Research Update on Immune Function 2010

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Immune Function – Pregnancy and Exercise – c. 2010 Ann Cowlin

During pregnancy, the immune system must first become pro-inflammatory to permit fertilization and implantation, then anti-inflammatory to protect the mother and fetus, and then again pro-inflammatory to allow for a rejection response to help expel the infant. These cytokine and chemokine shifts, described in depth in Mor’s Immunology of Pregnancy [1], occur roughly at the start of each trimester in a healthy pregnancy [2]. But, in a dysfunctional or preeclamptic pregnancy, there is not sufficient modulation at the critical points to sustain the appropriate inflammatory response [1]. Genes [3-4] and infection [1,5-7] can contribute to an inability of the maternal immune system to develop the appropriate level of inflammatory response for a robust trophoblast invasion. The resulting poorly functioning placenta underlies the inability of the immune system to counter microbial or metabolic stressors that can lead to hypertension, prematurity and low birth weight, or an inability to mount a rejection response near term.

However, women who exercise in the six months prior to pregnancy and/or during pregnancy show a greatly reduced risk for preeclampsia [8-11]. The most likely explanation involves the ability of aerobic exercise to modify inflammatory responses by reducing oxidative stress and preventing or reversing endothelial dysfunction [8,12]. This sets the stage for normal trophoblast invasion, which is essential for further appropriate inflammatory status as the pregnancy progresses. If preeclampsia does develop, exercise may still provide some protection against prematurity and low birth weight by attenuating the dysfunction [13].

There are not clear lines dividing the immunological effects of metabolic syndromes, sepsis, cardiovascular disease or chronic stress on maternal/fetal outcomes. Instead, all of these conditions are mediated by inflammatory responses that can result in preeclampsia, premature labor, uteroplacental insufficiencies, and downstream cardiovascular and metabolic health problems for mother and offspring. Some components of exercise help reduce the risk for and severity of adverse conditions mediated by inflammation. Immune system biomarkers provide cues as to how exercise functions to enhance maternal immune function and help prevent or ameliorate the severity of these conditions.

In a study examining whether exercise type was associated with systemic markers of inflammation, a significant lower likelihood of elevated inflammatory markers C-reactive protein, fibrinogen, and white blood cell levels, was found among joggers and aerobic dancers [14].  While the researchers also looked at swimming, cycling, calisthenics, weight lifting and gardening, and initially found differences, these differences were not significant when controlled for possible confounding factors such as age, race, sex, body mass index, smoking and health status. However, duration and intensity may have accounted for some variation among the forms of exercise studied. Immune system protection provided by physical activity likely has a quantitative threshold for protection, even if it permits a broad range of activity types [15].

On the other hand, frequent strenuous bouts of prolonged exercise are known to be associated with depressed immune cell function, which may be compounded by inadequate nutrition [16]. Pregnant patients with extremely high levels of activity need to be especially careful to eat an adequate diet and to include adequate fluid and electrolyte replacement during strenuous activity. Such women can be cautioned to shorten, make less intense, or perform fewer strenuous weekly workouts, as well as eat in accordance with their needs as an athlete during pregnancy.

During physical activity, muscle release of cytokine IL-6 differs from its release during an inflammatory response, in which it is a component of the pro-inflammatory response. IL-6 is a pivotal cytokine that helps stimulate the cascade of anti-inflammatory biomarkers. Muscle release of IL-6 occurs in the absence of the pro-inflammatory marker tumor necrosis factor alpha, while stimulating the anti-inflammatory cascade [17]. Although research remains to be done to gain a better understanding of exercise and immune function in pregnancy, it appears that adequate activity promotes appropriate immune responses in pregnancy that may help prevent or reduce the severity of disorders that are mediated by inflammation.

There is a relationship between the mediation of stress by corticotropin releasing hormone (CRH) and opioid peptides, and the effect of stress on disturbed reproductive function–disrupted menstruation, parturition and lactation–via inhibition of gonadotropins and oxytocin [18,19].  During labor, corticotropin and beta-endorphins are found at levels of those in athletes during maximal exercise; in addition, the placenta produces increasing amounts of CRH toward the end of pregnancy, signaling it may be involved in adaptive stress mechanisms to help mother and fetus withstand the stress of labor [18].  In a small sample, researchers found the responses of stress hormones and placental steroids in late pregnancy exercisers to be similar to those of non-pregnant exercisers [20].  Although the researchers found some incidence of uterine contractions brought on by increased levels of norepinephrine, the increase in epinephrine mitigates this effect and regular contractions did not start in any subjects [20].  Other studies have found that women who participated in recreational aerobic activities had a decreased risk of spontaneous preterm birth [13,21].

