Seasonal variation and the immune response: A fish perspective

Fish & Shellfish Immunology 22 (2007) 695e706 www.elsevier.com/locate/fsi

Seasonal variation and the immune response: A fish perspective Tim J. Bowden a,*, Kim D. Thompson b, Alison L. Morgan b, Remi M.L. Gratacap b, Sami Nikoskelainen c a

Department of Zoology, University of Aberdeen, Tillydrone Avenue, Aberdeen AB24 2TZ, Scotland, UK b Institute of Aquaculture, University of Stirling, Stirling FK9 4LA, Scotland, UK c Department of Biochemistry and Food Chemistry, University of Turku, Vatselankatu 2, Turku 20014, Finland Received 11 April 2006; revised 17 August 2006; accepted 25 August 2006 Available online 14 September 2006

Abstract The environment in which an animal lives affects the physiology and psychology of that animal. The greater the distance from the equator the more profound this influence becomes, as the environment becomes more variable over the years. Temperature, photoperiod, precipitation and other environmental conditions, which are directly or indirectly controlled by the season, can affect an animal. It is becoming apparent that these conditions may impact on the immune system, and this can affect animal health. This review looks at the known mechanisms for transducing environmental cues and how these can affect immune parameters and function. The main focus is fish, especially in relation to aquaculture and the associated disease risks. Work on other animal classes is included for comparison. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Photoperiod; Seasonal variation; Circadian rhythm; Melatonin; Biological clock; Immune system; Immunology; Fish

1. Introduction Short-term environmental impacts on our well being are usually reasonably obvious. Most people prefer the long sunny days of summer to the dark cold days of winter (a Scottish or Finnish summer is usually preferable to a Scottish or Finnish winter). This is especially true if you live at higher latitudes where the annual variation is more pronounced. We talk about seasonal affective disorder (SAD) with a certain degree of humour, yet it is clear that seasonal variations can have a very real impact on our bodies and our psychology [1]. One report discusses the causes of seasonal variation in the number of violent suicides, not very happy reading, but indicative nonetheless [2]. Much of the study in this area has been centred on the effect of photoperiod and temperature on animals in general and it is clear that these factors play a principle role in setting a daily and seasonal cycle by which animals can function. One of the main areas of study is reproduction [3,4]. Understanding the environmental triggers of reproduction in domesticated plant and animal species has allowed us to manipulate those factors so that we may control their reproductive cycle, allowing outof-season reproduction. * Corresponding author. Tel.: þ44 1224 31 5656. E-mail address: [email protected] (T.J. Bowden). 1050-4648/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.fsi.2006.08.016

