The effect of catecholamines of secretary immunoglobulin A

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The effect of catecholamines of secretary immunoglobulin A (sIgA)

A wealth of evidence supports interactive behaviour between the brain and the immune system. Extensive research yields support for the cross-communication between these two major adaptive systems of the body, collectively termed the "supersystems" Tada (1997). The autonomic nervous system (ANS) is one of two pathways which link and facilitates the modulation of these two systems upon each other. An important ANS component is the sympathetic nervous system (SNS), which releases chemical mediators, called catecholamines (CAs). These regulate the brain and immune system,are synthesized in the body from the amino acid tyrosine, and are classified as adrenal hormones. CAs are released into the blood circulation in response to stimulation of the SNS, and are known to modulate a diverse range of immune parameters. Immune cells have the ability to produce CAs and influence the CNS; and specific cytokines stimulates the SNS, interleukin (IL)-1, and IL-6, reflecting a positive feedback loop between the immune and neural functions. This highlights the bidirectional interconnection between the nervous and immune systems.

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Predominant CAs include norepinephrine (NE), and epinephrine (EPI). Communication between the SNS and immune system relies on the stimulated release of CAs and the corresponding binding to effector target cells. NE is released in response to a stressor, physical or psychological, from the SNS, whilst the adrenal medulla predominantly releases EPI. Catecholamines are transmitted via noradrenergic postganglionic sympathetic neurons, which innervate both the primary (generative) and secondary (peripheral) lymphoid organs (Felten and Felten. 1991). Neighbouring immune cells in the lymphoid organs are therefore exposed to the released CAs. Specific immune cells express receptors, called a and b-adrenoreceptors with various subtypes, in which catecholamines bind to. This binding leads to receptor activation, and a cascade of reactions which induces a sympathetic response. These responses are responsible for the influences on immunocompetent cells and effectthe functioning of the cells and immune system.

Responses vary according to the target cell, the concentration of CAs released, and the density of adrenergic receptors expressed on immune cells. B-lymphocytes are a class of immune cells responsible for humoral immunity,responsible for producing antibodies to kill pathogenic cells through a variety of process; opsonization, neutralization or activation of the complement system. In addition, they are antigen presenting cells (APCs) and contribute to the adaptive immune system. B-cells express b2-adrenergic receptors, of a moderate density, but lower than most other immune cells, including T-cells and natural killer (NK) cells.

Felten et al., 1985 evidenced innervations of secondary lymphoid tissues, illustrating noradrenergic (NA) nerve fibers were present among B cells neighbouring in the marginal zone and marginal sinus of the spleen. Innervations of the follicles are limited, yet the NA fibers are located towards the edges, (Madden, Sanders, Felten). Therefore, B-cells may encounter NE released from the NA fibers along the edges of the follicles and in the marginal zone of the spleen. All B-cells contained within primary and secondary lymphoid tissues are exposed to these sympathetic nerve innervations (Felten, S. Y., and J. A. Olschowka. 1987.), and subjected to released CAs.

NE release and the binding to its adrenergic receptor on B-cells enhance antibody production, Sanders, 19995 and Sanders et al., 1997. Activation of the b-2 Adrenoreceptors results in a series of protein regulated reactions and a subsequent increase of intracellular cAMP. Elencok et al evidence an increased expression of B7 costimulatory molecules, on B cells as a subsequent response to the elevation of intracellular cAMP . B7 molecules are costimulatory molecules and provide essential secondary signals to allow T-cell activation and proliferation. When the response is targeted to a T-dependent antigen, B cells require functional support from T-lymphocytes, specifically T-Helper cells (Th). An increased expression of B7 therefore facilitates the activation of Th-cells, and provides enhanced support to the B cells. Subsequently, the effector functioning of the B-cells improves, since support from Th-cells available.

Pollok et al., 1991 has suggested that a threshold level of intracellular cAMP must be reached before B cells can be activated. This suggests an increase of cAMP facilitates the achievement of the threshold level of cAMP, and thus activates B cells. Taken together, the elevated levels of cAMP, mediated by CAs release and stimulation of b-adrenergic receptor, appear to increase activation of T- and B-cells and ultimately increase the B-cell effector function of antibody production, as evidenced by Sanders, 1995. The influence of elevated intracellular cAMP has been displayed in figure X. B cells have fewer b-adrenergic receptors relative to T cells, and generate very little cAMP in response to CAs. Therefore CAs do not effect the b-cell migration (Elenkov et al).

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Other evidence proposes that CAs influence B-cells indirectly through their effects on T-cell cytokine secretion. T and B lymphocytes interact when T-dependent antigens are encountered. Th cells (CD4+), namely T-helper 2 (Th2) subset, are required to facilitate and support B cell processes. The cytokines released from T-cells influence the differentiation of Th cells into their respective subsets. The Th subsets have an indirect impact on the activation, functioning and assistance to B cells. Therefore CAs may play an important modulatory role through their effect on the preferred response of T cells to differentiate into TH1 or Th2; thus influence the Th1/Th2 balance. This effectively influences humoral immunity indirectly, as displayed in figure 3. Figure 3 highlights that production of CAs down-regulates Th1 activities and up-regulates Th2 and humoral responses at the level of APCs and Th1 cells.

NE suppresses the secretion of IL-12 which favours the differentiation of Th-cells into Th2 cells Elenkov et al., 1996. Therefore, Th2 cells cytokines and associated effector functions are indirectly up-regulated through the preferred differentiation into Th2 cells. In particular IL-10 promotes the differentiation of B cells to antibody secreting cells and boosts humoral immunity Elenkov et al., . IL-4 specifically increases the production of immunoglobulin IgE and IgG1 Sanders et al., 1997; Borger et al., 1998. Congruent to these effects, b-2 adrenergic receptor agonists, such as NE, down-regulate the cytokines produced by IF - y, which suppress cellular mediated immunity and macrophage activation Sanders et al., 1997; Borger et al., 1998.

