis and splenocyte responsiveness to mitogenic stimulation in vitro in chickens. However, evidence exists in fish where serum lysozyme level was related to season but not to photoperiodicity (Bowden et al. 2004) which likely suggests that not all immune functions are affected by melatonin. Further studies in ectothermic vertebrates are needed to estimate the relative importance of temperature, photoperiodicity and seasonality. Raffel et al. (2006) demonstrated the effects of temperature and season in their study of immunity in red-spotted newts (Notophothalmus viridescens). They hypothesized that rapid changes in environmental temperature are reflected by a delay in immune response. Seasonal effects were demonstrated


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by a significant variation in differential leukocyte counts and in lysozyme activity while temperature affected leukocyte counts but not the activity of lysozyme (Raffel et al. 2006).

The effect of photoperiodicity on lymphocyte proliferation is partly mediated via the effects of norepinephrine. Siberian hamsters (Phodopus sungorus), held in short-day conditions had elevated splenic norepinephrine (NE) concentrations which has been shown to reduce splenocyte proliferation in short day-length acclimatized animals (Demas et al. 2003). Therefore, the sympathetic nervous system in addition to melatonin, likely has a role in seasonal regulation of innate immunity. An important seasonal factor potentially affecting the immune functions in fish and other animals exposed to sunlight is UV radiation (e.g. Salo et al. 2000). However, the observed responses in fish, including changes in relative counts of different leukocyte types and in the phagocytosis of circulatory phagocytes, may be explained through the effects of stress and stress hormones (Salo et al. 1998; Salo et al. 2000).

In ectothermic animals seasonality in immune function is driven by variations in environmental temperature (reviewed for aquatic invertebrates by Mydlarz et al. 2006) and therefore we think that seasonal changes may largely indicate adaptation to temperature rather than seasonal factors per se. For instance, seasonal variations in the production of reactive oxygen species by amoebocytes were masked by large inter-individual variation and the positive effect of cold temperature in European starfish (Asterias rubens) (Coteur et al. 2004). Opposite to aquatic invertebrates where temperature often correlates negatively with measures of immunity (Mydlarz et al. 2006), terrestrial invertebrates often show enhanced immunity in warm temperatures. For example, in D. melanogaster, encapsulation ability increased with environmental temperature. Temperature and genetic background however, had a significantly positive interaction to the effect that the D. melanogaster lines selected against the endoparasitoid wasp (Leptopilina boulardi), had actually weaker encapsulation in higher temperatures (Fellowes et al. 1999). However, also pathogens and parasites adapt to temperatures which in turn make the host-parasite coevolution to operate on seasonal cycles and further increases the pressures for the host to adjust the immunity seasonally. As a conclusion, more work is required to explore the link between photoperiodicity and the immune system in invertebrates to determine if long-lived invertebrates have intrinsic seasonal changes in their immunity.

Aquatic environments are especially susceptible to seasonal fluctuations in several environmental parameters, which make it even more difficult to distinguish between the potential causes of the effect. Seasonal changes in aquatic environments may include variations in oxygen and CO2 levels as well as changes in acidity and salinity. Warm water, low oxygen and elevated levels of CO2 have been shown to impair innate immunity in the oyster (Crassostrea virginica), the shrimp (Litopenaeus vannamei), and in the crab (Callinectes sapidus), (Mydlarz et al. 2006). However, in Manila clam (R. philippinarum), increasing temperature was positively correlated with total and viable haemocyte counts, lysozyme and leucine aminopeptidase activities as well as increased capacity to fight Vibrio tapetis and to recover more readily from disease (Paillard et al. 2004). Similarly, antibacterial activity for blue mussels (Mytilus edulis), inoculated with LPS was higher at elevated temperatures (Hernroth 2003). Low dissolved oxygen levels have been shown to depress the immune system of Taiwan abalone (Haliotis diversicolor supertexta), and increase its susceptibility to Vibrio parahaemolyticus infection (Cheng et al. 2004). There are also recent indications that an increase in salinity may negatively modulate phagocytic activity in oysters (e.g. Gagnaire et al. 2006).


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Animals may be able to directly sense the level of threat by parasitism in their environment (Karvonen et al. 2004). Therefore, when the risk of parasitism in the environment increases, an individual’s immunological alertness or readiness against parasites and pathogens should rapidly increase. This has been shown, for example in invertebrates (e.g. Reeson et al. 1998; Barnes and Siva-Jothy 2000; Moret and Schmid-Hempel 2001; Moret and Siva-Jothy 2003). In some cases, the effect of an environmentally-triggered increase in immunity can be long lasting and even be maternally transferred to the next generation (Little et al. 2003). Unpredictable seasonal variations leading to an increase in the risk of parasitism should be reflected in the immune responses of animals.

