Special Feature for the Olympics: Effects of Excercise on the Immune System

Immunology and Cell Biology (2000) 78, 562–570; doi:10.1111/j.1440-1711.2000.t01-10-.x

Neuropeptides and their interaction with exercise and immune function

Ingibjörg H Jonsdottir1

1Institute of Physiology and Pharmacology, Department of Physiology, Göteborg University, Göteborg and Centre for Sport Science, Halmstad University, Halmstad, Sweden

Correspondence: Ingibjörg Jonsdottir, Institute of Physiology and Pharmacology, Department of Physiology, Box 432, 405 30 Göteborg, Sweden. Email: inga.jons@fysiologi.gu.se

Received 19 June 2000; Accepted 19 June 2000.

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Abstract

It is known today that the immune system is influenced by various types of psychological and physiological stressors, including physical activity. It is well known that physical activity can influence neuropeptide levels both in the central nervous system as well as in peripheral blood. The reported changes of immune function in response to exercise have been suggested to be partly regulated by the activation of different neuropeptides and the identification of receptors for neuropeptides and steroid hormones on cells of the immune system has created a new dimension in this endocrine–immune interaction. It has also been shown that immune cells are capable of producing neuropeptides, creating a bidirectional link between the nervous and immune systems. The most common neuropeptides mentioned in this context are the endogenous opioids. The activation of endogenous opioid peptides in response to physical exercise is well known in the literature, as well as the immunomodulation mediated by opioid peptides. The role of endogenous opioids in the exercise-induced modulation of immune function is less clear. The present paper will also discuss the role of other neuroendocrine factors, such as substance P, neuropeptide Y and vasoactive intestinal peptide, and pituitary hormones, including growth hormone, prolactin and adrenocorticotrophin, in exercise and their possible effects on immune function.

Keywords:

adrenocorticotrophin, endogenous opioid, exercise, growth hormone, hypothalmic–pituitary–adrenal axis, neuropeptide Y, serotonin, substance P, vasoactive intestinal peptide

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Introduction

Evidence from the fields of psychology, neurobiology, physiology and immunology has demonstrated that the immune, nervous and endocrine systems are functionally interconnected. This communication is believed to be very important and has been suggested to play a vital role in many different diseases, such as cancer and autoimmunity.1, 2, 3, 4

In the 1930s, Seley wrote about 'the syndrome that was produced by diverse nocuous stimuli' and showed that diverse factors, including excessive muscular exercise, could lead to a number of hypothalmic-pituitary-adrenocortical responses influencing immune function.5 We know today that the immune system is influenced by various types of psychological and physiological stressors, including physical activity.6, 7, 8 It is also well known that physical activity can influence neuropeptide levels both in the central nervous system and in peripheral blood.9, 10, 11 The reported changes of immune function in response to exercise has been suggested to be partly regulated by the activation of different neuropeptides. The most common neuropeptides mentioned in this context are the endogenous opioids activated by long-term aerobic exercise. Other neuropeptides, such as serotonin, substance P and vasoactive intestinal peptide (VIP), could also be of interest, as well as several neuroendocrine hormones including growth hormone (GH), prolactin and adrenocorticotrophin (ACTH).

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Immune system and nervous system: A bidirectional connection

A bidirectional communication between the nervous system and the immune system has been described by many authors.12, 13 The two pathways by which the central nervous system (CNS) may communicate with the periphery are neuroendocrine outflow, via the hypothalmic-pituitary-target-organ axis, and the autonomic nervous system (ANS), through direct nerve fibre connections with cells or the organs of the immune system. It is now evident that both the neuroendocrine system and the ANS provide links from the CNS to the immune system.13 Evidence for an adrenergic and peptidergic innervation of specific regions of primary and secondary lymphoid organs has established the links necessary for neural modulation of immunity. No evidence is available of any parasympathetic cholinergic innervation of the organs of the immune system.13, 14 Postganglionic noradrenergic sympathetic nerve fibres are widely distributed in organs of the immune system and the functional role of the ANS in immunoregulation has been described by many authors.15, 16, 17 The expression of beta-adrenoceptors on a variety of immune cells, including lymphocytes and macrophages, provides the molecular basis for these cells to be targets for catecholamine signalling. Large numbers of beta-adrenoceptors, mainly of the beta2 subtype, are found on NK cells18 and in vitro studies have shown that catecholamines selectively affect adhesion of NK cells to endothelial cells.19 We have demonstrated that catecholamines are involved in the exercise-induced augmentation of in vivo cytotoxicity in rats.20 The catecholamine effects, mediated by beta-adrenergic receptors, could include the recruitment of NK cells from the spleen or other sites to the circulating pool due to the reduced adhesion of NK cells to endothelial cells. Catecholamines could also directly augment the cytolytic activity of the cells.