Importantly, because expression of b2-ARs is limited to Th1 cells only, (Saanders et a., 1997), CAs don't directly influence cytokine produced by the Th2 cells (Elenkov et al). Instead, CAs down-regulate IL-12 and IFN-Y eradicating the inhibitory restraints on Th2 cells which are predominantly applied by these two cytokines (Sanders et al, 1997; Borger et al., 1998).Taken together, cellular-mediated immunity and corresponding process are suppressed whilst humoral-mediated immunity is boosted. Overall, CAs, via direct effect on T-cells, potentiate cytokines produced by Th2 cells, specifically IL-4, thereby promote humoral immunity and increase the differentiation of B cells into antibody secreting cells, increasing antibodies produced. This is summarized in table 1.

The increase of B cells in the blood and Ab production, associated with CAs release and adrenergic receptor stimulation, is also observed during exercise and stress. Studies ofexercise-induced immune effects show that these influences are SNS-mediated (reference) Following exercise, EPI and NE are released from the adrenal medulla and the sympathetic nerve terminals respectively. These bind to the associated receptors, such as b-2 AD receptors on B-lymphocytes and induce the diverse responses as previously discussed. These responses, such as enhanced interaction between T/B cells, increased cAMP, and the associated effects of suppressed Th1 response whilst increased Th2 response, contribute to the exercise-induced immune effects. Furthermore, psychological stress is also evidence to correlate with increased release of catecholamines. Stress is associated with stimulation ofHPA, and induces release of cortisol, the stress hormone.

The impact of physical and psychological stress on the production of the immunoglobulin sIgA has been extensively researched. There are five main classes of immungoglobulins which are secreted by B cells and mediate humoral immunity. Salivary secretory immunoglobulin A (sIgA), is a marker of mucosal immunity, and prevents pathogenic agents attaching to host cells and replicating Tomasi TB, (Plaut AG. 1985,)serving an important role in host defence (Lamm, 1998). The mucosal immune system is one of the proximal barriers to pathogens and pivotal in reducing upper respiratory tract infections (URTI).

Acute exercise and stress is stereotypically associated with an increase of blood lymphocytes; known as lymphocytosis, (Benschop, Schedlowski, Wienecke, Jacobs, & Schmidt). Lymphocytes become mobilized from marginal pools within the microvascuilature of lymphoid and non-lymphoid organs, including the spleen, bone marrow and lungs, (Nielsen, Secher, Kristensen, Christensen, Espersen, & Pedersen. 1997) to the circulation. (Rhind, Shek, Shinkai, & Shephard 1996.)

Mechanical (Foster, Martyn, Rangno, Hogg, & Pardy,1986) and/or neuroendocrine (McCarthy, & Dale, 1988) signals occurring with exercise and stress induce the demargination and redistribution response of immunocompetent cells, resulting in exchange of intravascular lymphocytes. These signals are triggered by SNS activation to release catecholamines, such as NE and EPI, and HPA activation HPA to release cortisol (Benschop, Schedlowski, Wienecke, Jacobs, & Schmidt, 1997).

During exercise, the response to released NE and stimulation of adrenergic receptors include vasoconstriction of arteries in the skin, viserca and blood redistribution to the working muscles and lungs (Perko, Nielsen, Skak, Clemmesen, Schroeder, & Secher 1998).These adaptations increase vascular shear stress and ultimately induce release of marginated cells into the bloodstream from the vascular endothelium wallsFoster, Martyn, Rangno, Hogg, & Pardy 1986). Lymphocytosis is thereby mediated by the SNS, and an effect induced by CAs.

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Furthermore, adrenocepter stimulation corresponds to changes of cellular adhesion, (Benschop, Schedlowski, Wienecke, Jacobs, & Schmidt 1997, affinity and expression of adhesion molecules on both immune cells and endothelial cells (Gabriel, & Kindermann. 1998). Adrenergic receptor stimulation reduces the 'stickiness' of lymphocytes, declining the adhesion between lymphocytes and endothelial walls. Subsequently, lymphocytes are released from the vascular 'marginal pools' and organs, into the peripheral blood (Goebel MU, Mills PJ. 2000). This further facilitates immunosurveillance and migration to tissues which leads to a homing of B cells to the site of infection Gabriel, & Kindermann. 1998).

A significant reduced number of B cells in the circulation, known as lymphopenia 1.hrs follows strenuous exercise. Multiple studies have evidenced B cell lymphopenia following exercise and show that this drop to baseline is congruent/parallel with EPI and NE blood concentration, presenting a transitory phenomenon (Murray, Irwin, Rearden, Zielger, Motulsky and Miasel, 1992).

Research of B-cell proliferation in response to exercise is inconsistent. Field Gougeon and Marliss (1991) argue that B-cell proliferation remains static. This suggests that changes to antibody production cannot be attributed to altered B cell proliferation. Paradoxically, Tvede 1989 discovered that when cultures of BMNC were induced with IL-2, which stimulates proliferation of T cells and hence up-regulates cellular-immunity, the expected suppression of B cell function (humoral immunity) was not observed. This suggested that the reduced function and competence of antibody-secreting cells post intense exercise may be served by monocytes or their cytokines (Tvede, Heilmann, Halkjaer, Kristensen and Pedersen (1989). IL-2 secretion is down-regulated by CAs, thereby reducing T cell proliferation and subsequent T/B interaction, indirectly suppressing humoral immunity. This may explain the suppression of immune response to intense exercise.

