First let’s clarify a couple of problems with the way the question’s formulated. Doing so will help us assimilate how much our understanding of immune system function has improved since the 1950s when proposed the now-defunct and wrong-headed self-non-self idea.
- One, since antibodies were among the first type of immune response scientists could quantify, it has become fixed in the public imagination as the essential feature of immune responses.
- Antibodies are indeed an essential but just one among many types of immune responses.
- In the case of sperm, not just antibodies but many other types of immune responses are possible and indeed observed, which I highlight in my answer.
- Two, sperm is produced by male bodies.
- So in the outmoded sense of self-non-self, sperm is self in the male body and becomes non-self when introduced into the female body.
- That means the male body shouldn’t but the female body should make immune responses against sperm.
- Thus, self-non-self dictates the female body’s immune system should recognize and reject the male sperm and yet how could our species exist if it were so?
- See how refining the way we ask the questions renders the self-non-self view untenable?
- And in fact, other models have long since displaced self-non-self to describe and understand immune function.
Antibodies to sperm are indeed possible (1), only they are a sign of sterility, not health.
- , described as the father of immunology, and , discoverer of human blood groups, injected sperm from a variety of species such as humans, bulls and rodents into other rodents and found serum of injected animals had capacity to agglutinate and immobilize sperm from these species (2, 3). In other words, injection of xenogeneic sperm induced rodent immune responses that included anti-sperm antibodies.
- In 1922, S. R. Meaker showed that women had anti-human sperm antibodies (4).
- This observation served as a basis for the first recorded trial for human contraception. In 1929, twenty women of proven fertility were injected with their husbands’ serum. At the one year follow-up, they were found to have become temporarily infertile (5).
- Based on this result, the US patent #2103240 was issued in 1937 for a contraceptive ‘spermatoxic‘ vaccine though no product was ever developed (6).
- In experimental animal models, female mice make anti-mouse sperm antibodies (7, 8).
- In fact, in humans, anti-sperm antibody is a sign of infertility (9, 10, 11, 12, 13).
Immune response to sperm falls under the purview of the field called
- For long, it along with the field of Psychoneuroimmunology were considered the rump of immunology and given short shrift by mainstream immunologists.
- Not much quality research ensued for several decades.
- That changed in recent decades with the advent of a newer generation of researchers, especially three researchers I call the three women who’re changing the face of Reproductive Immunology, literally and figuratively. They are
- B. Anne Croy, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Ontario Canada;
- Ashley Moffett, Department of Pathology and Centre for Trophoblast Research, University of Cambridge, Cambridge, UK (her prior papers published as Ashley Moffett-King);
- Sarah A. Robertson, The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia.
- This A2A is delightful for me since it gives me the opportunity to highlight Sarah Robertson‘s research. For over 20 years, she’s studied the female immune response to semen in humans, and in mouse and pig experimental models.
Sarah A. Robertson and other reproductive immunologists’ research shows that
1) Post-intercourse, anti-seminal fluid immune responses are part of normal female reproductive tract physiology,
2) This normal immune response consists of immune cells with regulatory function, i.e., immune responses that are non-pathologic and hence don’t damage the sperm.
- Female immune response to male seminal fluid is normal, indeed par for the course. Robertson even proposes that proper ‘priming’ of female immunity by seminal fluid is important for a healthy pregnancy (14).
- After sperm is injected during artificial insemination, there is influx of neutrophils, macrophages and lymphocytes in the human cervical mucus (15).
- In a more recent study, Robertson’s team showed that seminal fluid introduced during intercourse induces influx of dendritic cells, macrophages, memory T cells, and cytokines and chemokines into the human cervix (16).
- The degree and class of immune response distinguishes normalcy from immunopathology. How is female anti-male, i.e., anti-sperm and -seminal fluid response regulated? Through immune-regulatory molecules present in seminal fluid.
- Seminal fluid, i.e., the fluid sperm is packaged in, has components that regulate the female immune response against sperm and other components of the male reproductive tract.
- Seminal fluid is one of the body’s richest sources of TGF-beta (Transforming Growth Factor-beta; TGF-b1, -b2, -b3) and prostaglandins (17, 18). In fact, human seminal fluid has as much as~ 500micrograms per ml of TGF-beta, akin to not just a boatload but as much as a tanker load! This is true not just for humans but also for rodents and livestock suggesting abundance of TGF-beta is a highly evolutionarily conserved feature of seminal fluid. TGF-beta and prostaglandins are among the most important and potent immune-regulatory molecules, being pivotal and necessary for the generation of regulatory T cells (Tregs).