Another monoamine, serotonin (5-hydroxytryptamine), is also of interest when discussing the interaction between CNS and immune function. Serotonin is the most extensively studied neurotransmitter of the CNS and has been associated with the mood change and antidepressive effects seen after physical exercise. It is well known that central serotonergic systems are the targets for antidepressant/anxiolytic compounds.10 Data available from both animal and human studies have shown that acute physical activity can increase both serotonin synthesis and metabolism. Many studies have also shown that supply of the first precursor of serotonin, the branched-chain amino acid tryptophan, is increased during physical exercise and this has been suggested to be one of many factors causing fatigue during long-term exercise.10, 21, 22 Research available today confirms that serotonin can modulate the immune system in different ways, influencing many cell types, such as T cells, NK cells and macrophages.23 In vitro studies have shown that serotonin can augment NK cell cytotoxicity24 and regulated cytokine production from NK cells.25, 26 Serotonin has been shown to be important for T-cell activation as well as macrophage accessory function.27 Serotonin has also been shown to be important for other macrophage functions, such as cytokine production.26, 28 The association between exercise, serotonin and immune function shown in the literature is mainly an indirect relationship. Thus, increased transport of tryptophan into the brain increases the level of serotonin, but does also affect the synthesis of glutamine, which has been suggested to play a role in immune function during long-term exercise.21

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Neuroendocrine hormones

Neuroendocrine hormones derived mainly from the hypothalamus and the anterior pituitary have been suggested to be involved in immunomodulation. Identification of receptors for neuropeptides and steroid hormones on cells of the immune system has created a new dimension to endocrine– immune interaction.29, 30 Adrenocorticotrophin, GH and prolactin levels are increased in response to exercise31 and it has been demonstrated that lymphoid cells contain receptors for these hormones.32 It has been demonstrated that these hormones are able to modulate immune cells in different ways and thus could be involved in the exercise-induced augmentation of immune function.32, 33, 34 Adrenocorticotrophin has been shown to be able to influence wide range of immune cells, such as NK cells, macrophages, T cells and B cells.35, 36 It has also been shown that GH exerts important effects on the immune system, including stimulation of the spleen and thymus, modulation on the cytolytic activity of T cells and NK cells and stimulation of macrophage function.35, 36 Prolactin is another pituitary-derived hormone that has been suggested to play an important role in immune modulation, including T cell and macrophage function.35 A role for prolactin together with corticosterone in mediating increased chemotaxis of macrophages induced by exercise has been suggested.37

It is apparent that a multifactorial interaction between the cells of the immune system and the neuroendocrine hormones exists. Conversely, there is now evidence of production of neuroendocrine hormones by the cells of the immune system, suggesting that the signal from the immune system can activate the CNS and control the function of the neuroendocrine system.13, 35 The first evidence that the cells of the immune system could produce a peptide was the finding by Smith and Blalock showing that human lymphocytes could produce ACTH in a connection to virus infection.38 Since then, numerous peptides have been shown to be produced by different immune cells, including thyroid-stimulating hormone (TSH), GH, opioids, prolactin, follicle-stimulating hormone and luteinizing hormone.13, 35

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Endogenous opioid system

Opiates have been used by man for thousands of years and their analgesic, euphoric and addictive effects have been the subject of intense research throughout this century. The opioid system is silent under normal physiological conditions, unless challenged by a variety of stressors. During such circumstances, the opioid peptides are considered to play an important role as neurotransmitters and neuromodulators. Their role in analgesia and in behavioural and affective disorders has been widely studied. Endogenous opioid peptides seem also to be involved in other biological functions, such as cardiovascular regulation, respiration, gastrointestinal function, renal function, temperature regulation, metabolism, hormonal secretion, reproduction and immune function.39

Endogenous opioid peptides

There are three major prohormones, giving rise to three 'families' of opioid peptides: the endorphin, enkephalin and dynorphin families.