In contrast, most recent studies report an immediate increase of B cell proliferation post exercise (Gomez-Merino D, Drogou C, Chennaoui M, Tiollier E, Mathieu J, Guezennec CY (2005). Despite conflicting findings, research proposes that lymphocytosis may be attributed to the combination of demargination of B cells and any potential direct increases in B cell proliferation. Nevertheless, studies evidencing attenuation of lymphocytosis, when cultures were pre-treated with a b-adrenergic antagonist, such as propane, have proven that this can be attributed to the adrenergic system, (Ahlborg B, Ahlborg , 1970).

There is a wealth of evidence that regular physical activity may increase or decrease sIgA secretion rate or concentration and thereby enhance (Akimoto, Kumai , Akama T , Hayashi E, Murakami H , Soma R , Kuno S , Kono) or compromise the immune system respectively (Karacabey, Saygin, Ozmerdivenli, Zorba , Godekmerdan , Bulut ). Exercise training has been associated with increases in IgA values (Fahlman MM , Morgan AL , McNevin N , Boardley DJ , Topp R ), unchanging values (35 Sari-Sarraf V , Reilly T , Doran D , Atkinson G, and reducing values ( Tharp GD , Barnes MW ).

Accordingly, moderate physical activity either stimulates or has no effect on Ig, whereas intense exercise corresponds to reduced Ig levels (Gleeson M, Pyne DB, Callister R, 2003). Sanders postulate that NE enhances antibody production. Greater B cell proliferation and differentiation increases the concentration of functional effector cells of a particular immunogenic specificity, and thereby reflects the catecholamine-induced augmented Th2 response. Suppression of cellular mediated immunity and Th1 response, and increased Th2 response promotes differentiation of B cells into antibody secreting cells, explaining the reason for increased antibody production under submaximal exercise conditions. In addition, T lymphocyte proliferation declines during and up to a few hours after exercise (198). This is caused by the decrease of CD4 cells (,145,82), and explainsthe down regulatory response of Th1 response exerted by CAs. Taken together this observation during exercise is reflected in the down-regulated response of Th1 response as mediated by NE.

Intensive exercise has evidenced up to 70% decreases of sIgA, which may remain for several hours (MacKinnon, Chick, Vanas and Tomasi 1987). This reflects the observed lymphopenia and suggests the immune system may be temporarily impaired post-exercise. This also confirms knowledge of CAs. Extreme exercise reduces NE release, and thereby dilutes the SNS response to exercise [Lehmann MP, Baumgartl P, Wiesenack C, Seidel A, Baumann J, Fischer S, Spori U, Genmdrisch G, Kaminski R, Keul J, 1992]. Since antibody production is critically influenced by NE [Sanders and Munson], lower levels of NE are likely to reduce sIgA synthesis. Collectively it appears exercise duration and intensity determines the subsequent effect on the immune system, which explains the mixed findings, reflects and substantiates the effects of CAs.

Ig isotype switching may be an additional explanation for the suppression of IgA found in studies (McKune, Smith, Semple, Wadee, Fickl, Villa, Gómez-Gallego, San Juan, Lucia, A.(2006). The TH2 cytokines, IL-4, IL-6, and IL-13 are responsible for Ig isotype switching (Roitt I, Brostoff J, Male D, 2001). CAs up-regulate Th2 response thus stimulates the production of Th2 cytokines. Therefore isotype switching may resulting a reduction of SIgA and an alternative increase of a different Ig.

Chronic stress matches the effects of intense exercise and is associated with reductions in sIgA (Gallagher et al., 2008; Phillips et al., 2006). In contrast, acute stressors increase sIgA (Ring, Drayson, Walkey, Dale, & Carroll, 2002;). Stress activates the sympathetic-adrenal medullary (SAM) axes, which according to Glaser, (2005) can suppress functions of the immune system. Stimulation of the HPA axis by stress, leads to secretion of stress hormones, including cortisol, which can dysregulate immune function (Rabin, 2005). Fan (2009) evidenced that chronic stressors were associated with suppression of both cellular and humoral measures, whilst acute stressors were associated with increased secretion of IgA antibody, consistent with Segerstrom and Miller. 2004) meta analyses. Along duration and high intensity of the stressor, either physical or psychological, appears to suppress the immune system.

Positives and negatives of these effects

Although there are several possible mechanisms, it has been proposed that URTI may result from a reduction in levels of sIgA (GleesonM, McDonaldAW, CrippsAW, PyneDB, ClancyRL, FrickerPA.1995). Exercise and stress can potentially enhance or compromise immune function in the short term. If immunosuppression results, even if transitory, this provides a window of opportunity for infection if the person is exposed to pathogens. Further studies suggest participation in sports, such as triathalon, may decrease the level of SIgA secretion rate. (Steerenberg PA, Van Asperen IA, Van Nieuw Amerongen A, Biewenga J, Mol D, Medema GJ, 1997).The authors affirm that during the race,athletes are exposed to microorganisms and a decreased SIgA level may increase the risk of infections. This post exercise status may last up to a few days and is known as the open-window phenomena when susceptibility is dramatically increased as the immune system is suppressed. .

This reflects current findings which indicate that elite athletes are susceptible to URTI, either immediately before or more importantly during major competitions (Heath GW, Ford ES, Craven E, Macera CA, Jackson KL, Pate RR. 1991.