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The daily cycles are called circadian rhythms. These are, approximately, 24-h cycles in the physiological processes of living beings including, animals, plants, fungi, and cyanobacteria. The name comes from the Latin ‘circa’ meaning roughly and ‘dies’ meaning day. Strictly speaking circadian rhythms are endogenously generated. However, light and temperature can both modulate this response. The behaviour and physiology of fish are strongly influenced by light (both seasonal and manipulated) conditions. For example, in winter, post-smolts of Atlantic salmon (Salmo salar), exposed to continuous light in 14 m deep-sea cages, maintain a constant swimming speed [5]. However, fish kept under natural photoperiod cease swimming at dusk and are more dispersed during the dark-phase. The reproductive cycle of rainbow trout is controlled by the yearly pattern of photoperiod. Rainbow trout are highly responsive to abrupt changes in day length with combinations of long and short-day signals producing advances and delays in spawning [6]. There are now strong indications that these circadian and seasonal cycles can affect the health of an animal. From a personal viewpoint, we are interested in how such factors affect the immune system of fish and whether we can intervene and control these effects to improve the health of fish at particular times of year. Fish appear to exhibit seasonal fluctuations in their susceptibility to different infectious diseases [7e9]. Whether this is due to increased prevalence of the pathogen, or due to increased susceptibility in the host, is important. For example gilthead sea bream (Sparus aurata) cultured in the Mediterranean Sea can be affected by ‘‘winter syndrome’’. This causes chronic mortalities during the winter months becoming acute as the temperature begins to rise [10]. Cold-water vibriosis as the name suggests is a bacterial disease that is most frequently observed in winter in a variety of cultured species including the salmonids [11]. Fungal pathogens of fish also demonstrate a seasonal pattern of infection [12]. Epizootic ulcerative syndrome (EUS) outbreaks across Asia-Pacific usually occur during the colder seasons of the year when the temperature is below 25  C. Proliferative Kidney Disease (PKD) is a temperature-dependent parasitic disease of freshwater salmonid fish. Studies have shown that naturally infected fish subsequently held under laboratory conditions developed clinical PKD at 12e18  C but not at 9  C [13]. Consequently, water temperature regimes have been used to prevent the occurrence of PKD. This review looks at environmental factors with a seasonal periodicity that can impact on the immune system, and consequently on health. The review will focus on issues relating to aquaculture species, as this is of particular interest. However, wider issues such as an understanding of how environment, and specifically seasonality, affects psychology, as seen in human subjects, allow us the possibility to extrapolate into species that we can only investigate from an objective standpoint. 2. Seasonality Many organisms respond to seasonal change physiologically, behaviourally or both. Fish display a strong association to season, especially with regard to their breeding strategies, with young fish often being produced when environmental conditions are most favourable. Thus, seasonality dominates the life cycle of fish. It co-ordinates their reproductive activity, affects body weight and condition, influences food intake and locomotor activity and is also believed to co-ordinate their immune response [14]. All these events are synchronised with seasonal changes in climate (mainly temperature), day length and food supplies [14]. The complex mechanism that allows eurythermal fish to synchronise these events to seasonal change requires the animal to sense physical changes in the environment (e.g. temperature, photoperiod) with a corresponding transduction into molecular signals. This mechanism is not yet completely understood, although it is known that eurythermal fish rely on cues from the external environment to achieve this synchronisation [15]. These cues are often described as ‘‘proximate’’ whilst those that give an animal the greatest chance of survival are described as ‘‘ultimate’’ cues [14]. Although a number of environmental cues have been suggested as possible proximate cues, day length, or photoperiod, has received the most attention. It has been found to be the principle determinant in the sexual maturation of salmonids, bass, the breams, mullet, flatfish, the sciaenids and serriolids [14], which collectively comprise the major intensively farmed species. Thus, seasonality is a complex event made up of many potential cues, with the principle cues being changes in temperature and day length. The responses of some animals to seasonality are controlled through one of the principle cues or a combination of them both. The secondary cues can be directly related to the principle cues (e.g. water quality, food supply and quality, pollution). Species living in arid or semi-arid habitats, for example, are likely to adapt their life cycle through the cessation of reproduction during periods of water shortage [16]. The magnitude of information