Pro-opiomelanocortin This precursor gives rise to one beta-endorphin molecule and is unique among the three opioid peptide precursors in that it contains only one copy of the opioid-defining amino-acid sequence. Pro-opiomelanocortin (POMC) is also unique in containing other biologically active peptide hormones that are unrelated to opioid peptides. These other hormones, ACTH and several melanocyte-stimulating hormones (MSH) are part of the stress hormonal system. The location of beta-endorphin-containing nerve cells within the CNS is limited to the hypothalamus, with extensive projections throughout the brain, and to the nucleus tractus solitarius in the brainstem. The proximity of beta-endorphin- containing neurons to brain nuclei involved in autonomic control theoretically gives beta-endorphin the fascinating possibility of influencing a wide range of autonomic functions. Another beta-endorphin system is found in the anterior pituitary, where it is coreleased with ACTH into the systemic circulation.40 beta-Endorphin has also been found in peripheral tissues, mainly in the gastrointestinal tract.41 It is generally agreed today that immune cells can produced POMC-derived peptides and it is suggested that these immune cell-derived peptides seem to play an important physiological role, such as in pain control.42

Pro-enkephalin This precursor contains the sequence for at least seven opioid peptides of the enkephalin family, four copies of met-enkephalin, one of leu-enkephalin and two extended sequences of met-enkephalin.43 Enkephalins are extensively distributed throughout the CNS and they are present at all levels of the neuraxis, from the cortex to the spinal cord.44 Peripherally, enkephalins are found within several organ systems, such as the adrenal medulla, reproductive tissues,43 sympathetic ganglia45 and the gastrointestinal tract.41 It has also been shown that enkephalins can be produced by immune cells and that these immune-derived enkephalins play an important regulatory role in immune responses.46

Prodynorphin This precursor yields peptides of the dynorphin family, mainly dynorphin A and B. In addition, dynorphins are widely distributed throughout the CNS, including the amygdala, several hypothalmic nuclei, midbrain periaqueductal grey, the brainstem nucleus tractus solitarius and the dorsal horn of the spinal cord.47 Dynorphins have also been found peripherally, in the heart and in the gastrointestinal tract.41

Opioid receptors

The opioid peptides exert their actions by binding to membrane-bound receptors. Several types of opioid receptors have been described, but the three most studied and best established receptor types are mu, delta and kappa and they have all been found on the surface of different immune cells.42 The presence of multiple mu-receptor types, including a high- affinity site termed mu1 and a low-affinity mu2 site, is now acknowledged. The delta and kappa receptors have also been divided into subtypes delta1 and delta2 and k1 and k2, respectively.48 The opioid receptors are present at multiple brain nuclei and they are also present in the spinal cord and in peripheral organs.40 beta-Endorphin is considered to have high affinity to mu and delta receptors. The enkephalins preferentially bind to delta receptors, whereas dynorphin has highest affinity to the kappa receptor.49