While some changes are transitory and related to the acute effect of intense exercise, the changes in leukocyte numbers [Order U, Dufaux B, Uhlenbruck G, Liesen H. 1990] and cytokine levels [Sprenger H, Jacobs C, Nain M, Gressner AM, Prinz H, Wesemann W, Gemsa D. 1992)in peripheral blood have been shown to persist for several days

The concentration and secretion rate of SIgA has been shown to correlate closely with URTI (Liew FY, Russell SM, Appleyard G, Brand CM, Beale J. 1984). Low resting levels of SIgA correlate with an increased risk of URTI incidence (14). It has been suggested that susceptibility to URTI is due to impaired immune function (Keast D, Cameron K, Morton AR 1988; Nieman DC, Nehlsen-Cannarella SL. 1991). Studies support that post strenuous or endurance exercise, there is an increased incidence of upper respiratory tract symptoms (URTS) [28]. Reduced levels of SIgA are likely to impair the body's ability to mount an antibody response (Mackinnon LT 1996).

However, studies of systemic immunity in sedentary and moderately exercising subjects indicate enhanced immune responses following moderate exercise [Nehlsen-Cannarella SL, Nieman DC, Balk-Lamberton AJ, Markoff PA, Chritton BW, Gusewitch G, Lee JW.,(1991) and Hickson RC, Boone JB. 1991. This is likely to reflect optimal NE release and facilitative effects on antibody production. Therefore, although temporary risk to URTI is greater for a few days after exercise, overall those who are conditioned have a more effective immune system, suggesting exercise benefits the immune system long-term.

In conclusion, psychoneuroimmunology research evidences a distinct bidirectional relationship between the CNS and the immune system, and the confirmation of neuroendocrine-induced alterations of specific immune functions (e.g. Shavit et al 1984). CAs promote lymphocytosis and enhanced functional activity of B cells when released in moderate levels, which coupled together enhance the immune system. Such adaptations are also evident by exposure to stress, both physical and psychological, and the associated CAs release offer explanations for these changes.

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Glaser, R. (2005). Stress-associated immune dysregulation

and its importance for human health: a personal history of

psychoneuroimmunology Brain, Behavior, and Immunity,

19, 3-11.

Lamm, M.E. (1998). Current concepts in mucosal immunity.

IV. How epithelial transport of IgA antibodies relates

to host defense. American Journal of Physiology -

Gastrointestinal and Liver Physiology, 274, G614-G617.

Gallagher, S., Phillips, A.C., Evans, P., Der, G., Hunt, K., &

Carroll, D. (2008). Caregiving is associated with low secretion

rates of immunoglobulin A in saliva. Brain, Behavior,

and Immunity, 22, 565-572.

Ring, C., Drayson, M., Walkey, D.G., Dale, S., & Carroll, D.

(2002). Secretory immunoglobulin A reactions to prolonged

mental arithmetic stress: Inter-session and intra-session reliability.

Biological Psychology, 59, 1-13

Rabin, B.S. (2005). Stressor-induced alteration of health

across the life span: There is more to it than immunology.

Clinical and Applied Immunology, 5, 207-224.

Phillips, A.C., Carroll, D., Evans, P., Bosch, J.A., Clow, A.,

Hucklebridge, F., & Der, G. (2006). Stressful life events are

associated with low secretion rates of immunoglobulin A in

saliva in the middle aged and elderly. Brain, Behavior, and

Immunity, 20, 191-197.

immunoglobulin A (sIgA) after a major academic exam.

International Journal of Psychophysiology, 37, 219-232.

Gaab, J., Blattler, N., Menzi, T., Pabst, B., Stoyer, S., &

Ehlert, U. (2003). Randomized controlled evaluation of the

effects of cognitive-behavioral stress management on cortisol

responses to acute stress in healthy subjects. Psychoneuroendocrinology,

28, 767-779.

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Jeffery, A.D. (2006). The relaxation response: Reducing

stress and improving cognition in healthy aging adults.

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191.

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mechanisms of mucosal immunity. Biochemical Society

Transactions, 25, 457-462.

Klentrou, P., Cieslak, T., MacNeil, M., Vintinner, A., &

Plyley, M. (2002). Effect of moderate exercise on salivary

immunoglobulin A and infection risk in humans. European

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Volkmann, E.R. & Weekes, N.Y. (2006). Basal sIgA and

cortisol levels predict stress-related health outcomes. Stress

and Health, 22, 11-23

Dynamic changes in salivary c o r t i s o l a n d s e c r e t o r y

immunoglobulin A response to a c u t e s t r e s s

Yaxin Fan,1 Yiyuan Tang, Qilin Lu,1 Shigang Feng,1 Qingbao Yu,1 Danni Sui,1

Qingbai Zhao,1 Yinghua Ma1 and Song Li1 Stress and Health 25: 189-194 (2009)

MackinnonLT. Immunoglobulin, antibody, and exercise.Exerc Immunol Rev 1996;2: 1-35

MalmC. Exercise immunology: The current state of man and mouse.Sports Med 2004;34: 555-566

30 PetersonCG, EnanderI, NystrandJ, AndersonAS, NilssonL, VengeP. Radioimmunoassay of human eosinophil cationic protein (ECP) by an improved method. Establishment of normal levels in serum and turnover in vivo.Clin Exp Allergy 1991;21: 561-567

Yang, E.V., & Glaser, R. (2002). Stress-induced immunomodulation

and the implications for health. International

Immunopharmacology, 2, 315-324.

