Integrative and Comparative Biology Advance Access originally published online on October 26, 2006
Integrative and Comparative Biology 2006 46(6):1060-1071; doi:10.1093/icb/icl050
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Evolution of reproductive–immune interactions
Boston University 5 Cummington Street, Boston, MA 02215, USA
Correspondence: 1E-mail: bram{at}bu.edu
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The comparative approach in biological sciences has provided valuable insights into the role of different organ systems in adaptation and evolution, and seeks to establish unifying themes. This approach also plays a key role in identifying model species and systems for the study of specific questions and problems. Further, by applying the concept of homology, information about nonmammalian species may be used either to directly understand mammalian/human regulatory processes, or to formulate hypotheses for direct testing. Individual physiological systems function in a milieu provided by the integrated activities of all of the systems to adapt, adjust and sustain the organism in its environment. The overlapping interfaces between the different physiological systems provide fertile ground for new insights and to enhance our knowledge. These interdisciplinary areas are of great importance if we are to understand the full complexity of organismal function. Of particular interest are the interactions between the reproductive system and the immune system. The reproductive system is unique in that its primary role is to assure the continuity of the species, while the immune system provides internal protection and thus facilitates continued health and survival. The modus operandi of these 2 morphologically diffuse systems involves widely distributed chemical signals in response to environmental input, and both systems must interact for the normal functioning of each. While the major focus of reproductive–immune research has historically been with mammals, and has provided substantial insight into the interactions between these physiological systems, comparative studies offer unique perspectives. Further, dysregulation of normal physiological interactions between the reproductive and immune systems can lead to disorders and diseases effecting one system or the other. Thus, comparative studies of these interactions may shed some light upon the evolutionary mechanisms involved in such cases.
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Reproductive–immune interactions: A comparative review |
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In mammals, the effects of the hypothalamic–pituitary–adrenal axis on the immune system are well established (Medawar and Sparrow 1956
; Schreck and Maule 2001; Wrona 2006), but interactions between the hypothalamic–pituitary–gonadal (HPG) axis and immune system are less well understood. It is known that the hormones of the HPG axis (releasing hormones, gonadotropins, sex steroids and numerous relevant growth factors) affect both the innate and acquired immune systems by up or downregulation of the cells and factors they produce (Tanriverdi and others 2003). Reproductive hormones have been implicated in the development, as well as modulation, of the immune system (Mann and others 1994). Gonadotropin releasing hormone (GnRH) and its receptor (GnRH-R) are expressed in various subsets of immune cells (Marchetti and others 1989; Jacobson and others 1998; Chen and others 1999), and the sex hormones also have binding sites in lymphomyeloid tissues and peripheral immune cells (Kawashima and others 1992; Suenaga and others 1998). Sex differences in in vitro leukocyte proliferation have been described since 1974 (Barnes and others 1974). Although the effects of estrogen, progesterone and testosterone on white blood cells are diverse, they have demonstrated an overall inhibitory effect on leukocyte proliferation (Beagley and Gockel 2003; Morale and others 2003). Also, these steroids have been shown to exert dose- and time-dependent effects on apoptosis in mononuclear cells (Evans and others 1997; Cutolo and others 2002), T- and B-lymphocytes (Mor and others 2001; Grimaldi and others 2002), neutrophils (Molloy and others 2003), and cancer cells (Denmeade and Isaacs 1996). Of great potential importance, interactions between the reproductive hormones and the immune system have been investigated due to correlations in autoimmune diseases. That is, women experience improvement in disease symptoms during pregnancy, when hormone levels increase, and an amelioration of diseases such as rheumatoid arthritis and systemic lupus erythematosus have been demonstrated by various investigators (Holdstock and others 1982; Mattsson and others 1991; Ostensen and Villiger 2002; Beagley and Gockel 2003).
