Special Topics in Immunology:

Reproductive Immunology

The Journal of Reproductive Immunology states that this field of study “encompasses normal and pathological processes of reproductive tracts, gametes, fertilization, implantation, gestation, parturition and lactation, including host defense to infectious disease…developmental immunology and immunology of reproductive neoplasms, as well as application of immunological techniques in elucidation of reproductive processes or dysfunction.”[i] With this definition, we can see that reproductive immunology is more than tolerance and protection of the fetus and pregnant woman. It also includes women’s diseases related to pregnancy, the defense of the reproductive systems (man and woman) and how immunological problems in those organs affect the body’s homeostasis.

One topic covered by Reproductive Immunology is investigation of causes and treatment of infertility, which is a hot topic in medicine today. The Centers for Disease Control report that about 12% of people of reproductive age are affected by infertility.[ii] The shear number and availability of infertility internet support groups is indicative of the extent of the problem. At www.sharedjourney.com you can learn about the possible causes of infertility, explore options like IVF and adoption, and read success stories from other previously infertile couples.[iii] At www.rialab.com women with immune related miscarriages can receive consultations for possible solutions.[iv] These are only two of innumerable support groups.

Figure 1 - Screenshots from Shared Journey and Reproductive Immunology Associates websites.

A condition that is more common than expected and studied by this field is Recurrent Spontaneous Abortion. Thanks to the advances in medical history documentation and detection of pregnancy at an earlier period, we know that the etiology of this condition is 1 in 300 pregnancies.[v] This condition is a classical example of immunological mechanisms gone wrong; here the mother’s immune system attacks the fetus or related structures instead of modulating to maintain pregnancy. Reproductive immunology has given the insights of the causes of this condition and is leading us to find treatment options and eventually prevention.

Figure 2 – Model for immunological basis of Recurrent Spontaneous Abortion. From www.rialab.com/miscarriages_prevented.php

Reproductive immunology is an important and expanding science that addresses many medical issues as stated in the introduction. The Clinical Cases that are presented in the next section, portray some classical examples of diseases know by the general public that are finally being understood and in some cases treated with success. But these diseases are only a fraction of conditions that are studied in the field of reproductive immunology.

Clinical Correlations

Recurrent Spontaneous Abortions

One factor related to miscarriage is the natural killer (NK) cells which seem to have a role in recurrent spontaneous abortions (RSA). The major role of NK cells is to cause an inflammatory response mainly by the release of IL-10 in the endometrial layer thereby increasing angiogenesis in the decidua. Thus, NK cells normally assist in early fetal development. Studies show that women with RSA have increased NK cell counts.[vi] Hyperactive NK cells probably cause RSA by damaging maternal endocrine cells responsible for producing and secreting the hormones essential for pregnancy. Another hypothesis that is gaining much acceptance is that involvement of the complement system, causes an inflammatory reaction that produce placental hypoxia eventually leading to abortion.[vii] (See figure 2)

Gestational Diabetes

Reproductive immunology has many areas of study, including women’s diseases related to pregnancy. For example Gestational Diabetes (GD) is an insulin intolerance that is recognized during pregnancy without previous diabetes history. Studies show that GD is related to fetal monocyte activation by the mother’s immunoglobulins against paternal HLAs, as is the case of Rh Hemolytic Disease of the Newborn and Pre-eclampsia (hypertension and generalized edema in the pregnant woman).[viii] Scientist hypothesized that by some defect in the barriers dividing the mother and fetus, the mother’s immune system come in contact with antigen particles that are really biological structures from the fetus.