33 SandersVM, MunsonAE. Norepinephrine and the antibody response.Pharmacol Rev 1985;37: 229-248

GleesonM, McDonaldAW, CrippsAW, PyneDB, ClancyRL, FrickerPA. The effect on immunity of long term intensive training in elite swimmers.Clin Exp Immunol 1995;102: 210-216

LehmannMP, BaumgartlP, WiesenackC, SeidelA, BaumannJ, FischerS, SporiU, GenmdrischG, KaminskiR, KeulJ. Training-overtraining: Influence of a defined increase in training volume vs. training intensity on performance, catecholamines and some metabolic parameters in experienced middle- and long-distance runners.Eur J Appl Physiol 1992;64: 169-170

Salivary sIgA is a

major effector against pathogens causing upper

respiratory tract infections (URTI) by preventing

adherence of virus to the nasal and oral mucosa

(Mestecky & Russell, 1997). Lower basal salivary

sIgA levels are associated with increased susceptibility

to URTI (Klentrou, Cleslak, MacNeil,

Vintinner, & Plyley, 2002; Volkmann & Weekes,

2006). sIgA down-regulation could be a means by

which stress increases susceptibility to URTI.

High intensity exercise, thus greater levels of released CAs appear to reduce B cell functioning capacity, and thus suppress humoral immunity. In contrast, moderate intensity exercise appears to induce facilitative response of B cells, including lymphopenia and up-regulated B-cell proliferation and antibody production. Ab promoted production and increased B cell proliferations is likely to be due to increased cAMP and the subsequent effects this has on T cell activation and thus T/B cell interaction, which increases functional competency of ab secreting cells. B cell differentiation increase, as explained by unregulated Th2 response and down regulated Th1 response, will further contribute to the improved Ab production observed after exercise. Therefore, the effects of exercise on immunity are explained by the effects of CAs have on B cells.

Observed effect of exercise on immune sysem

Explanation / Effect of CA B cells

Lymphocytosis

cAMP mediated increased activation and interaction of B/T cells

B cells differentiation increased

Upregualted Th2 response and suppressed Th 1 response

Ab production decrease following long duration, high intensity exercise

Ab production unimpaired after submax exercsie

cAMP mediated increased activation and interaction of B/T cells

Upregualted Th2 response and suppressed Th 1 response

33 Sanders VM, Munson AE. Norepinephrine and the antibody response.

Pharmacol Rev 1985; 37: 229-248

Nehlsen-Cannarella SL, Nieman DC, Balk-Lamberton AJ, Markoff

PA, Chritton BW, Gusewitch G, Lee JW. The effects of moderate

exercise training on immune response. Med Sci Sports Exerc 1991;

23:64-70.

9 Hickson RC, Boone JB. Physical exercise and immunity. In:

Plotnikoo N, Murgo A, Faith R, Wyburn J, eds. Stress and

immunity. Boca Raton: CRC Press, 1991:211-34.

Order U, Dufaux B, Uhlenbruck G, Liesen H. Lymphocyte subsets

during the first hours and days after a 2 5 h running test. J Clin Lab

Immunol 1990; 32:97-102.

Sprenger H, Jacobs C, Nain M, Gressner AM, Prinz H, Wesemann

W, Gemsa D. Enhanced release of cytokines, interleukin-2 receptors

and neopterin after long-distance running. Clin Immunol Immunopathol

1992; 63:188-95.

1 Douglas DJ, Hanson PG. Upper respiratory infections in the

conditioned athlete. Med Sci Sports Exerc 1978; 10:55.

2 Peters EM, Bateman ED. Ultramarathon running and upper

respiratory tract infections. An epidemiological survey. S Afr Med

J 1983; 64:582-4.

3 Levando VA, SuzdalNitskii S, Pershin BB, Zykov MP. Study of

secretory and antiviral immunity in sportsmen. Sports Training

Med Rehab 1988; 1:49-52.

4 Heath GW, Ford ES, Craven E, Macera CA, Jackson KL, Pate RR.

Exercise and the incidence of upper respiratory tract infections.

Med Sci Sports Exerc 1991; 23:152-7.

Keast D, Cameron K, Morton AR. Exercise and the immune

response. Sports Med 1988; 5:248-67.

6 Nieman DC, Nehlsen-Cannarella SL. The effects of acute and

chronic exercise on immunoglobulins. Sports Medicine 1991;

11: 183-201.

19 Hoffman-Goetz L, Pedersen BK. Exercise and the immune system:

a model of the stress response? Immunol Today 1994; 115:382-7.

Mackinnon LT. Immunoglobulin, antibody, and exercise. Exerc Immunol

Rev 1996; 2: 1-35

Hwoever, it is well reported by Several crosssectional studies have demonstrated higher levels of serum immunoglobulins in highly physically active people when compared to sedentary controls [16, 17] . Moderate exercise has also been shown to increase serum immunoglobulins [26].