One of the most studied reproductive–immune interactions occurs during pregnancy, a relationship first recognized by Sir Peter Medawar (1953). During this period the maternal immune system is alerted to the presence of the fetal allograft by paternally derived histocompatibility antigens. The maternal immune system may potentially reject the "foreign" fetus, but under normal circumstances it is tolerated. Precisely what mechanisms are primary in this tolerance are not clear and different mechanisms may play a role at different times of embryo–fetal development (Thellin and Heinen 2003). Many fetal immune evasion mechanisms have evolved that appear to generate nonspecific inhibition of both the innate and adaptive arms of the immune system during pregnancy (reviewed in Trowsdale and Betz 2006). A major factor in this tolerance is the pregnancy hormone, progesterone (Siiteri and Stites 1982). This hormone aids in the initial establishment of pregnancy by the induction of the decidua in the estrogen-primed endometrium. One of the best characterized examples of the importance of progesterone (P4) in pregnancy maintenance to date was demonstrated in an elegant study by Erlebacher and colleagues (2004). This study showed that pregnancy failure (that is, embryo resorption) in mice early in gestation occurred not through immune cell activation at the maternal–fetal interface, but rather through decreased P4 synthesis by the corpus luteum. They showed that luteal insufficiency was induced by activated NK cells, required the actions of the proinflammatory cytokine TNF-
and that it was associated with impaired prolactin receptor signaling. It is also thought that population expansion of regulatory T-cells (CD4+CD25+), critical for maintenance of pregnancy, may be driven by reproductive hormones (Aluvihare and others 2004).
Immune cells and their factors are frequently implicated in ovarian regulation (Adashi 1990; Brannstrom and Norman 1993), and the removal of critical immune tissues, especially during the neonatal period, can induce pathologies in the ovaries and testes (Hattori and Brandon 1979). Cytokines regulate the growth, differentiation and death of various cellular components of the ovary. They also regulate the number and composition of the lymphocytes that produce many of the other ovarian cytokines (Nash and others 1999). Follicular fluid in humans has been shown to contain the proinflammatory cytokines, tumor necrosis factor- (TNF-) and interleukin-1ß (IL-1ß) (Terranova and Rice 1997), which exert chemotactic activity on immune cells (Herriot and others 1986). The cyclic regression of reproductive tissues in seasonally breeding animals is a physiological circumstance in which degenerating cells are eliminated. The invasion of the ovaries of adult rats by macrophages occurs during follicular atresia (Gaytan and others 1998), and in various species, development of the corpus luteum coincides with the appearance of neutrophils and macrophages (Wang and others 1992; Brannstrom and others 1994). Both neutrophils (Brannstrom and others 1995) and macrophages (Araki and others 1996) play a part in ovulation via changes in myeloperoxidase activity and production of macrophage-colony stimulating factor, respectively.
Less is known of reproductive–immune interactions in the nonmammalian vertebrate classes. Progress has been hindered by a lack of genetic information, cell surface markers and recombinant proteins for experimental use. However, some emphasis has been placed on reproductive–immune studies in birds and reptiles. In these groups it is thought that reproductive effort compromises the immune defense of individuals, increasing their susceptibility to infectious disease (Gustafsson and others 1994). It is suggested that increased testosterone (T) levels enhance male competitive success while restraining immune responses (Moore ad Marler 1987; DeNardo and Sinervo 1994). Other investigators have provided evidence that the immune system is suppressed by reproductive effort in that antibody response to immune challenge and parasite resistance are reduced (Richner and others 1995; Deerenderg and others 1997; Nordling and others 1998). Thus, an evolutionary trade-off between reproductive fitness and immune defense has been hypothesized due to T having an overall immunosuppressive effect (Folstad and Karter 1992).
The presence of lymphocytes in the gonads of birds has been long noted, and cells specific to B-cell (Zettergren and Cutlan 1992) and T-cell (Withanage 2003) lineages have been demonstrated in the chicken ovary. It is thought that estrogen (E2) is one of the factors that stimulate the influx of T-cells in the hen ovary (Barua and Yoshimura 1999). Pasanen and colleagues (1998) demonstrated constitutive progesterone receptor (PR) expression in the bursa and thymus of the chicken. Expression of the PR was detected in B-lymphocytes and macrophages, but not T-lymphocytes, and was increased during sexual maturation and after treatment with E2.