Anti-Sperm Antibodies

As part of fertilization and conception problems, one of the targets in recent studies is the Anti-Sperm Antibodies (ASA). These antibodies can impair the fertilizing capacity of human spermatozoa, acting negatively on sperm motility, cervical mucus penetration and in vitro gamete interaction. These have also been linked to semen hypersensitivity, a condition in which the woman experiences the symptoms of any other allergy. Few treatments are thought to be successful. Treatment options focus on decreasing ASA production and removing ASA already bound to sperm. The first is based on a treatment with corticosteroids, and the other by in vitro capacitation of sperm where it is possible to remove the entire immune complex without damaging the cell.[ix]

However, some cytokines are released within the sperm that help to regulate the immune system preventing a response against the embryo. Studies conclude that TGF is a potent immune-deviating cytokine with pivotal roles in inducing active immune tolerance in mucosal and peripheral tissues. Seminal TGF deposited in the female tract at insemination is activated and interacts with female tract cells to elicit an inflammatory cascade. It is reasonable to postulate that seminal antigens are shared by the conceptus, seminal TGF may act to facilitate induction of maternal immune tolerance to conceptus antigens and thereby promote implantation success.[x]

Discussion Questions

1. What is the role of antisperm antibodies in infertility?

2. What other immune related conditions or cytokines might cause infertility?

3. What about immunosuppression in pregnant women? How are women immunosuppressed and why is this important to the health of the fetus?

Multiple Choice Questions

1. What is true about NK cells function in pregnancy?
1. NK cells play an important role in the 3^rd trimester.
2. NK cells are hypersensitive in pregnant women.
3. NK cells have no role in normal pregnancy
4. NK cells are important in preparing the endometrial layer for implantation.

2. According to the CDC, what percentages of people in reproductive age are affected by infertility?
1. 15
2. 7
3. 39
4. 12

3. What article would you find classified as a study of reproductive immunology?
1. Toll like receptor signaling and pre-eclampsia
2. Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients
3. Women with Multiple Implantation Failures and Recurrent Pregnancy Losses have Increased Peripheral Blood T Cell Activation
4. CD57+ Cells and Recurrent Spontaneous Abortion

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References

[i] About Journal of Reproductive Immunology. Journal of Reproductive Immunology: The International Journal for Clinical and Clinical Reproductive Immunobiology. Available at: http://www.journals.elsevierhealth.com/periodicals/jri. Accessed April 11, 2010.

[ii] Assisted Reproductive Technology: Home. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/art/. Accessed April 11, 2010.

[iii] Shared Journey. Shared Journey: Your path to fertility. 2010. Available at: http://www.sharedjourney.com/index.html. Accessed April 11, 2010.

[iv] Reproductive Immunology Associates. 2010. Available at: http://www.rialab.com/ Accessed April 11, 2010.

[v] Berek, Jonathan, & Novak, Emil. (2007). Berek & Novak's Gynecology. Hong Kong: Lippincott Williams & Williams.

[vi] Kwak-Kim, J and Gilman-Sachs, A. Clinical Implication of Natural Killer Cells and Reproduction. Am J Reprod Immunol. 2008; 59: 388-400.

[vii] Hahn, Sinuhe, Anurag Kumar-Gupta, Carolyn Troeger, Corinne Rusterholz, and Wolfgang Holzgreve. "Disturbances in placental immunology: ready for therapeutic interventions?." Springer Semin Immun. 2006.27 (2006): 477-493. Print.

[viii] Steinborn A., Saran G, Schneider A, Fersis N, Sohn C, Schmitt E. The Presence of gestational diabetes is associated with increased detection of anti-HLA-class II antibodies in the maternal circulation. American Journal of Reproductive Immunology, 2008: 56, 124-134.

[ix] Lombardo, F, L Gandini, and A Lenzi. "Antisperm immunity in assisted reproduction." Journal of Reproductive Immunology. 2004.62 (2004): 101-109. Print.

[x] Robertson S.A., Ingman Wendy V., O’Leary Sean, Sharkey David J., Tremellen Kelton P. "Transforming growth factor β—a mediator of immune deviation in seminal plasma"
Journal of Reproductive Immunology, Volume 57, Issue 1, Page 109