Exercise and endogenous opioid systems

The endogenous opioids can be activated by different stressors and their influence on a wide range of biological functions has been suggested. Plasma levels of met-enkephalin are elevated both during and after exercise.50, 51, 52 A similar rise in plasma levels of dynorphin has also been demonstrated in a response to exercise.52 The majority of studies dealing with exercise and plasma levels of endogenous opioids are studies on beta-endorphin. There are numerous studies showing that plasma levels of beta-endorphin are increased by physical activity.53 In most of these studies, peak values of beta-endorphin are reached within 15 min after exercise; 1 h after termination of exercise the beta-endorphin levels have returned to pre-exercise values. Concomitant secretion of beta-endorphin and ACTH has been reported after exercise.54, 55 Because beta-endorphin and ACTH are secreted in equimolar concentrations from the adenohypophysis, most beta-endorphin measured in peripheral blood reflects corelease with ACTH rather than activation of CNS beta-endorphin pathways.56 It has been shown that stress-specific increases in plasma beta-endorphin levels are not always associated with increased beta-endorphin levels in the brain.57 Furthermore, responses to exercise such as changes in mood, anxiety and pain perception do not correlate with changes in levels of circulating opioids.55, 58 In addition, the blood–brain barrier is fairly impermeable to circulating peptides,59, 60 emphasizing the need for caution when attempting to assess central opioid system activity from peripheral plasma opioid levels. A commonly used experimental strategy to study the opioid system and physiological adjustments to exercise is the use of opioid receptor antagonists. The most widely used opioid antagonist is naloxone, which has high affinity to mu receptors, although higher doses also block delta and kappa opioid receptors.49 Some physiological adaptations to exercise can be reversed by naloxone, while other functions are not influenced. Again, a confounding factor in these studies is that some opioid receptors are poorly antagonized by naloxone. Furthermore, it has been hypothesized that higher doses of naloxone are required to antagonize the effects of endogenously released opioid peptides than the effects of exogenously administered opioid analogues.

Rather few studies have addressed the question of whether the CNS opioid system is activated by exercise. Taken together, these studies indicate an activation of CNS opioid systems after prolonged exercise but not after brief strenuous exercise.61, 62 Hoffmann et al. have found significantly increased CSF levels of immunoreactive beta-endorphin after 5 weeks of voluntary exercise in spontaneously hypertensive rats (SHR) compared with sedentary controls.63 In the same model, it has been shown that prolonged voluntary exercise affects CNS dynorphinergic and enkephalinergic mechanisms.64 The activation of the CNS opioid system during exercise appears to be mediated by the stimulation of A-delta or group III afferents, arising from the contracting muscles.65

Opioids and immune function

It is generally accepted that opioid peptides, in particular beta-endorphin, can influence a variety of immune functions.1, 66, 67, 68 Most studies have indicated that beta-endorphin enhances NK cell activity and interferon production in vitro69, 70, 71 and some authors have shown that these effects can be completely or partly reversed by naloxone, indicating that an opioid receptor is involved.72, 73, 74 beta-Endorphin has also been shown to modulate macrophage function, as well as other immune components such as T-cell and B-cell functions.1, 30, 36, 67, 68 It has been speculated that two separate receptors might exist (naloxone insensitive and naloxone sensitive) in beta-endorphin regulation on immune cells, in this case on macrophage function.36

The effects of met-enkephalin on immune function seem to be less clear. Thus, some authors have demonstrated that met-enkephalin can augment NK cell cytotoxicity75 and macrophage function,76, 77 while others have failed to show any effects of met-enkephalin.78 Marotti and coworkers have demonstrated different effects on macrophage function and NK cell activity following i.p. injection of met-enkephalin.79 Recently, the immunomodulatory role of met-enkephalin on murine splenic T-cell and B-cell function has been demonstrated, interestingly showing some gender-related differences. Thus, met-enkephalin enhances the proliferation of T cells only in males and not in females. B-cell proliferation is enhanced in males, but decreased in females.80 This study clearly shows a need for caution when making conclusions about enkephalins and their effects on immune function. The effects of dynorphin on immune function have not been as extensively studied as the effects on beta-endorphin and met-enkephalin. Dynorphin has been shown to influence immune functions, such as enhancement of macrophage function,81, 82 lymphocyte proliferation and IL-2 production from rat splenocytes.83 In the latter study, the authors suggested that the effects of dynorphin are mediated via the kappa opioid receptor.