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relating to the effects of secondary cues on the physiology of fish is considerable, much of which is not presented in a seasonal context. We therefore have chosen to focus on the two primary cues in this review e photoperiod and temperature. 2.1. Photoperiod Photoperiod has been defined as the light fraction of a 24-h day that changes with season [17]. The first published evidence of a photoperiod response was by Garner and Allard in the early 1920’s [4,18] who were investigating flowering in tobacco plants. They found a particular variety of tobacco plant that flowered later than other tobacco plants, with flowering induced by reducing day length. An early study carried out by Hoover and Hubbard in 1937 [19], investigating seasonal cues in fish, looked at the timing of reproduction in brook trout (Salvelinus fontinalis) and found that fish given a seasonal light cycle shorter than a 12-month period could be induced to spawn several months earlier than control fish on a standard 12-month cycle. This confirmed that photoperiod manipulation could induce out-of-season spawning so important in modern aquaculture. Photoperiodism uses the annual changes in day length to time seasonal adaptations in physiology and behaviour. The ability to alter the physiological state in tune with environmental rhythms can give an organism a significant adaptive advantage [20]. The effect on reproduction has been the area most studied where photoperiodism is a response to a proximate factor (day length), which is not itself responsible for reproductive success. Some believe photoperiod is a far more reliable cue than temperature in terms of anticipating seasonal change [16]. The measurement of day length is usually accomplished by a mechanism involving a circadian oscillator [21]. In mammals it appears that most cells have the components of a functional biological oscillator. However, these peripheral clocks are influenced by, or slaves of, the master circadian pacemaker found within the suprachiasmatic nuclei (SCN) of the hypothalamus. The cells of the SCN receive light information from unknown non-visual photoreceptors in the eye. Following this the SCN drives melatonin synthesis and release from the pineal gland through a multisynaptic pathway. Photoperiodic timing of seasonal physiology in mammals depends on three linked processes. The first is the entrainment of the activity of the SCN by the lightedark cycle. The second is the synthesis of the indole amine hormone, melatonin, by the pineal gland, which is driven by the SCN. This process may be considered as the encryption of the photoperiodic time cycle. Melatonin is synthesised and secreted by the pineal gland during the dark period of the lightedark cycle. The third is the decoding of this encryption by tissues sensitive to melatonin [22]. However, this is not absolute as pinealectomy in mammals, which results in cessation of melatonin synthesis, abolishes seasonal responses but has little effect on circadian organisation, although some physiological effects have been described [23,24]. It would seem that melatonin signal generation is more complicated in non-mammalian vertebrates and subject to broad inter-species variation including, multiple oscillators, multiple photic input, and multiple sites of melatonin generation [25]. Thus, melatonin is seen as being the photoperiod transducer [26]. The pineal gland, which produces this hormone, has been a source of mystery for many centuries. Originally, it was thought to be a valve regulating the flow of spirits between the ventricles of the brain. Much later Descartes described it as being the ‘seat of the soul’. It was not until the late 1950’s that melatonin was discovered [27,28]. Melatonin is the primary secretion of the pineal gland and is known to play a major role in the regulation of biological rhythms [29]. Although still unclear, it is believed that melatonin reacts with high-affinity G-protein coupled receptors [30,31]. The lipophilic nature of melatonin may also allow it to pass through the cell membrane directly and possibly interact with putative melatonin receptors. In vertebrates there appear to be several types of high and low affinity melatonin receptors (MT1, MT2 and Mel1c e high-affinity, MT3 e low affinity), although not all receptor types are found in all vertebrates, for instance Mel1c is non-mammalian [32,33]. MT3 appears to be something of an anomaly in that it is not a transmembrane receptor like MT1 and MT2, rather it is an enzyme, quinone reductase 2 [34]. The lack of specific ligands has made traditional study difficult, but this lack also indicates possible new melatonin pathways [34]. The pars tuberalis, a structure within the pituitary, contains a very high density of melatonin receptors and is thought to be of primary importance to the melatonin control of photoperiod-dependent seasonal functions, especially in the annual sexual cycle [29]. Whilst clock genes (a canonical group of genes with interacting functions that are necessary for the expression of a circadian rhythm) are widely expressed in mammalian

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tissues, except for those in the SCN and retina, they do not exhibit a cell-autonomous self-sustaining rhythm. Instead it would appear that the cyclical expression in peripheral tissues is driven by the SCN. Since there are melatonin receptors in the SCN this would implicate exogenous melatonin in circadian regulation. The presence of the MT1 and/or MT2 receptors appears to be required for the photoperiod effects of melatonin [35,36]. However, other neural mechanisms may also be involved. It is interesting to note the conservation of the circadian system through the animal phyla. Whilst changes occur to overcome differences in physiology, the overall pattern of light transduction is remarkably similar from invertebrates to vertebrates, especially at the molecular level [37e39]. 2.2. Temperature Temperature is a well-known principal environmental cue. It has been studied extensively with regard to reproduction, animal behaviour and immune response [40e42]. Many organisms are known to use temperature to modulate seasonal events, particularly poikilothermic animals [43]. As poikilotherms, the body temperature of fish varies with that of its surroundings. It is therefore not surprising that temperature should be the principal cue for anticipating seasonal events allowing the immune system of fish, in this case trout, to be adjusted accordingly [44]. However, it is still unclear whether temperature influences on melatonin synthesis actually affect seasonality, especially in poikilotherms. Melatonin production is affected not only by photoperiod, but also by several other environmental conditions. Studies have shown that excessive thermal exposure, either too hot or too cold, changes levels of serum melatonin. For example, it has been shown that rodents exposed to cold have increased serum melatonin levels [45]. Contrary to this it was reported that Atlantic salmon maintained at 12  C showed significantly higher levels of dark-phase plasma melatonin compared with groups maintained at 4  C [46]. One author suggested that temperature regulates the amplitude of the circadian melatonin rhythm in poikilotherms, whereas photoperiod controls the duration of the nocturnal rise [47]. This reflects the seasonal changes experienced by poikilothermic animals [48]. Effects of this modulation of melatonin amplitude on downstream physiology are still hypothetical. The dual regulation of melatonin synthesis is believed to have an adaptive significance, especially when considering that animals experience very similar photoperiods but different temperatures, twice during the circannular cycle, prior to and after equinoxes [48]. In mammals, studies on the differentiation of the equinoxes led to the characterisation of the process known as photorefractoriness [49,50]. This is where animals that are held at constant photoperiod spontaneously revert to a physiological state associated with the opposite photoperiod [51]. This allows animals to anticipate a coming season without having to experience the actual relevant photoperiod. In reptiles, another poikilothermic animal group, temperature also affects melatonin production with indications that temperature and light induced separate patterns [52]. It has not as yet been established which stages of melatonin production are affected by temperature. It is known that the level of rate limiting enzyme for melatonin synthesis, serotonin N-acetyl-transferase (AANAT), exhibits pronounced seasonal change and is affected by temperature. However, other steps such as the availability of serotonin have not yet been fully investigated [48]. 3. Seasonality and immunity The effects of season on the immune system of mammalian species are considered to be an adaptive or survival mechanism to help animals cope with the more physiologically demanding winter environment such as decreased temperature, increased energy needs, decreased food availability, and increased stress [53]. Immune responses of many animals, including ectotherms, are known to vary seasonally. In general, parameters are suppressed during winter and raised in summer [54], and whilst the majority of research has been carried out in mammals, the importance of seasonality on the immune response of fish is increasingly being recognised. Whilst there is a reasonable body of work on factors influencing the immune response of both farmed and wild fish species (e.g. water quality, temperature, feed availability) it is not in a seasonal context and therefore this work will not be discussed here. Early work on the effect of seasonality on fish was based on individual species or pathogens affecting wild fisheries [55,56]. Seasonal variation in haematological and immune parameters has been found in tench (Tinca tinca) [57e60], while seasonal trends in lysozyme activity have been observed in dab (Limanda limanda L.), halibut (Hippoglossus