References

1. Mor, G. Immunology of Pregnancy. Series: Medical Intelligence Unit. Springer. 2006.

2. Mor G. Chapter 19: Trophoblast as Immune Regulator, Immunology of Pregnancy. Series: Medical Intelligence Unit. Springer. 2006.

3. Bilban M, Haslinger P, Prast J et al. Identification of Novel Trophoblast Invasion-Related Genes: Heme Oxygenase-1 Controls Motility via Peroxisome Proliferator-Activated Receptor {gamma}, Endocrinology 150(2):1000-1013. 2009.

4. Pang, ZJ, Xing FQ. Expression profile of trophoblast invasion-associated genes in the preeclamptic placenta., British Journal of Biomedical Science 60(2):97-101. 2003.

5. Gomez L and Parry S. Trophoblast infection with chlamydia pneumoniae induceplacental dysfunction and preeclampsia. American Journal of Obstetrics and Gynecology 199(6):S11. 2008.

6. Arechavaleta-Velasco F, Ma Y, Zhang J, McGrath CM and Parry S. Adeno-Associated Virus-2 (AAV-2) Causes Trophoblast Dysfunction, and Placental AAV-2 Infection Is Associated with Preeclampsia, American Journal of Pathology 168:1951-1959. 2006.

7. Goncalves LF, Chaiworapongsa T, Romero R. . Intrauterine infection and prematurity. Mental Retardation and Developmental Disabilities Research Reviews, 8(1), 3-13. 2002.

8. Weissgerber TL, Wolfe LA, Davies, GAL. The Role of Regular Physical Activity in Preeclampsia Prevention Med Sci Sports Exerc 36(12):2024-2031, 2004.

9. Rudra CB, Williams MA, Lee IM, Miller RS, Sorensen TK. Perceived exertion during prepregnancy physical activity and preeclampsia risk. Medicine & Science in Sports & Exercise, 37(11), 1836-41. 2005.

10. Sorensen TK, Williams MA, Lee IM, Dashow EE, Thompson ML, Luthy DA. Recreational physical activity during pregnancy and risk of preeclampsia. Hypertension, 41(6), 1273-1280. 2003

11. Saftlas AF, Logsden-Sackett N, Wang W, Woolson R, Bracken MB.  Work, leisure-time physical activity, and risk of preeclampsia and gestational hypertension. American Journal of Epidemiology, 160(8):758-765. 2004.

13. Cowlin AF, Brancato R, Mor G, Zelterman D, DeZinno, P. Effect of community-based group prenatal physical activity on preeclampsia risk, Poster Presentation, Soc Gyn Investigation Conference, March 2008, and Slide Presentation, Amer College Sports Med Conference, May 2008.

15. Juhl M, Andersen PK, Olsen J, Madsen M, Jørgensen T, Nøhr EA, Andersen AN. Physical exercise during pregnancy and the risk of preterm birth: A study within the danish national birth cohort, Am J Epidemiol. 167(7):859-856. 2008.

18. Laatikainen, T. J. Corticotropin-releasing hormone and opioid peptides in reproduction and stress. Ann. Med. 23(5):489-496, 1991.

19. Magiakou MA, Mastorakos G, Webster E, Chrousos GP. The hypothalamic-pituitary-adrenal axis and the female reproduc-tive system.  Ann. NY Acad. Sci . 816:42-56, 1997.

20. Rauramo I, Andersson, B, Laatikaines TJ. Stress hormones and placental steroids in physical exercise during pregnancy.  B JObstet.Gynecol. 89:921-925, 1982.

21. Berkowitz GS, Kelwey JL, Holford TR, Berkowitz RL. Physical activity and risk of spontaneous preterm delivery.  J. Reprod.Med. 28(90):581-588, 1983.

1 Comment

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