Condition-dependence of innate immunity

Innate immune functions have been demonstrated to involve condition-dependent components, which ultimately and proximately link seasonal fluctuations in the availability of food and nutrients to seasonal variation in immune functions (Zapata and Cooper 1990). Recent direct evidence for the effect of resource-dependence of immunity comes from T. molitor beetles (Siva-Jothy and Thompson 2002; Rantala et al. 2003a). Physiologically, the nutritional status of vertebrates could be reflected in the innate immune response via the effect of hormones such as leptin (Nelson 2004).

In general, host condition may affect the outcome of parasitism in two ways: 1) by affecting susceptibility and 2) reducing survival from infection (Krist et al. 2004). In snails, for example, host condition did not affect susceptibility but however, good physiological condition significantly reduced parasitism-induced mortality (Krist et al. 2004). In contrast, in birds it was found that physiological condition positively affected host resistance via androgen levels (Duckworth et al. 2001). We suggest that host life-history decisions during the annual cycle can be seen as ways to manage overall condition and therefore the trade-off between current and future reproduction (c.f. Heino and Kaitala 1999). In the case of so called terminal investment, for example, an animal may sacrifice all of its resources for one last reproductive event (Weil et al. 2006b). A change in direction favouring reproduction over longevity may occur within a seasonal time scale and have important implications in population level studies.

4. EVOLUTIONARY SIGNIFICANCE AND DIRECTIONS OF FUTURE RESEARCH

Theory predicts that short-lived species with high reproductive effort should rely more

heavily on innate immune defenses than long-lived species that should optimally invest more in adaptive immunity (Lee 2006; see also Martin et al. 2007b). Lee (2006) also predicted that individuals should down-regulate their non-specific defenses at the time of greatest energy needs (such as reproduction) and if possible, rely on specific immunity. Kurtz et al. (2004) showed that three-spined stickleback G. aculeatus with suboptimal Major histocompatibility complex (MHC) -combinations showed higher granulocyte proportion, higher respiratory burst of phagocytes, and higher parasite burden than individuals having optimal MHC allele


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combinations. Therefore, MHC-driven adaptive immunity and its efficiency in relation to innate immunity will open new fields of research and promise interesting results. The way individuals express innate and adaptive immune functions may thus not depend only on species and season, but also on individual genetics. Further, MCH-driven immunity may generate differences in individual-level life-history trade-offs and alter optimal life-history strategies substantially between individuals. Therefore, immunocompetence and the subsequent fitness value of individuals is a function of several arms of immunity. To fully understand the evolution of the innate immune system, it is necessary to understand the interactions of all the different components of immunity during a seasonal cycle, and how that is reflected by reproductive output and parasitism.

Future comparative studies addressing this issue and examining the amplitude of seasonal fluctuations in animals having different life-histories are warranted. Moreover, the extent by which different cells of the immune system are distributed between circulation, immunological organs and target tissues during an annual cycle need to be understood to clarify innate immunological capacity. The adaptive significance and mechanisms of immunoredistribution remain to be explored. In order to compare different components of the immune system with descriptive parameters of immunocompetence, statistical methods like principal component analysis will turn out fruitful (Vainikka et al. 2005b).

Innate immunity is considered moderately cheap to produce but expensive to maintain. Therefore optimal combinations of innate and adaptive immunity may save energy and therefore be evolutionarily selected for (Schmid-Hempel 2003). Optimal levels of immunity within and between sexes for example are related to the mating system of an animal (Klein 2000), and this may be dependent on season. Studies using selective lines in short-lived vertebrates could demonstrate such trade-offs between the innate and specific immune system particularly if animals were selected for some life-history trait that is traded-off against immunity. Duchemin et al. (2007) studied seasonality of immune parameters in two batches of Pacific oysters C. gigas that differed by their ploidy, diploid′s and triploid′s. This approach is required to understand genetic aspects of the sensitivity of an animals’ immune system to environmental factors. We also hypothesize that seasonal reproduction-related changes in immunity are more pronounced in short-lived species and that a positive correlation between the amplitude of seasonal change in innate immunity and reproductive effort is found across species.

In invertebrates, high levels of synergy between different aspects of immunity and dosage-dependent mechanisms are proposed to explain high specificity of innate immunity (Schulenburg et al. 2007). These effectiveness-enhancing mechanisms are likely also acting in the innate immune system of vertebrates. However, the magnitude of these mechanisms should show seasonal patterns as predicted by theory. Future studies will show if this is the case.

Ecological immunology is approaching a state where different facets of immunity are understood more clearly than before. The roughest division between specific and non-specific immunity certainly warrants interesting study objectives, such as the recently discovered inducible capacities of the innate immunity. In order to better understand the relative importance of innate immune functions during different times of the year further experimental studies must be conducted. To achieve the most reliable overall picture it is recommended to simultaneously study as many aspects of immunity as possible. Organisms are likely adapted to resist current threats which vary along the annual cycle. Therefore, such seasonally varying


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threats should be identified and it should be experimentally tested if animals show better resistance to temporal threats at the time they usually occur. Reproduction likely sets its own constrains by requiring production of non-self, and therefore immunologically susceptible, cells within the body. Self-damage during an immune challenge and its relationship with, for example, antioxidant level is poorly understood in wild animals and warrants further studies. Bright male coloration for example, might correlate with immunity partly because antioxidant-dependent coloration makes the animals tolerant against the damage of using the immune system.