Several authors have discussed the possible role of circulating endogenous opioids in the immunomodulation seen after physical exercise. Thus, some studies have suggested that beta-endorphin is part of the regulatory pathway of the enhancement of NK cell activity seen after exercise,84 while others have failed to show any effects of beta-endorphin on exercise-induced modulation of NK cells.85 However, circulating endogenous opioids have been shown to be involved in the suppression of T-cell activity seen after exercise (swimming) in rats.86, 87 It has also recently been shown that plasma levels of pro-enkephalin peptide F are increased in response to exercise in humans and are correlated with the increased number of specific antibody producing B cells, and the authors suggest that peptide F may play a modulatory role on immune cell function during exercise.88

Accumulating evidence supports the hypothesis that the central endogenous opioid system is part of the regulatory pathway between the central nervous system and the immune system. Thus, Jankovic and Radulovic have demonstrated that the central enkephalin opioid system can modulate both humoral and cell-mediated immune reactions and that the effects are mediated through CNS opioid receptors.89 Several authors have shown that acute central opioid receptor activation induces suppression of NK cell cytotoxicity.90, 91, 92, 93 It has been speculated that several physiological mechanisms could account for these effects on NK cell activity, including the involvement of the hypothalmic–pituitary–adrenal axis or alternatively changes in sympathetic nervous outflow. Furthermore, central opioid-induced suppression of in vivo NK cell activity has been shown to be mediated by central mu opioid receptors.94 Acute and chronic administration of beta-endorphin into the CNS, but not dynorphin or enkephalin, has been shown to increase NK cell activity,95, 96 while others have shown that acute administration of enkephalins does affect both NK cell and macrophage function.97 Most studies available on the central opioid system and NK cell function dealing with acute activation of the CNS opioid system have shown immunosuppression, while chronic activation seems to enhance NK cell activity. It is possible that suppression or enhancement of natural cytotoxicity might be induced via different opioid receptors. It is also possible that the same receptor type could mediate different effects of opioids on the immune system in a dose-dependent way.

We have recently shown that central beta-opioid receptor mediates the enhancement of natural immunity seen after chronic voluntary exercise. To my knowledge, this is the first time that central opioid receptors have been shown to be involved in the exercise-induced modulation of immune function.98 Figure 1 shows several hypothetical pathways involved in the exercise-induced modulation of enhanced natural immunity.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

It has been suggested that central delta opioid receptors are involved in the exercise-induced enhancement of natural immunity. The figure shows several hypothetical peripheral pathways behind this modulation. The two pathways by which the CNS may communicate with the periphery include neuroendocrine outflow, via the hypothalmic–pituitary–target organ axis, and the automatic nervous system, through direct nerve fibre connections with cells or the organs of the immune system.

Full figure and legend (50K)

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Vasoactive intestinal peptide

Vasoactive intestinal peptide was first discovered as a gastrointestinal hormone, but is today also known as a neuropeptide. Vasoactive intestinal peptide is widely distributed in the CNS, as well as in the intrinsic neurons of the gastrointestinal tract. Vasoactive intestinal peptide and acetylcholine coexist in the parasympathetic nerve terminals.99 Vasoactive intestinal peptide has been shown to be elevated in plasma after aerobic exercise.100, 101, 102, 103 Thus, VIP is increased after short-term exercise lasting for more than 20 min101 as well as after 5 days of exercise.103 Less is known about the changes in VIP levels in the CNS. Thus, physical exercise in rats did not change the VIP immunoreactivity in the hippocampus at the same time as increased activities of neuropeptide Y, neurokinin A and substance P were demonstrated.104 Vasoactive intestinal peptide has been shown to influence the immune system in different ways, but the modulatory role of VIP in the immune system is not fully understood.105, 106 The anatomical basis of the interaction between VIP and immune function comes from the fact that VIP-containing nerves have been found on lymphoid organs. Furthermore, both high- and low-affinity receptors for VIP are found on immune cells and the interaction of VIP with these receptors can alter a variety of immune responses, mostly demonstrated in vitro. Thus, VIP has been shown to decrease lymphocyte migration, especially in gut-associated lymphoid tissue. It has also been shown to inhibit mitogen-induced proliferation responses, inhibit IL-2 production from T cells, influence antibody production in different ways and either inhibit or stimulate NK cell activity, depending on factors such as the source of NK cells and their activational state, as well as the different methodologies used in studies. It is also one of many neuropeptides shown to be produced by immune cells, first in mast cells, but later in several different types of leucocytes.106 Few studies have made attempts to correlate the increased levels of VIP with changes in immune function during and after physical exercise. Wiik and coworkers have shown in humans that strenuous exercise results in increased plasma levels of VIP, combined with upregulation of high-affinity VIP receptors on mononuclear leucocytes, indicating a possible role of increased levels of VIP during exercise and changes in immune function.107