In birds, the immunologic effects of gonadal steroids vary both between species and within the same species based upon a number of factors. In European starlings, T induced suppression of both cell-mediated and humoral immunity (Duffy and Ball 2002), while in red jungle fowl seasonal changes associated with increased T affected only humoral responses (Zuk and others 1998). T caused involution of the bursa of Fabricius and E2 suppressed the proliferative response of ConA- and LPS-stimulated peripheral blood lymphocytes in chickens (Gallus domesticus) (Le Dourain and others 1980). Landsman and colleagues (2001) found that high concentrations of E2 and dihydrotestosterone (DHT) decreased lymphocyte proliferative response to mitogens in chickens, but without mitogenic stimulation the sex steroids had no effect. Further, at physiological doses, E2 significantly enhanced the proliferative responses to mitogens. In another study, DHT suppressed bursal growth and E2 significantly enhanced the humoral response to Escherichia coli and sheep erythrocytes. The antiandrogen, flutamide, and the antiestrogen, tamoxifen, counteracted this effect (Leitner and others 1996). While Novotny and colleagues (1983) found that DHT was also a potent inhibitor of proliferation in the avian bursa, Bhanushali and colleagues (1984) showed that androgens have different effects on the bursa of chickens depending on dose and timing of administration. If sufficient amounts are given during bursal development, androgens may delay or permanently impair development of humoral immune responses. However, if given after bursal development is complete, androgens cause precocious migration of lymphoid cells without maturation. Khan and colleagues (1996) showed that E2 enhanced migration of T-cells from lymphoid organs to the oviduct, whereas P4 inhibited the migration of T-cells. Removal of gonadal steroids by castration was found to decrease thymic weight and impair cell-mediated immunity in chickens (Mashaly 1984), and also led to a slight enlargement of the bursa (Glick 1984). Mase and Oishi (1991) also showed that T treatment induced significant reduction in relative weight of the bursa, thymus and spleen to body weight.
While the chicken has been the primary avian species represented in reproductive–immune studies, other species have shed light on these interactions as well. In pigeons (Columba livia), Selvaraj and Pitchappan (1985) demonstrated that the influence of E2 on the immune system depends on the age and sex. While hormonal influence was marginal in males, humoral immune responses were enhanced in 1-month-old, but not 3 to 4-month-old female birds. Cell-mediated immune responses were depressed in females of both age groups, and involution of thymus and bursa were consistently noted. In seagulls (Larus ridibundus), splenic leukocytes showed a response similar to that reported in chickens and mammals (Munoz and Fuente 2003). That is, during the postmigratory resting period in seagulls E2 levels are high and leukocyte proliferation is low. Also, when E2 levels are lower in these birds, immune responses (adherence, chemotaxis and proliferation) are increased. In the bursa and thymus of the Japanese quail, E2 causes disappearance of lymphocytes (Razia and others 2005). In free-ranging male red-winged blackbirds (Agelaius phoeniceus) tested at the peak breeding period, and in captive nonbreeding male song sparrows (Melospiza melodia), investigators showed that there was no relationship between plasma T levels and humoral immune response (Hasselquist and others 1999; Owen-Ashley and others 2004).
Several labs have investigated immune effects on ovarian granulosa cells and sex steroid production in chickens. Bursectomy markedly increased the size of the testes, number of Leydig cells, and levels of circulating T and DHT (Pedernera and others 1980). The bursa is thought to interfere with gonadal development by preventing expression of luteinizing hormone receptors (Vaticon and others 1980). Within the gonads of mammals, the proinflammatory cytokines, TNF- and IL-1ß, are produced primarily by interstitial macrophages and, with few exceptions, inhibit secretion of sex steroids (Saez 1994; Gnessi and others 1997). It is thought, for this reason, that periods of chronic inflammation and systemic infection are associated with depressed gonadal functioning. In laying hens, treatment of granulosa cells from preovulatory follicles with TNF- consistently inhibited P4 secretion (Bryan and others 1997). Onagbesan and colleagues (2000) found that TNF- produced by chicken macrophages, as well as recombinant human TNF-, modulate growth and differentiation of granulosa cells, as well as production of P4 by follicles. Cytokines, however, have also been described as factors of growth and differentiation in the gonads (Hales 2000). In the chicken, TNF- induced increases in Ca2+ mobilization demonstrating a cytokine-dependent signaling pathway for the regulation of granulosa cell function (Soboloff and others 1995).
