Reproduction Immunology

Reproductive Immunology refers to the field of medicine that studies the interaction between the immune system and components related to the reproductive system.⁵ The concept has been used by fertility clinics to explain fertility problems and pregnancy complications that are observed when immunological tolerance is not achieved.⁵ The role of the immune system in pregnancy is a very important issue in reproductive immunology and has evolved significantly since the term was first used. One important issue currently on the forefront of reproductive immunology is trying to redefine the role of the immune system in pregnancy. There are some that believe that the concept of pregnancy associated with immune suppression has created a misconception of pregnancy as a state of immunological weakness and increased susceptibility to infectious diseases.¹ The question that needs to be addressed is whether the maternal immune system is a friend or a foe to the fetus. Fundamental immunology usually protects the host from pathogens, which is normally dependent on the innate immune system’s ability and capacity to orchestrate cell migration to survey, recognize, and respond to invading pathogens.¹ Studies conducted by Colins et al. have demonstrated that immune cells such as NK cells, dendritic cells and macrophages are essential for the trophoblast to reach endometrial vascularity during first trimester and therefore prevent the termination of pregnancy. In addition, a study conducted by the Division of Reproduction and Child Health in the University of Birmingham, evaluated the how presence of CD4+ CD25+ T regulatory cells that suppress antigen-specific immune responses are important for allograft tolerance, such as the fetus.

Another important issue in reproductive immunology is the role of the zona pellucida in immune recognition. Fertilization is the process of the union between spermatozoa and oocyte to form a zygote. The zona pellucida has a fundamental role in this process: it contains adhesion molecules, like carbohydrates and proteins, which mediate the union of gametes.³ These molecules are also important for immunological recognition. There are times when the mammalian zygote could be recognized by the immune system after fertilization due to the expression of foreign paternal histocompatibility markers.³ The zona pellucida is essential in protecting the zygote from being destroyed by the immune system. Studies have shown that female patients with autoantibodies against antigens of the zona pellucida are susceptible to infertility.³ Furthermore, studies done on animal models have reinforced the importance antibodies play in fertilization. Shanhai Jiao Tong University School of Medicine showed that active immunization with autoantigenic sperm protein (tNASP) antigen induced a strong antibody response that caused fertility inhibition.⁷ Finally, antibodies to certain organisms such as Helicobacter pylori have an impact on female fertility. It has been demonstrated that anti-H. pylori antibody in the cervical mucus can be involved in the infertility of females by interfering with sperm progression.² These immunological issues further illustrate the importance of reproduction immunology and its clinical application in medicine.

Clinical applications

Development of Genetically-engineered Human Sperm Immunocontraceptives

The world’s increasing population is directed towards a dangerous zone; Earth cannot provide sufficient resources for the amount of individuals living on this planet. This brings in play numerous problems resources for the amount of individuals living on this planet. This brings in play numerous problems such as global warming, pollution, disease and more, requiring ways to control the population expansion. Unintended pregnancies are a concern contributing to the population explosion even with the various contraceptive methods available. This article presents the proposal of better, more effective methods such as anti-sperm immunocontraception. These vaccines primarily target luteinizing hormone-releasing hormone (LHRH/GnRH). They may be useful in clinical situations that require suppression of sex steroid secretion, such as in uterine fibroids, polycystic ovary syndrome (PCOS), endometriosis, and precocious puberty.⁴ Using sperm-specific human antibodies, which inhibit sperm function in vitro may provide a once a month immunocontraceptive. Several approaches were reviewed such as genomics, proteomics, gene knockout, and hybridoma technology, to delineate sperm antigens that affect fertilization or fertility and can be used for the development of an effective vaccine. The presence of antibodies to a sperm antigen in immunoinfertile men and women indicate that it is: a) immunogenic in humans, b) relevant to fertility/infertility, and c) probably sperm specific since these individuals are healthy without any immunopathology concomitant with infertility. The sperm-ZP binding site constitutes the preferred target for immunocontraception.⁴Although several delineated antigens that are sperm-specific and have a role in fertility have been tested and have functioned in vitro, only few have successfully caused contraception effect in vivo in animals. Naz explains how thus far no study has achieved 100% infertility after immunization with any of the antigens; 75% has been the maximum reduction in fertility obtained. Another approach was using a cocktail of sperm antigens, data obtained from this trial indicated that the proteins involved in sperm-egg fusion can also be used for contraceptive vaccine development. However, this method also resulted in only a 73.3% reduction in fertility. Naz explains in the article the factors considered crucial in the progress of the development of the vaccine: 1) variability of the immune response, 2) attainment and maintenance of high antibody titers, 3) time lag from the first injection to the time to achieve reasonably good antibody titers which generally takes three months, and 4) uncertainty regarding how long the antibody titer will remain in circulation to exercise the contraceptive effects.