Mackinnon LT. Immunoglobulin, antibody, and exercise. Exerc Immunol

Rev 1996; 2: 1-35

21. Ahlborg B, Ahlborg, G. Exercise leukocytosis with and without

beta-adrenergic blockade. Acta Med Scand 1970;187:241-246

1 Akimoto T , Kumai Y , Akama T , Hayashi E , Murakami H , Soma R , Kuno

S , Kono I . Eff ects of 12 months of exercise training on salivary secretory

IgA levels in elderly subjects . Br J Sports Med 2003 ; 37 : 76 - 79

35 Sari-Sarraf V , Reilly T , Doran D , Atkinson G . The eff ects of single and

repeated bouts of soccer-specifi c exercise on salivary IgA . Arch Oral

Biol 2007 ; 52 : 526 - 532

20. Kohut ML , Arntson B , LeeW , Rozeboom K , Yoon KJ , Cunnick JE , McElhaney

J . Moderate exercise improves antibody response to infl uenza

immunization in older adults . Vaccine 2002 ; 22 : 2 298 - 2306

11 Grant RW , Mariani RA , Vieira VJ , Fleshner M , Smith TP , Keylock KT ,

Lowder TW , McAuley E , Hu L , Chapman-Novakofski K , Woods JA . Cardiovascular

exercise intervention improves primary antibody response

to keyhole limpet hemocyanin (KLM) in previously sedentary older

adults . Brain Behav Immun 2008 ; 22 : 923 - 932

16 Karacabey K , Saygin O , Ozmerdivenli R , Zorba E , Godekmerdan A , Bulut

V . The eff ects of exercise on the immune system and stress hormones

in sportswomen . Neuro Endocrinol Lett 2005 ; 26 : 361 - 366

17 Karacabey K , Peker I , Saygin O , Ciloglu F , Ozmerdivenli R , Bulut V . Eff ect

of acute aerobic and anaerobic exercise on humoral immune factors

in elite athletes . Biotechnol & Biotechnol Eq 2005 ; 19 : 175 - 180

26 Nehlsen-Cannarella SL , Nieman DC , Balk-Lamberton AJ , Markoff PA ,

Chritton DB , Gusewitch G , Lee JW . The eff ects of moderate exercise

training on immune response . Med Sci Sports Exerc 1991 ; 23 :

64 - 70

21 Kohut ML , Senchina DS . Reversing age-associated immunosenescence

via exercise . Exerc Immunol Rev 2004 ; 10 : 6 - 41

7 Fahlman MM , Morgan AL , McNevin N , Boardley DJ , Topp R . Salivary

s-IgA response to training in functionally limited elders . J Ageing Phys

Act 2003 ; 11 : 502 - 515

8 Gleeson M , Hall ST , McDonald WA , Flanagan AJ , Clancy RL . Salivary IgA

subclasses and infection risk in elite swimmers . Immunol Cell Biol

1999 ; 77 : 351 - 355

9 Gleeson M , McDonald WA , Pyne DB , Clancy RL , Cripps AW , Francis JL ,

Fricker PA . Immune status and respiratory illness for elite swimmers

during a 12-week training cycle . Int J Sports Med 2000 ; 21 :

302 - 307

44 Tharp GD , Barnes MW . Reduction of saliva immunoglobulin levels by

swim training . Eur J Appl Physiol 1990 ; 60 : 61 - 64

45 Whitham M , Laing SJ , Dorrington M , Walters R , Dunklin S , Bland D ,

Bilzon JL , Walsh NP . The infl uence of an arduous military training program

on immune function and upper respiratory

10 Gleeson M , Pyne DB , Callister R . The missing links in exercise eff ects

on mucosal immunity . Exerc Immunol Rev 2004 ; 10 : 107 - 128

Goebel MU, Mills PJ. Acute psychological stress and exercise and

changes in peripheral leukocyte adhesion molecule expression and

density. Psychosom Med 2000;62:664-70.

Gleeson M, Pyne DB, Callister R. Exercise effects on mucosal immunity

and risk of upper respiratory illness. Int SportMed J 2003; 4: 1-13

Lehmann MP, Baumgartl P, Wiesenack C, Seidel A, Baumann J, Fischer

S, Spori U, Genmdrisch G, Kaminski R, Keul J. Training-overtraining:

Influence of a defined increase in training volume vs. training intensity

on performance, catecholamines and somemetabolic parameters

in experienced middle- and long-distance runners. Eur J Appl Physiol

1992; 64: 169-170

Changes in Mucosal and Humoral Atopic-Related Markers and Immunoglobulins in Elite Cyclists Participating in the Vuelta a España

McKune, A. J. - Smith, L. L. - Semple, S. J. - Wadee, A. A. - Fickl, H. - Villa, J. G. - Gómez-Gallego, F. - San Juan, A. F. - Lucia, A.(2006) volume 27, issue 7, 560-567 International journal of sports medicine

32 Roitt I, Brostoff J, Male D. Immunology. Edinburgh: Mosby, 2001.

Tomasi TB, Plaut AG. Humoral aspects of mucosal immunity.

In: Gallin JI, Fauci AS, eds. Advances in host defense mechanisms.

New York: Raven Press, 1985; 31-61.

4. Benschop, R. J., M. Schedlowski, H. Wienecke, R. Jacobs, and R. E. Schmidt. Adrenergic control of natural killer cell circulation and adhesion. Brain Behav. Immun. 11: 321-332, 1997[Medline].

Rhind, S. G., P. N. Shek, S. Shinkai, and R. J. Shephard. Effects of moderate endurance exercise and training on in vitro lymphocyte proliferation, interleukin-2 (IL-2) production, and IL-2 receptor expression. Eur. J.Appl. Physiol. 74: 348-60, 1996.

36. Nielsen, H. B., N. H. Secher, J. H. Kristensen, N. J. Christensen, K. Espersen, and B. K. Pedersen. Splenectomy impairs lymphocytosis during maximal exercise. Am. J.Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): R1847-R1852, 1997

Foster, N. K., J. B. Martyn, R. E. Rangno, J. C. Hogg, and R. L. Pardy. Leukocytosis of exercise: role of cardiac output and catecholamines. J. Appl. Physiol. 61: 2218-2223, 1986

McCarthy, D. A., and M. M. Dale. The leucocytosis of exercise. A review and model. Sports Med. 6: 333-363, 1988[

Perko, M. J., H. B. Nielsen, C. Skak, J. O. Clemmesen, T. V. Schroeder, and N. H. Secher. Mesenteric, coeliac and splanchnic blood flow in humans during exercise. J. Physiol. (Lond.) 513: 907-913, 1998[

Carlson, S. L., D. J. Beiting, C. A. Kiani, K. M. Abell, and J. P. McGillis. Catecholamines decrease lymphocyte adhesion to cytokine-activated endothelial cells. Brain Behav. Immun. 10: 55-67, 1996

19. Gabriel, H. H.W., and W. Kindermann. Adhesion molecules during immune response to exercise. Can. J.Physiol. Pharmacol. 76: 512-523, 1998

Murray DR, Irwin M, Rearden CA, Ziegler M, Motulsky H, Maisel AS. Sympathetic and immune interactions during dynamic exercise: mediation via a ß2-adrenergic-dependent mechanism. Circulation 1992; 86: 203-13

290

290.