Important future directions include the establishment of experiments that test the role of the sympathetic nervous system, i.e. ultimately social environment, in the seasonal regulation of immunity (Demas et al. 2003). Currently, the role of social interactions and stress are not fully understood especially in the seasonal context. A full understanding would require the inclusion of the effects of the nervous system in addition to effects of the stress steroids. Another highly topical subject of study is the adaptive character of the innate immune system. For example, macrophage receptors and qualities change as a response to immunological challenges, and even invertebrates raise stronger immune responses following a previous challenge (Bowdish et al. 2007). Therefore, the line between the adaptive and the innate immune system is going to be more obscured in the future. Linking the innate immunity with other physiological demands during the annual cycle remains as a challenge for the definition of the ecologically meaningful immunocompetence. How temperature- and photoperiodicity-dependent immune functions respond to for example global warming, pose an important research question for the near future, and warrants research on the phenotypic plasticity of the immune functions.

5. CONCLUSION

Most organisms outside the tropics live in seasonally fluctuating environments. Exposure to parasites varies simultaneously with an animals’ reproductive cycle, which creates a seasonally fluctuating fitness landscape to which animals become adapted over evolutionary time. Environmental cues such as temperature and photoperiodicity offer exogenous proximate cues, which individuals use to adjust their internal physiology with the help of melatonin and corticosteroids. Reproduction affects the innate immunity via the immunomodulatory effects of sex hormones, and annual changes in condition set constrains for the operation of the immune system. The internal physiological rhythms of animals arise from seasonal variation in the environment leading to seasonal reproduction, seasonally varying immunity and eventually evolution of the host and its parasites in seasonal cycles.

Studies demonstrating that immunological acclimatization to environmental temperature may be delayed and depend on the time of the year suggests that animals have intrinsic environmentally triggered adaptations to seasonal changes. In general, animals may enhance cell-mediated innate immune responses in winter-time, while some humoral facets of immunity may be down-regulated. In ectothermic vertebrates, innate immunity, compared to the specific immune response, is less significantly affected by temperature and is therefore an essential component of an animal’s health during winter. The current consensus is that reproduction-associated alterations coupled with adaptation to winter conditions are the


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driving factors for seasonal changes in immune defenses (Martin et al. 2007a). We agree with these conclusions concerning the role of seasonal variation in innate immunity and suggest that comparative studies between animals that differ in their life-history strategies will likely shed more light on the subject.

Noting the importance of how seasonality affects immune defenses and understanding the reasons behind this is crucial for studies into immunological ecology. Avoiding potential problems in the interpretation of data investigating immunity in an ecological or evolutionary context mean taking into account the seasonal nature of the immune variables. Thus, the effect of seasonality on immunity needs to be understood and acknowledged in immunological ecology.

Currently, increases in concentration or activity of innate immune factors are often considered to indicate good or effective immunity. However, the optimal level of constitutive immunity is not the same as the maximum level because the maintenance of intensive active immunity requires energy (Viney et al. 2005). Moreover, strong inflammatory responses may be injurious to a host’s own tissues, and therefore, seasonal tolerance to parasitic infection may sometimes turn out more advantageous than parasite clearance associated eventually with greater self-damage. Measuring immune parameters in individuals that differ in their current parasite loads becomes challenging due to the same reasoning. Seasonal increases in parasite load may affect immune parameters in wild animals in non-consistent ways. Further discrepancies may therefore arise from correlational field studies. Demonstrating the link between a priori measured innate immune functions and the seasonal ability of organisms to resist a parasitic challenge remains to be examined.

ACKNOWLEDGEMENTS

During the manuscript preparation, AV was supported by the European Marie Curie Research Training Network FishACE (Fisheries-induced Adaptive Changes in Exploited Stocks), funded through the European Community's Sixth Framework Programme (Contract MRTN-CT-2004-005578). RK was supported by University of Oulu and Emil Aaltonen foundation. External reviewers, Maija Vainikka, Aki Puhka and Sirpa Kaunisto are acknowledged for their helpful comments on the manuscript.

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Reviewed by: 1. Jouni Taskinen, Department of Biology, University of Jyväskylä, Jyväskylä, Finland. 2. Russell Easy, Department of Biology, Saint Mary’s University, Halifax, Nova Scotia, Canada.

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Raine Kortet1 and Anssi Vainikka - UEF...regulation (Zapata and Cooper 1990; Zapata et al. 1992)....

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