Reproductive immune interactions have been noted in several species of lizards. Increased T levels and T administration caused variations in ectoparasite loads and hematological parameters (Viega and others 1998; Klukowski and Nelson 2001), as well as T-cell-mediated immune suppression (Belliure and others 2004). Further, extensive studies of the wall lizard (Hemidactylus flaviridis) have indicated that the morphology of immune tissue and the decreased leukocyte activity associated with heightened T levels both vary with season. Hareramadas and Rai (2001) demonstrated involution of the thymus between autumn and winter, when T levels rise, and regeneration of the thymus in spring and summer, when T levels have decreased. The investigators further showed that this result was possibly caused by T, DHT and E2 via inhibition of thymocyte proliferation and induction of caspase-dependent apoptosis indirectly through thymic epithelial cells via a genomic pathway (Hareramadas and Rai 2006). It was also demonstrated in this species that there is sexual dimorphism in phagocytic activity of splenic macrophages, with females having a greater phagocytic index (Mondal and Rai 1999). In vitro studies of sex hormones and their receptor antagonists showed that while DHT suppressed phagocytosis, E2 either suppressed or had no effect depending on dose and duration of treatment. E2 treatment also increased mast cell number in the lizard, Podarcis s. sicula, whereas T had the opposite effect. These effects were inhibited by the receptor antagonists, tamoxifen and cyproterone acetate, respectively (Minucci and others 1995).
Lymphocytic infiltration and the formation of lymphoid aggregates have been noted in the gonads of several species of turtles, including Chelydra serpentina (Yntema 1981), Emys obicularis (Belaïd and others 2001) and Testudo graeca (Belaïd and others 2004). Similarly, as in the lizard, T has an immunosuppressive effect in turtles, which changes with season. For instance, in Mauremys caspica, when circulating T levels are lower in winter and spring, chemotaxis, antibody-dependent cellular cytotoxicity, natural killer cell activity and mitogen-induced proliferation of lymphocytes are all increased (Munoz and others 2001). Also, T injected into this species caused a decrease in the mitotic index of the thymic cortex during the first 2 weeks post-treatment, followed by that of medullary lymphocytes at 4 and 6 weeks post-treatment (Varas and others 1992).
Similar to birds and reptiles, frog (Rana pipiens) B-cells have been noted in the urogenital tissues during embryogenesis and prior to the onset of feeding (Zettergren 1982). In contrast to reptiles, however, neither in frogs nor in chicks were aggregates of lymphoid cells noted in the gonad (Belaïd and others 2004). Very little is known regarding reproductive–immune interactions in amphibians, but it has been shown that differentiation and proliferation of mast cells are induced by E2 in the gonads of both the toad, Bufo viridis (Minucci and others 1994), and the frog, Rana esculenta (Di Matteo and others 1995). In the frog, this effect may also be dependent upon temperature and reproductive cyclicity, and was counteracted by the estrogen receptor antagonist, tamoxifen (Izzo and others 2004).
Information on reproductive–immune interactions in teleost fish has focused on a number of model species. In the common carp (Cyprinus carpio L.), phagocytosis, superoxide anion and nitric oxide production were all suppressed by E2, P4 and T in a dose-dependent way (Watanuki and others 2002). E2, P4 and 11-Keto T were also shown to suppress the phagocytic activity of macrophages in vitro (Yamaguchi and others 2001). However, the effects of sex hormones on the adaptive immune system are more puzzling in carp. While the plasma levels of IgM and IgM-secreting cells decreased during spawning, and sex steroids have demonstrated immunosuppressive effects (Hou and others 1999), a positive correlation has also been noted between sex hormones and plasma IgM levels (Suzuki and others 1996). Furthermore, recent reports have not demonstrated an effect of sex hormones on apoptosis (Saha and others 2003), numbers of IgM-secreting cells or IgM secretion in vitro (Saha and others 2004). In goldfish (Carassius auratus), E2 has been shown to suppress mitogen-induced proliferation of peripheral blood lymphocytes and to inhibit chemotaxis and phagocytosis in macrophage cell lines (Wang and Belosevic 1994). In chinook salmon (Oncorhynchus tshawytscha) T suppressed antibody-forming cell lines and has been shown to kill salmonid leukocytes in vitro (Slater and Schreck 1993). During sexual maturation and migration to freshwater, salmonids display high levels of sex hormones in the plasma (Maule and others 1996) and sexually mature males and females demonstrate immune deficiencies at this time in their life cycle. These include an inability to produce isohemagglutinins, antibodies produced by immature fish (Ridgeway 1962) and a greater frequency of ectoparasitic infestations (Pickering and Christie 1980). In rainbow trout (Oncorhynchus mykiss), E2 and 11-Keto T, respectively, cause stimulation and inhibition of lymphocyte proliferation (Cook 1994).