TOMASI TB, TRUDEAU FB, CZERWINSKI D, AND ERREDGE S. Immune parameters in athletes before and after strenuous exercise. J Clin Immunol 2: 173-178, 1982

MacKINNON LT, CHICK TW, VANAS A, AND TOMASI TB. The effect of exercise on secretory and natural immunity. Adv Exp Med Biol 216: 869-876, 1987

TVEDE N, HEILMANN C, HALKJAER KRISTENSEN J, AND PEDERSEN BK. Mechanisms of B-lymphocyte suppression induced by acute physical exercise. J Clin Lab Immunol 30: 169-173, 1989

TVEDE N, PEDERSEN BK, HANSEN FR, BENDIX T, CHRISTENSEN LD, GALBO H, AND HALKJAER KRISTENSEN J. Effect of physical exercise on blood mononuclear cell subpopulations and in vitro proliferative responses. Scand J Immunol 29: 383-389, 1989

FIELD CJ, GOUGEON R, AND MARLISS EB. Circulating mononuclear cell numbers and function during intense exercise and recovery. J Appl Physiol 71: 1089-1097, 1991

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Benschop, R. J., M. Schedlowski, H. Wienecke, R. Jacobs, and R. E. Schmidt. Adrenergic control of natural killer cell circulation and adhesion. Brain Behav. Immun. 11: 321-332, 1997[Medline].

Nielsen, H. B., N. H. Secher, J. H. Kristensen, N. J. Christensen, K. Espersen, and B. K. Pedersen. Splenectomy impairs lymphocytosis during maximal exercise. Am. J.Physiol. 272 (Regulatory Integrative Comp. Physiol. 41): 1847-1852, 1997

Rhind, S. G., P. N. Shek, S. Shinkai, and R. J. Shephard. Effects of moderate endurance exercise and training on in vitro lymphocyte proliferation, interleukin-2 (IL-2) production, and IL-2 receptor expression. Eur. J.Appl. Physiol. 74: 348-60, 1996.

Foster, N. K., J. B. Martyn, R. E. Rangno, J. C. Hogg, and R. L. Pardy. Leukocytosis of exercise: role of cardiac output and catecholamines. J. Appl. Physiol. 61: 2218-2223, 1986

McCarthy, D. A., and M. M. Dale. The leucocytosis of exercise. A review and model. Sports Med. 6: 333-363, 1988[

Perko, M. J., H. B. Nielsen, C. Skak, J. O. Clemmesen, T. V. Schroeder, and N. H. Secher. Mesenteric, coeliac and splanchnic blood flow in humans during exercise. J. Physiol. (Lond.) 513: 907-913, 1998[

Carlson, S. L., D. J. Beiting, C. A. Kiani, K. M. Abell, and J. P. McGillis. Catecholamines decrease lymphocyte adhesion to cytokine-activated endothelial cells. Brain Behav. Immun. 10: 55-67, 1996

19. Gabriel, H. H.W., and W. Kindermann. Adhesion molecules during immune response to exercise. Can. J.Physiol. Pharmacol. 76: 512-523, 1998

Goebel MU, Mills PJ. Acute psychological stress and exercise and changes in peripheral leukocyte adhesion molecule expression and density. Psychosom Med 2000;62:664-70.

Murray DR, Irwin M, Rearden CA, Ziegler M, Motulsky H, Maisel AS. Sympathetic and immune interactions during dynamic exercise: mediation via a ß2-adrenergic-dependent mechanism. Circulation 1992; 86: 203-13

FIELD CJ, GOUGEON R, AND MARLISS EB. Circulating mononuclear cell numbers and function during intense exercise and recovery. J Appl Physiol 71: 1089-1097, 1991

TVEDE N, HEILMANN C, HALKJAER KRISTENSEN J, AND PEDERSEN BK. Mechanisms of B-lymphocyte suppression induced by acute physical exercise. J Clin Lab Immunol 30: 169-173, 1989

Ahlborg B, Ahlborg, G. Exercise leukocytosis with and without beta-adrenergic blockade. Acta Med Scand 1970;187:241-246

TOMASI TB, TRUDEAU FB, CZERWINSKI D, AND ERREDGE S. Immune parameters in athletes before and after strenuous exercise. J Clin Immunol 2: 173-178, 1982

MacKINNON LT, CHICK TW, VANAS A, AND TOMASI TB. The effect of exercise on secretory and natural immunity. Adv Exp Med Biol 216: 869-876, 1987

Akimoto T , Kumai Y , Akama T , Hayashi E , Murakami H , Soma R , Kuno S , Kono I . Eff ects of 12 months of exercise training on salivary secretory

IgA levels in elderly subjects . Br J Sports Med 2003 ; 37 : 76 - 79 16 Karacabey K , Saygin O , Ozmerdivenli R , Zorba E , Godekmerdan A , Bulut

V . The eff ects of exercise on the immune system and stress hormones in sportswomen . Neuro Endocrinol Lett 2005 ; 26 : 361 - 366

Fahlman MM , Morgan AL , McNevin N , Boardley DJ , Topp R . Salivary s-IgA response to training in functionally limited elders . J Ageing Phys Act 2003 ; 11 : 502 - 515