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Substance P

Substance P is another neuropeptide involved in the bidirectional communication between the nervous and immune systems. Substance P is present in specific neurons of the brain, primary sensory neurons and plexus neurones of the gastrointestinal tract. Substance P is a member of a group of neuropeptides called tachykinins.99 Substance P has been shown to be affected by exercise in different ways. Increased immunoreactivity of substance P has been found in the hippocampus after 3 weeks of exercise in rats104 and in the spinal cord after static exercise in cats.108 Circulating levels of substance P have been found to be elevated in humans only after, but not during, exercise.109 Substance P has been shown to modulate the immune system in different ways, such as by increased T-cell proliferation, increased immunglobulin synthesis by B cells and increased cytokine production by monocytes.110 Substance P has also been shown to increase both lymphokine-activated killer cell cytotoxicity111 and NK cell cytotoxicity,112 both in in vitro studies. Substance P seems to play an important regulatory role in macrophage function, thus it has been shown that the peptide can augment production by murine and human macrophages of cytokines such as IL-12, IL-10 and TNF.113, 114 Substance P can also augment nitric oxide production in murine macrophages.115 Receptors for substance P have been described on human and murine lymphocytes and substance P is also one of many neuropeptides shown to be produced by immune cells, mainly from cells involved in inflammation, such as eosinophils and macrophages.68, 105, 116 To my knowledge, no study has attempted to combine the exercise effects on substance P and the effects on immune function.

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Neuropeptide Y and other neuropeptides

Neuropeptide Y (NPY) is a neurotransmitter, costored with noradrenalin in perivascular sympathetic nerve endings and mediator of the sympatho-adrenomedullary system. Plasma levels of NPY are increased during high-intensity sympathetic nerve stimulation, by a variety of different stressors and during physical activity.104, 117, 118 Neuropeptide Y is present in primary and secondary nerve fibres of the spleen and NPY mRNA expression has been demonstrated in human lymphocytes and monocytes as well as in matured macrophages.119 Neuropeptide Y has been shown to be able to modulate a variety of immune functions. Based on the fact that NPY interacts with both the autonomic nervous system and the HPA axis, it has been speculated that the peptide could be important in the modulation of immune function during exercise.120 von Horsten and coworkers have studied the effects of centrally administered NPY on innate immune function. Thus, it has been shown that NPY administration initially causes immunosuppression, followed by stimulation of granulocytes and NK cells.121 Furthermore, Nair and coworkers have demonstrated NPY-induced suppression of NK cells in vitro.122 Neuropeptide Y has been shown to inhibit human macrophage function, but stimulates murine macrophages.123, 124 It has also been shown to be able to modulate T-cell function as well as calcitonin gene-related peptide (CGRP)125 and Kawamura and coworkers have shown that NPY is able to enhance IL-4 production and inhibits IFN-gamma production from T cells. In the same study, it has been shown that CGRP is able to inhibit IFN-gamma production from T cells, but has no effects on IL-4 production.126 Other neuropeptides, such as neurotensin, MSH and bombesin, are known to affect immune function127, 128, 129 and have been shown to be elevated during exercise.130, 131 Hence, these peptides may also play a role in exercise-induced immunomodulation.

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Concluding remarks

The neuropeptides mentioned in the present paper, together with neuroendocrine hormones from the pituitary and some monoamines, such as serotonin, are all influenced by physical exercise and they have all been shown to affect immune function. Despite this knowledge, few attempts have been made to combine these links and study the possible role of these neurotransmitters in exercise-induced modulation of immune function. Some studies have shown that both peripheral and central opioid systems seem to play a role in the modulation of immune function in response to exercise. Both VIP and NPY have also been suggested to be involved in the exercise-induced modulation of immune function. More studies are necessary to confirm this. It is likely that several other neuropeptides play a role in the effects of exercise on immune function. Further research is needed to better explain the relationship between neuropeptides and exercise-induced modulation of immune function.

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