Innate Immunity in the Human Female Reproductive Tract: Endocrine Regulation of Endogenous Antimicrobial Protection Against HIV and Other Sexually Transmitted Infections

The female reproductive tract contains specific antimicrobial molecules and cytokines, which are found within it. These molecules and cytokines levels can be altered by varying factors. Alpha defensins can have antibacterial activity that fight against many pathogenic agents, including HIV-1. However the alpha defensins HD5 and HD6 have been reported to actually enhance the replication of HIV. ⁸ Beta defensins HBD 1-6 are reported to inhibit HIV-1 by interacting directly with the viral envelope that acts on target cell populations. This decreases HIV-1 co-receptors and stops early stages of replication. ⁸
The uses of hormonal contraceptives have been proven to affect the antimicrobial levels of the female reproductive tract. Studies have shown that sequential oral contraceptives can suppress the cyclic changes of many immunological proteins like IgG, IgA and Lysozyme. ⁸ Another study has shown that SLP1 levels in luminal epithelial secretions were decreased in the upper female respiratory tract in women who were taking a combined oral contraceptive. Antimicrobials of the female reproductive tract have many inhibitory effects on a spectrum of STI (Sexually Transmitted Infections). ⁸ The innate immune system of the female reproductive tract plays an important role in protecting against multiple pathologies. Studies have shown that in both HIV (+) and HIV (-) women display anti-HIV activity within their female reproductive tract secretions. However, there is a decline in anti-HIV activity with the progression of the disease. Anti-HIV molecules and chemokines include SLP1, ELAfin, RANTES and SDF1. These molecules and chemokines can block the co-receptors CXCR4 and CCR5. ⁸ They may also inhibit HIV post infection. In the case of HSV, studies have shown that there is anti-HSV activity in the Cervico-Vaginal lavages. Interestingly, in the case of HPV, Human Alpha Defensins 1, 2, 3 and 5 inhibit sexually transmitted HPV infections. ⁸ This might explain why most women can clear the infection over time. Gonorrhea has shown to be an important cofactor in HIV infection. This is because it induces alpha defensins HD5 and 6 which enhance HIV replication. In women with low SLP 1 levels within their vaginal secretions may have a higher risk of contracting Chlamydia trachomatis. Elafin expression is upregulated in infection of the oviduct epithelial cells. This suggests that Elafin plays a role in the innate immune response to Chlamydia trachomatis infection. Candida albicans which commonly causes yeast infections acts as a commensal microbe as long as the levels remain under control. If the levels rise too high a yeast infection may occur. Both the upper and lower female reproductive tract secretions inhibit both forms of Candida albicans: the previously mentioned non-pathogenic yeast and the pathogenic hyphal form. ⁸ The preceding research and studies show that there is a definite direction for research into the clinical applications of immunologic reactions to HIV, which may gradually provide a means of combating the virus.

Interleukin-6 Enhances the Fertilizing Capacity of Human Sperm by Increasing Capacitation and Acrosome Reaction

Recent studies have shown that male infertility may be treated by the use of Interleukin-6. Rajesh and Kaplan discovered that IL-6 enhances the fertilizing capacity of human sperm. It does so by increasing human sperm penetration rates, increasing the acrosomal reaction, and increasing the acrosin concentration released from sperm.⁹ These results are obtained by incubating the sperm with an IL-6 concentration between 60-600pg/100μL. Overall using Interleukin-6 through clinical application will help treat male infertility.