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hippoglossus L.) and plaice (Pleuronectes platessa) [61e63]. Leucocyte counts for tench were found to be significantly lower in winter and spring compared with those measured during summer and autumn [60]. It has been suggested that a shortening in day length may induce changes in the immune system in preparation for winter, and this is corroborated by the highest white cell counts being recorded in tench during the autumn months [60]. Lymphocyte numbers have been reported to vary significantly in the lymphoid organs of wild brown trout (Salmo trutta L.) throughout the year [64]. The spleen and kidney of these fish appeared to have similar annual patterns of lymphocyte distribution, with high numbers of lymphocytes found in spring and autumn and two periods of lymphoid involution in summer and winter [64]. In tench, the alternative complement pathway activity has been shown to be greater in winter for both males and females [57]. These findings indicate the importance of this pathway in ectotherm vertebrates, with its predominance during cold periods when the adaptive immune response is depressed, suggesting a more important role for the innate system in winter compared to the specific system [57]. Morgan et al. [65] reported a significant correlation between season and several immune parameters of rainbow trout, Oncorhynchus mykiss. Serum lysozyme activity, levels of respiratory burst by head kidney macrophages, blood cell counts (red and white) and acquired antibody titres against Vibrio anguillarum, were all found to be positively correlated with season, while haematocrit values were found to be negatively correlated. The determination of specific environmental cues and the influence of the neuroendocrine system are presently areas of particular interest in the study of the effects of seasonal variation on the immune response of vertebrates [24,66]. 3.1. Temperature and immunity The effect of temperature on the immune response of ectotherms such as teleosts is of particular interest, especially as fishes are unable to regulate their internal temperature [67]. Temperature has been found to be the principle environmental cue stimulating changes in the immune response of many different fish species, affecting both innate and acquired immune responses [68]. Higher temperatures (in the physiological ‘normal’ range) have been reported to enhance immune responses in fish whereas lower temperatures adversely affect immune function [68], with an optimum temperature for greatest activity [44]. It had been previously suggested that the innate immune system is unaffected by temperature, whereas the acquired system is temperature-dependent [69]. However, this is now accepted not to be the case. Both acquired and innate immune systems are significantly affected by temperature [70]. It appears that in sockeye salmon (Oncorhynchus nerka) the immune response of fish reared at 8  C is more dependent on the innate immune response rather than the acquired immune response compared to fish reared at 12  C [71]. Channel catfish and tench adapt well to low temperatures of 12  C and exhibit enhanced respiratory burst by head kidney macrophages at this temperature, suggesting an improved ability by the fish to kill invading bacteria [57,72]. 3.2. Photoperiod and immunity Seasonal adaptation can be both initiated and/or terminated by changes in photoperiod. The annual cycle of changing photoperiod is a very precise temporal cue for determining the time of year [73]. It has already been well established that photoperiod influences growth, feeding, parr/smolt transformation in Atlantic salmon and reproduction. It is therefore entirely feasible that photoperiod influences the fishes immune function. To date the majority of work examining the effects of photoperiod on the immune response has been carried out in mammals with very few studies carried out in fish. Several studies have found significant effects of photoperiod on immune response [74,75], especially in rodent models [76e79]. 3.2.1. Mammals Associations have been reported between the duration of environmental light and the immune response of mammals, with short photoperiods (8L:16D) appearing to enhance humoral immunity compared to long photoperiods (16L:8D) [80]. It has been suggested that photoperiod provides Siberian hamsters (Phodopus sungorus) with a useful cue to anticipate environmental stressors, allowing them to adjust their immune function accordingly [78]. Augmentation of immune function in hamsters exposed to a short-day regime may occur in preparation