Sari-Sarraf V , Reilly T , Doran D , Atkinson G . The eff ects of single and repeated bouts of soccer-specifi c exercise on salivary IgA . Arch Oral Biol 2007 ; 52 : 526 - 532

44 Tharp GD , Barnes MW . Reduction of saliva immunoglobulin levels by swim training . Eur J Appl Physiol 1990 ; 60 : 61 - 64

Gleeson M, Pyne DB, Callister R. Exercise effects on mucosal immunity and risk of upper respiratory illness. Int SportMed J 2003; 4: 1-13

Mackinnon LT. Immunoglobulin, antibody, and exercise. Exerc Immunol Rev 1996; 2: 1-35

Lehmann MP, Baumgartl P, Wiesenack C, Seidel A, Baumann J, Fischer S, Spori U, Genmdrisch G, Kaminski R, Keul J. Training-overtraining:

Influence of a defined increase in training volume vs. training intensity on performance, catecholamines and somemetabolic parameters in experienced middle- and long-distance runners. Eur J Appl Physiol 1992; 64: 169-170

33 Sanders VM, Munson AE. Norepinephrine and the antibody response. Pharmacol Rev 1985; 37: 229-248

Ring, C., Drayson, M., Walkey, D.G., Dale, S., & Carroll, D. (2002). Secretory immunoglobulin A reactions to prolonged mental arithmetic stress: Inter-session and intra-session reliability. Biological Psychology, 59, 1-13

Rabin, B.S. (2005). Stressor-induced alteration of health across the life span: There is more to it than immunology. Clinical and Applied Immunology, 5, 207-224.

Phillips, A.C., Carroll, D., Evans, P., Bosch, J.A., Clow, A., Hucklebridge, F., & Der, G. (2006). Stressful life events are associated with low secretion rates of immunoglobulin A in saliva in the middle aged and elderly. Brain, Behavior, and Immunity, 20, 191-197.

Gallagher, S., Phillips, A.C., Evans, P., Der, G., Hunt, K., & Carroll, D. (2008). Caregiving is associated with low secretion rates of immunoglobulin A in saliva. Brain, Behavior, and Immunity, 22, 565-572.

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Glaser, R. (2005). Stress-associated immune dysregulation and its importance for human health: a personal history of psychoneuroimmunology Brain, Behavior, and Immunity, 19, 3-11.

Changes in Mucosal and Humoral Atopic-Related Markers and Immunoglobulins in Elite Cyclists Participating in the Vuelta a España

McKune, A. J. - Smith, L. L. - Semple, S. J. - Wadee, A. A. - Fickl, H. - Villa, J. G. - Gómez-Gallego, F. - San Juan, A. F. - Lucia, A.(2006) volume 27, issue 7, 560-567 International journal of sports medicine

32 Roitt I, Brostoff J, Male D. Immunology. Edinburgh: Mosby, 2001.

9 Gleeson M , McDonald WA , Pyne DB , Clancy RL , Cripps AW , Francis JL , Fricker PA . Immune status and respiratory illness for elite swimmers during a 12-week training cycle . Int J Sports Med 2000 ; 21 : 302 - 307

Order U, Dufaux B, Uhlenbruck G, Liesen H. Lymphocyte subsets during the first hours and days after a 2 5 h running test. J Clin Lab Immunol 1990; 32:97-102.

Sprenger H, Jacobs C, Nain M, Gressner AM, Prinz H, Wesemann

W, Gemsa D. Enhanced release of cytokines, interleukin-2 receptors and neopterin after long-distance running. Clin Immunol Immunopathol 1992; 63:188-95.

Keast D, Cameron K, Morton AR. Exercise and the immune response. Sports Med 1988; 5:248-67.

Nehlsen-Cannarella SL, Nieman DC, Balk-Lamberton AJ, Markoff

PA, Chritton BW, Gusewitch G, Lee JW. The effects of moderate exercise training on immune response. Med Sci Sports Exerc 1991; 23:64-70.

9 Hickson RC, Boone JB. Physical exercise and immunity. In:

Plotnikoo N, Murgo A, Faith R, Wyburn J, eds. Stress and immunity. Boca Raton: CRC Press, 1991:211-34.

Dynamic changes in salivary c o r t i s o l a n d s e c r e t o r y immunoglobulin A response to a c u t e s t r e s s

Yaxin Fan,1 Yiyuan Tang, Qilin Lu,1 Shigang Feng,1 Qingbao Yu,1 Danni Sui,1

Qingbai Zhao,1 Yinghua Ma1 and Song Li1 Stress and Health 25: 189-194 (2009)

Liew FY, Russell SM, Appleyard G, Brand CM, Beale J.

Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity. Eur J Immunol 1984; 14: 350-356.

Steerenberg PA, Van Asperen IA, Van Nieuw Amerongen

A, Biewenga J, Mol D, Medema GJ. Salivary levels of immunoglobulin A in triathletes. Eur J Oral Sci 1997; 105: 305-309.

8 Gleeson M , Hall ST , McDonald WA , Flanagan AJ , Clancy RL . Salivary IgA subclasses and infection risk in elite swimmers . Immunol Cell Biol 1999 ; 77 : 351 - 355

45 Whitham M , Laing SJ , Dorrington M , Walters R , Dunklin S , Bland D , Bilzon JL , Walsh NP . The infl uence of an arduous military training program on immune function and upper respiratory

10 Gleeson M , Pyne DB , Callister R . The missing links in exercise eff ects on mucosal immunity . Exerc Immunol Rev 2004 ; 10 : 107 - 128

Deinzer R, Kleineidam C, Stiller-Winkler R, Idel H.

Prolonged reduction of salivary immunoglobulin A (sIgA) after a major academic exam. Int J Psychophysiol 2000; 37: 219-232.