Whereas in mammals phagocytosis is carried out by mononuclear cells and neutrophils, teleost fish demonstrate a marked morphological heterogeneity of leukocytes, especially granulocytes. Monocytes/macrophages and acidophilic granulocytes are the primary phagocytic cells of fish (Rowley and others 1988; Esteban and Meseguer 1994), and the latter may be functionally equivalent to the neutrophils of higher vertebrates, as indicated by morphological and cytochemical features (Lopez-Ruiz and others 1992; Meseguer and others 1994). Recent evidence has also demonstrated that B-cells play an important role in fish phagocytosis. In this mechanism, antigen–antibody complexes with bound complement component, C3d, bind both the B-cell receptor and complement receptor type 2 (CR2) on B-cells, leading to a lowered threshold for B-cell activation (Sunyer and others 2005; Boshra and others 2006). 11-KT and E2 modulate intracellular accumulation of IL-1ß in acidophilic granulocytes of the gilthead seabream only upon activation by immunologic stimuli, such as LPS or Vibrio DNA (Chaves-Pozo and others 2005a). Without stimulation, this immune response does not occur. 11-KT and E2 also regulate the respiratory-burst activity of seabream acidophilic granulocytes from the head kidney (Chaves-Pozo and others 2005b). Thus, it is believed that sex hormone-regulated release of IL-1ß from acidophilic granulocytes is involved in modifying gonadal function in the seabream. Further, Chaves-Pozo and colleagues (2005c) demonstrated that the acidophilic granulocytes are involved in reorganization of the germinal compartment of the testes in this species.
There have been few studies of immune influence on the gonads of teleosts. Lister and Van Der Kraak (2002), however, investigated the role of proinflammatory cytokines on steroid synthesis at multiple sites along the HPG and steroid biosynthetic pathways in goldfish (Carassius auratus). They showed that TNF- affected basal T production differentially, depending upon gonadosomatic indices (GSI), an index of relative gonad to body weight. In goldfish with low GSI, TNF- increased T production over basal levels, while in those with high GSI, TNF- decreased T production over basal levels. Further, in goldfish with high GSI, IL-1ß decreased T production. TNF- and IL-1ß both significantly inhibited human chorionic gonadotropin-stimulated T production in the presence of substrates (25-hydroxy cholesterol, pregnenolone and 17-hydroxy progesterone).
Fish also respond to stress-induced infections in various ways that maintain homeostasis. Important physiological processes that are modulated when fish respond to stress are hormonal status and immune function. For instance, during infection, serum E2 levels are significantly reduced and remain at a low level while infection progresses, whereas T levels gradually increase along with the phagocytic activity of macrophages of the pronephros and spleen during infection (Wendelaar-Bonga 1997).
Although leukocytes of various lineages have been noted in the gonads of all vertebrate classes, the autonomous nature of the epigonal organ associated with the gonads of elasmobranchs, and its persistence throughout development and adult reproductive life is unique. The epigonal organ is considered to be a "bone marrow equivalent" tissue and supplies lymphoid and myeloid cells to the rest of the body (Miracle and others 2001; Rumfelt and others 2002). All the lymphomyeloid lineages present in higher vertebrates have been identified in the epigonal organ (Zapata 1981; Fange and Pulsford 1983), and some work has been done to characterize the relative importance of the epigonal organ with respect to establishing the B-cell repertoire in these animals (Dooley and Flajnik 2005).
There have been a few studies in elasmobranchs that provide useful information for the early vertebrate evolution of reproductive–immune interactions. Cateni and colleagues (2003) demonstrated IL-1 and IL-1ß, as well as the specific membrane receptor, IL-1 receptor type I, in the yolk sac placenta of the smoothhound shark, Mustelus canis. Paulesu and colleagues (2005) suggested that this may have important implications for studies of the evolution of materno–fetal immunotolerance. Of potential functional significance, they noted a strong protein sequence similarity between the IL-1 receptor cytoplasmic domain and the cytoplasmic domain of toll-like receptors. Because these immune receptors are involved in immune responses to microbial products in species from insects to humans (O'Neill and Greene 1998), this suggests possible similarities in mechanisms of signal transduction. Haines and colleagues (2005) have demonstrated 2 immunoglobulin isotypes (7S IgM and IgNAR) in both external and internal yolk sacs, and suggested transfer of passive immunity from mother to developing embryo via a system similar to that in the chicken. In a single study investigating immune/epigonal influences on the gonad of the dogfish shark, Squalus acanthias, Piferrer and Callard (1995) demonstrated the presence of an epigonal growth-inhibitory factor (EGIF) and considered it to be responsible for inhibition of spermatogenesis in this species.