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for seasonal stressors such as low temperatures and reduced food availability, which would otherwise increase susceptibility to infection [78]. Research over the last decade has indicated that melatonin has immunoregulatory properties in human and rodent models, enhancing antibody production to T-dependent antigens in normal mice [81] and restoring impaired T-helper cell activity in immunocompromised mice [82]. It has also been reported to activate and increase the cytotoxicity of human monocytes and increase their secretion of IL-1 and production of reactive oxygen species [83], and enhance antigen presentation and IL-1 and TNFa production in mouse splenic macrophages [82]. More recently melatonin has been shown to enhance IL-2, IL-6 and INFg production by human CD4þ cells [84]. Changes in these cytokines have been associated with the seasonal changes in mood and behaviour, such as Seasonal Affective Disorder [85]. 3.2.2. Avian Photoperiod manipulation is very important to the poultry industry, and a great deal of interest has focused on photoperiod manipulation in birds. It has been reported that lighting conditions significantly affected the immune parameters of Japanese quail [80]. Birds exposed to continuous light had a significantly lower immune response compared to birds that experienced a diurnal cycle of melatonin via a lightedark photoperiod [80]. This goes some way to corroborate work carried out on starlings where birds exposed to long day photoperiods exhibited a suppressed immune response [86]. 3.2.3. Reptiles and amphibians Reptiles and amphibians represent other poikilothermic animal groups. There is considerable work in these groups on the effect of photoperiod [53]. In reptiles, there is evidence for some diversity in the regulation of melatonin production by the pineal organ. Regulation may occur by an intrapineal circadian oscillator as for Anolis carolinensis, Sceloporus occidentalis and Iguana iguana [87e89]. Alternatively, it may be regulated by light or extrapineal oscillators in species that lack an ‘‘intrapineal’’ clock such as Dipsosuarus dorsalis and Christinus marmoratus [52,90,91]. In amphibians, such as the Japanese newt (Cynops pyrrhogaster), melatonin is regulated by both external stimuli and endogenous clocks [92]. It may also play a significant role in metamorphosis along with other endocrine factors such as thyroxine and corticosteroids [93]. As for the immune function, a study on turtle peripheral blood leucocytes found a pronounced seasonality in their function when looking at adherence, chemotaxis and proliferation [94]. Similar responses of the immune system have been seen in other reptile species [95e98]. 3.2.4. Fish Photoperiod manipulation is now increasingly used by the aquaculture industry to supply the market with a continuous source of out-of-season fish, which reach market size in the shortest possible time. It has been used successfully to inhibit maturation and/or to enhance growth, with long day-lengths (16L:8D, 24L:0D) shown to increase growth rates in salmonids [46]. The effect of these changes on the endocrine system has been studied [99]. Alterations in photoperiod have profound effects on levels of the hormones testosterone, estradiol, and cortisol, all of which have been found to alter immune cell function [75]. It is known that prolonged changes in the natural photoperiod adversely affect the immune response of rainbow trout, but the fish rapidly resume normal function after returning to a normal photoperiod [74]. It has been reported that changes in the photoperiodic regime of rainbow trout produce detectable chronic stress in the form of elevated cortisol [74]. Haematological changes were not generally effected. Thrombocyte numbers were lowered by artificial photoperiods, but all other haematological parameters were unchanged. Rainbow trout maintained under three different photoperiods (constant light, 18L:6D, 6L:18D) exhibited different haematocrit values over a three-month trial carried out in winter [44]. Fish maintained on a short-day regime had a significantly higher haematocrit value compared to fish maintained on constant light and long day photoperiod regimes. However, when this experiment was repeated in summer using fish from the same stock as the winter experiment the results were not duplicated. It has been reported that photoperiodic trials designed to delay maturation in salmonids involving constant light are most likely to be successful and generate significant results if they are started between the summer and winter solstices (Taylor, J., Personal Communication, Institute of Aquaculture, University of Stirling). This was the case for the winter trial and maybe why photoperiod significantly affected haematocrit values [44]. Some researchers believe that photoperiod and temperature are both reliable principle seasonal cues in aquatic animals [14]. Fish are therefore not dependent on one particular principle cue. It would appear that rainbow trout