Questions

1.Materno-fetal tolerance is a crucial immunological mechanism necessary to prolong the pregnant state. Which T-regulatory cells suppress the antigen-specific immune response against the fetus?

a. CD8+ CD40+

b. Cytotoxic lymphocytes

c. Plasma cells

d. CD4+ CD25+

e. Natural killer cells

2. A 25 year old female volunteered to participate in a clinical trial for inmunocontraception, which of the following methods do you expect will be tested?
a. Nuva ring

b. Physical boundaries

c. Sperm-ZP vaccine

d. Ortho Cept

e. Rhythm method

3. The immune system can recognize the zygote of a gravid woman as foreign leading to miscarriages or infertility. Antibodies can develop towards:

a) Expression of foreign paternal histocompatibility markers and antigens of the zona pellucida

b) CD4+, CD25+ T regulatory cells

c) Dendritic cells

d) Macrophages

Discussion questions

1. 
   
   Why would female patients with autoantibodies against the zona pellucida be susceptible to infertility?



2. 
   
   What immunologic disadvantage can be caused by oral contraceptives?



3. 
   
   Mention some of the immune cells found to play a role in reproductive immunology.

Answers

1. 
   
   D



2. 
   
   C



3. 
   
   A

Discussion questions

1. 
   
   The activation of an immune response against the zona pellucida or any of its components could cause an inhibition of the acrosome reaction necessary for the process of sperm binding and subsequent fertilization and zygote formation.



2. 
   
   Studies show that oral contraceptives supress cyclic changes in immunological proteins such as IgG, IgA and lysozymes.



3. 
   
   Natural killer cells, dendritic cells, macrophages and T regulatory cells.

References

1. Ann, NY. Inflammation and pregnancy: the role of the immune system at the implantation site. Academic Science. 2011; 122(1):117-122. doi: 10.1111/j.1749-6632.2010.05938.x.
   
   


2. Ambrosini G, Andrisani A, Fiore C, Faggian D. Anti-Helicobacter pylori antibodies in cervical mucus: a new cause of infertility. Eur J Obstet Gynecol Reprod Biol. 2011; 155(2):155-160. Accessed December 28, 2010.
   
   


3. Clark, G. The mammalian zona pellucida: a matrix that mediates both gamete binding and immune recognition? System biology reproduction medicine. 2010; 56(5):349-364.



4. Naz, R. Development of genetically engineered human sperm immunocontraceptives. J Reproductive Immunology. 2009; 83(1-2):145-150. Accessed October 23, 2009.



5. Pearson, H. Immunity’s Pregnant Pause. Nature. 2002; 420(6913):265-266. http://www.ncbi.nlm.nih.gov/pubmed/12447413.



6. Somerset, D., Zheng, Y., Kilby, M., Sansom, D., & Drayson, M. Normal human pregnancy is associated with an elevation in the immune suppresive CD25+ CD4+ regulatory t-cell subset. Immunology. 2004; 112(1):38-43. http://www.ncbi.nlm.nih.gov/pubmed?term=15096182.



7. Wang M, Shi JL, Cheng GY, Hu YQ, Xu C. The antibody against a nuclear autoantigenic sperm protein can result in reproductive failure. Asian J Androl. 2009; 11(2):183-192. Accessed February 16,2009.



8. Wira CR, Patel MV, Ghosh M, Mukura L, Fahey JV. Innate immunity in the human female reproductive tract: endocrine regulation of endogenous antimicrobial protection against HIV and other sexually transmitted infections. Am J Reproductive Immunology. 2011; 65(3):196-211. doi: 10.1111/j.1600-0897.2011.00970.x.



9. Naz RK, Kaplan P. Interleukin-6 Enhances the Fertilizing Capacity of Human Sperm by Increasing Capacitation and Acrosome Reaction. Journal of Andrology. 1994; 15(3): 228-233. http://www.andrologyjournal.org/cgi/reprint/15/3/228. Accessed April 2, 2011
   

Appendix

1. 
   
   video from: http://www.youtube.com/watch?v=GeigYib39Rs



2. 
   
   Diagram of sperm and egg fusion in the fertilization process. Image from: http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Dresser/review%20paper.htm



3. 
   
   Diagram of the acrosome reaction. Image from: http://www.jci.org/articles/view/23213/figure/1