In recent studies of the oviparous skate, Leucoraja erinacea, we have described the close morphological and vascular arrangements linking the epigonal organ and ovaries. The gonadal artery passes through a mesovarium en route to the epigonal–ovary complex (EOC). The vasculature and connective tissue of the mesovarium serve to separate the EOC from direct contact with any other tissues of the body. Once in the EOC, blood may pass directly to the general circulation after perfusing the epigonal tissue, carrying leukocytes to the body for various pleiotropic functions. This is possible via the ovarian vein, which leaves the EOC anteriorly prior to perfusion of the entire tissue complex. Therefore, blood may re-enter the general circulation without passing through the ovarian follicles. Alternatively, after passing through the capillary beds of the epigonal organ or follicular wall, blood enters venous sinuses, where it bathes the entire EOC before rejoining the venous system. This may allow for important "education" of lymphomyeloid cells with regard to gonadal functions and vice-versa (Lutton and Callard, unpublished data).
In reproductively inactive adult Leucoraja erinacea, the small (<5mm) ovarian follicles are completely encapsulated by the epigonal organ. As the animals become reproductively active, the follicles appear to be somewhat randomly dispersed throughout the dorsolateral portion of the EOC. When the follicles are fully developed, the epigonal organ is partially displaced and wraps around the ventromedial edge and posterior portion of the entire EOC. Direct cellular contact between epigonal cells and the follicle wall is maintained in some follicles, with others separated from the epigonal tissue by an ovarian epithelium. Leukocytes are common within the follicular thecal layer, and this is more readily observed as the follicles grow progressively larger (Lutton and Callard unpublished data). In atretic follicles, infiltration by leukocytes is frequently observed, suggesting a role for leukocytes in the process of atresia similar to that in mammals (Gaytan and others 1998), reptiles (Guraya and Varma 1976) and birds (Barua and Yoshimura 1999).
During the reproductive cycle, marked changes in gonadal weight are seen. The gonadosomatic indices (GSI) of reproductively inactive skates are significantly lower than are those of reproductively active skates. Epigonal weight relative to body weight, or epigonadosomatic index (ESI), however, remains the same whether the animals are reproductively active or inactive. To further investigate the relationship between ESI and reproductive states, cellular turnover (proliferation and apoptosis) was investigated in the epigonal organ during the inactive and active phases of the ovarian cycle. Paraffin-embedded epigonal tissues were stained for proliferating cell nuclear antigen (PCNA), and in reproductively active animals, but not reproductively inactive ones, mitosis of leukocytes in blood vessels was observed throughout the tissue. Terminal UTP nick end-labeling (TUNEL) demonstrated that apoptosis was also greater in reproductively active skates than in reproductively inactive ones (Lutton and Callard unpublished data).
In vitro experiments utilizing cultured epigonal cells from female Leucoraja erinacea further suggested potential effects of the ovaries on the epigonal organ. Physiologically relevant concentrations of E2, P4 and T all reduce incorporation of [3H]-thymidine over 24 h. In addition, agarose gel DNA-fragmentation analysis and activated caspase-3 Ab-labeling demonstrated that P4 and T, but not E2, induce apoptosis of epigonal cells. These data suggest that ovarian activation may increase cellular turnover by enhancing both proliferative and apoptotic activity of epigonal cells (Lutton and Callard unpublished data). This finding supports the idea that lymphomyeloid tissues are dynamic structures with the capacity to change in cellular composition due to influence from endocrine factors (Yoffey and Courtice 1970) even though gross tissue mass does not change.
A relationship between the reproductive and immune systems has also been noted in invertebrates. The roles of ecdysone and juvenile hormone in the regulation of gametogenesis and ovarian development of invertebrates have been investigated for more than 3 decades (Spielman and others 1971; Garcia and others 1979; Terashima and others 2005). In insects, hematopoiesis originates from the head mesoderm and the larval lymph gland and is thought to occur only during development (Evans and others 2003). It seems clear, however, that at least subsets of the adult hemocyte population originate from the embryonic head mesoderm and larval lymph gland (Holz and others 2003). The hemolymph of adults consists of only a few terminally differentiated cell types whose functions resemble those of the vertebrate myeloid lineage (Lanot and others 2001). 20-hydroxyecdysone (20E) increases DNA synthesis in the corpus allatum, the gland responsible for juvenile hormone production (Chiang and others 1997). Further, 20E enhances proliferation of cells from the hematopoietic organ of insects (Nakahara and others 2003). Therefore, while the sex hormones of vertebrates seem to have an overall inhibitory effect on leukocyte proliferation (Beagley and Gockel 2003; Morale and others 2003), at least one of the hormones responsible for gonadal regulation and development in insects has a stimulatory effect on the proliferation of blood cells.