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do not use photoperiod as their principle cue for modulating the immune system [44], although it is well documented that photoperiod is the principle cue for other events, especially reproduction [14]. There is evidence to suggest that Atlantic salmon do not use temperature to regulate smolting [99,100]. It has been suggested that fish are most likely to respond to changes in photoperiod when they are younger. As the fish ages melatonin production decreases, possibly because melatonin is no longer as important as a transducer of information [101]. 4. Seasonal variation in immunity e a human perspective It has been recognised that outbreaks of disease, and susceptibility to disease, fluctuate seasonally in most mammalian species, including humans. To make predictions about the illness and to establish the causes of seasonal fluctuations it is important to determine the extent to which seasonal fluctuations in disease occurrence reflect seasonal changes in susceptibility to disease or a fluctuation in the cause of disease [16]. People make interesting subjects for studies of biological systems that can have both a physiological and a psychological output. Unlike any other species, you can ask a person how they feel and get a subjective response. Research on other species is entirely objective and psychological changes are only evident when presented through another media, such as physiology or behaviour. Unlike most other mammalian species, the food resources and availability in developed countries no longer affect human seasonal cycles. Man no longer possesses a seasonal reproductive cycle unlike most mammalian species. However, behaviour as well as physiological activity may affect the susceptibility to diseases. As already mentioned, light affects the secretion of melatonin and this hormone has an effect on the immunity and well being of humans as well. A good example of the effect of light on humans is seasonal affective disorder (SAD) characterised by recurrent episodes of winter depression. Patients having SAD and who live in temperate and boreal regions experience a longer duration of the nocturnal period of active melatonin secretion in winter than in summer [102]. Lambert et al. [103] took blood samples from 101 healthy men, and evaluated the relation between concentration of serotonin metabolites, weather conditions and season. The authors showed that the turnover of serotonin by the brain was lowest in winter and that the rate of production of serotonin by the brain was directly related to the prevailing duration of bright sunlight, giving evidence to the notion that changes in release of serotonin by the brain underlie SAD. In humans it has been shown that several diseases have a seasonal aspect, some of which are dependent on variations in immune functions of the host and some of which are dependent on the occurrence of the pathogens [104]. Seasonal cycles of infectious diseases have been variously attributed to changes in atmospheric conditions, the prevalence or virulence of the pathogen, or changes in host behaviour or immunity [104]. Studies have shown that expression of hormones and cytokines show seasonal variations that can affect immune functions. Andersson and coworkers [20] evaluated the effect of season on the levels of serum hormones such as, inhibin B, testosterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone, and sex hormone-binding globulin in healthy men. A clear seasonal effect was observed in LH and testosterone levels, but not in the levels of the other hormones. LH and testosterone levels peaked during JuneeJuly, with minimum levels present during wintereearly spring. On the other hand, testosterone levels peaked in healthy men during autumn in northern Norway [105]. Additionally, many other immunity parameters have been shown to express seasonal variation in healthy human populations. Levi et al. [106] showed that the number of T suppressor/cytotoxic cells and natural killer cells (NK) in blood peaked in October, November, and December. In Sweden, Afoke et al. [107] studied the numbers of various leucocyte subpopulations in blood of children and found significant increases in CD4þ T-helper cells, total T-lymphocytes and CD4þ/CD8þ T-cell ratio during the spring season. While the levels of CD8þ T-cells and total B lymphocytes remained statistically unchanged during all four seasons, the levels of natural killer cells and macrophages increased significantly during the autumn and summer seasons, respectively. Additionally, the authors measured the levels of immunoglobulins G, A, M and E, and all the immunoglobulin subpopulations remained statistically unchanged during all four seasons. However, MacMurray et al. [108] suggested that during the winter period, adrenalecorticoid induced depression of T-cell function, which is accompanied by elevated B-cell function and elevated serum immunoglobulin levels, takes place in healthy people. Clinical trials and epidemiological observations have shown that increased fibrinogen levels in plasma correlates with an increased frequency of vascular events such as the potential risk of acute myocardial infarction and stroke in humans. Sharp initial increases in both respiratory disease and stroke mortality in winter were synchronous, and the amplitudes of mortalities were strongly associated with the time of year and temperature in US [109]. Hermida et al. [110] studied hypertensive patients in Spain and showed that fibrinogen levels are aligned to seasonal variations with

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the peak levels in February. Additionally, it has been suggested that cardiovascular risk factors, such as fibrinogen levels, provide further possible evidence for the marked seasonal variation in death from ischaemic heart disease and stroke in the elderly people [111]. Fibrinogen level is also regulated in healthy people since it was reported that the fibrinogen levels of healthy citizens in Italy were higher during the winter period compared to the summer period [112]. High cholesterol levels correlate well with coronary artery disease in human and cholesterol levels in serum, which appear to be aligned to seasonal variation, peaking in December in men and in January in women [113]. Seasonal variation may affect immunity. It may also have an effect on many diseases. Perhaps the best-documented evidence of such dependence of disease development and changes in immunity parameters is the onset of multiple sclerosis (MS) in humans [114]. It was shown that, in Japan, the total number of attacks was significantly higher in the warmest (July and August) and coldest (January and February) months [114]. It has also been demonstrated that increases in the prevalence of multiple sclerosis (MS) are associated with temperate latitudes [115]. Crosssectional studies suggest seasonal variation of both interferon (IFN)-gamma production and the number of active MRI lesions in MS [116e118]. Killestein et al. [119] studied the contribution of T-cells on MS and the authors observed a significant seasonal variation in T-cell activation as measured by the ability of T-cells to secrete tumour necrosis factor-a and IFN-g with maximum values being found in samples obtained during the autumn. Mortalities caused by various forms of heart disease have been shown to correlate with season and specifically temperature. The highest mortalities due to heart failure observed in Europe were during winter [120,121]. Also, acute myocardial infarction peaked during the winter [122] as did sudden deaths in Germany [123]. 5. Conclusion Aquaculture fish production has increased significantly over the past few decades and with it the incidence of disease outbreaks, often associated with an intensification of the culture conditions. Disease, in turn, has caused substantial economic loss to the aquaculture industry. In order to mitigate disease outbreaks in aquaculture, it is necessary to develop disease control strategies based on a better understanding of the effects of husbandry methods and environmental stressors on the health status of farmed fish. In the culture of Atlantic salmon it is common to vaccinate in the autumn before transfer from freshwater to seawater. The principle period for this transfer occurs during the spring. However, production developments are such that significant inputs occur also during the late summer/early autumn, and to a much lesser extent, during the late winter/early spring. Using such knowledge it may be possible to carry out husbandry practices (vaccination, transfer, grading) at a time when the animal is known not to be seasonally immunocompromised. It is clear that the environment affects the immune system of fish. Predicting the consequences of this is not so easy. Variations occur between fish species and specific immune parameters. If seasonally associated changes can be anticipated, it may be possible to bolster the immune system at times when they are known to be immunosuppressed, as under artificial photoperiod regimes, with the application of immunomodulators such as immunostimulants prior to exposure to stressful events. 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Artificial light and season affects vertical distribution and swimming behaviour of post-smolt Atlantic salmon in sea cages. J Fish Biol 2001;58:1570e84. [6] Davies B, Bromage N, Swanson P. The brainepituitaryegonadal axis of female rainbow trout Oncorhynchus mykiss: effects of photoperiod manipulation. Gen Comp Endocrinol 1999;115:155e66. [7] Lillehaug A, Lunestad BT, Grave K. Epidemiology of bacterial diseases in Norwegian aquaculture e a description based on antibiotic prescription data for the ten-year period 1991e2000. Dis Aquat Organ 2003;53:115e25. [8] Ondrackova M, Reichard M, Jurajda P, Gelnar M. Seasonal dynamics of Posthodiplostomum cuticola (Digenea, Diplostomatidae) metacercariae and parasite-enhanced growth of juvenile host fish. Parasitol Res 2004;93:131e6.

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