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This review has attempted to cover the literature pertaining to reproductive–immune interactions in all animal taxa. We suggest that more emphasis on the comparative approach in this field, with particular focus on the elasmobranch model, will provide important insights into interactions between the endocrine (reproductive) and immune systems. One may assert that comparative studies of reproductive–immune interactions may enhance an understanding of such relationships in other vertebrate groups, including the human, in which there are well-established examples, both of immune influence on reproductive processes and of hormonal effects on the immune system. As illustrated in this review, sex hormones are major factors regulating immune responses (Roberts and others 2001
; Tanriverdi and others 2003) and immune cells and the factors they produce (for example, chemokines and cytokines) are frequently implicated in gonadal activities and in regulation of the female reproductive tract (for recent reviews see Bukulmez and Arici 2000; Townson and Liptak 2003; Itoh and others 2005; Wira and others 2005). Ovulation and implantation are examples of inflammatory processes, and pregnancy is a period in which the immune system must be tightly regulated to avoid rejection of the fetal allograft. Of importance to this effect, as noted by Trowsdale and Betz (2006), "despite the systemic effects that pregnancy has on the maternal immune system, it seems that the mother's immunosuppression is restricted to responses directed against the fetus and autoimmune targets. After all, both mother and developing fetus depend on the maternal immune system for the protection against pathogens." These processes require either enhanced or suppressed activity of various immune cells and their factors, as well as proper regulation of sex hormones (Davis and Rueda 2002; Abrahams and others 2003; Erlebacher and others 2004).
We hope that such comparative studies will illuminate undefined mechanisms underscoring interactions of immune cells/factors and hormones between tissues, particularly those implicated in connective tissue disorders and autoimmunity. Dysregulation of normal physiological interactions between the reproductive and immune systems can lead to disorders and diseases effecting one system or the other. It has been shown in nonmammalian vertebrates that testosterone may play a role in compromising the immune defense of individuals, increasing their susceptibility to infectious disease (Gustafsson and others 1994), and that enhanced levels may inhibit immune responses (Moore ad Marler 1987; DeNardo and Sinervo 1994). Other investigators have provided evidence that the immune system is suppressed by reproductive effort in that antibody response to immune challenge and parasite resistance are reduced (Richner and others 1995; Deerenderg and others 1997; Nordling and others 1998). Thus, an evolutionary trade-off between reproductive fitness and immune defense has been hypothesized because testosterone is thought to have an overall immunosuppressive effect (Folstad and Karter 1992).
However, while androgens consistently inhibit immune function, as demonstrated in this review, the effects of female reproductive hormones in each vertebrate group are variable depending upon a number of important factors. These variables include, but are not limited to, seasonality, hormone concentration, tissue type and model under investigation. Numerous mammalian studies have demonstrated increases in immune activity caused by female reproductive hormones (reviewed in Wira and others 2004 and Kayisli and others 2004), and these may shed some light on the possible mechanisms of steroidal effects prevalent in autoimmunity (reviewed in Ahmed and others 1985; Grossman and others 1991; Verthelyi 2001). For instance, T helper 1 (TH1) cells secrete proinflammatory cytokines, such as TNF- and IL-1ß, and promote cell-mediated immune responses. T helper 2 (TH2) cells secrete cytokines that promote antibody production. While in multiple sclerosis (MS) and rheumatoid arthritis (RA) TH1 responses prevail, in systemic lupus erythematosus (SLE) TH2 responses are characteristic. Progesterone promotes the development of a TH2 response, which antagonizes the emergence of TH1 cells. This may explain why in MS and RA symptoms improve during pregnancy, while in SLE they do not (Whitacre and others 2005).
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From the symposium "Ecological Immunology: Recent Advances and Applications for Conservation and Public Health" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 4–8, 2006, at Orlando, Florida.
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