- Seminal fluid also has abundant HLA-G (19), a very important immune-regulatory Human Leukocyte Antigen involved in modulating mother’s immune response to the fetus.
- Anti-sperm T cell responses of recurrent miscarriage women have fewer Tregs (20).
- In other words, the kind of female anti-seminal fluid immune response that ensues in the female reproductive tract after intercourse determines whether fertilization can even happen.
- Tyler, Albert. “THE FOURTH OLIVER BIRD LECTURE APPROACHES TO THE CONTROL OF FERTILITY BASED ON IMMUNOLOGICAL PHENOMENA.” Journal of Reproduction and Fertility 2.4 (1961): 473-506.
- Metchnikoff, Elie. Etudes sur la resorption des cellules. 1899.
- Landsteiner, Karl. “Zur Kenntnis der spezifisch auf Blutkorperchen wirkenden Sera.” Zbl. Bakt 25 (1899): 546.
- Meaker, Samuel R. “Some aspects of the problem of sterility.” The Boston Medical and Surgical Journal 187.15 (1922): 535-539.
- Baskin, M. J. “Temporary sterilization by the injection of human spermatozoa. A preliminary report.” American Journal of Obstetrics & Gynecology 24.6 (1932): 892-897.
- Vazquez‐Levin, Mónica H., Clara I. Marín‐Briggiler, and Carolina Veaute. “Antisperm Antibodies: Invaluable Tools Toward the Identification of Sperm Proteins Involved in Fertilization.” American Journal of Reproductive Immunology 72.2 (2014): 206-218.
- Edwards, R. G. “Immunological control of fertility in female mice.” (1964): 50-53
- McLaren, Anne. “Immunological control of fertility in female mice.” Nature 201.4919 (1964): 582-585.
- Franklin, Robert R., and C. Dean Dukes. “ANTISPERMATOZOAL ANTIBODY AND UNEXPLAINED INFERTILITY.” Obstetrical & Gynecological Survey 19.5 (1964): 796-798.
- Isojima, Shinzo, Tien Shun Li, and Yoshio Ashitaka. “Immunologic analysis of sperm-immobilizing factor found in sera of women with unexplained sterility.” Am J Obstet Gynecol 101 (1968): 677-683.
- Mettler, L., P. Scheidel, and D. Shirwani. “Sperm antibody production in female sterility.” International journal of fertility 19.1 (1974): 7-12.
- Rümke, P., et al. “Prognosis of fertility in women with unexplained infertility and sperm agglutinins in the serum.” Fertility and sterility 42.4 (1984): 561-567.
- Shibahara, Hiroaki, et al. “Diagnosis and treatment of immunologically infertile women with sperm-immobilizing antibodies in their sera.” Journal of reproductive immunology 83.1 (2009): 139-144.
- Robertson, Sarah A., John J. Bromfield, and Kelton P. Tremellen. “Seminal ‘priming’ for protection from pre-eclampsia—a unifying hypothesis.” Journal of reproductive immunology 59.2 (2003): 253-265.
- Pandya, Ila J., and Jack Cohen. “The leukocytic reaction of the human uterine cervix to spermatozoa.” Fertility and sterility 43.3 (1985): 417-421; Thompson, L. A., et al. “The leukocytic reaction of the human uterine cervix.” American journal of reproductive immunology 28.2 (1992): 85-89.
- Sharkey, David J., et al. “Seminal fluid induces leukocyte recruitment and cytokine and chemokine mRNA expression in the human cervix after coitus.” The Journal of Immunology 188.5 (2012): 2445-2454.
- Kelly, R. W., and H. O. Critchley. “Immunomodulation by human seminal plasma: a benefit for spermatozoon and pathogen?.” Human Reproduction 12.10 (1997): 2200-2207.
- Robertson, Sarah A., et al. “Transforming growth factor β—a mediator of immune deviation in seminal plasma.” Journal of reproductive immunology 57.1 (2002): 109-128.
- Larsen, Margit Hørup, et al. “Human leukocyte antigen-G in the male reproductive system and in seminal plasma.” Molecular human reproduction 17.12 (2011): 727-738.
- Liu, Chaodong, Xian-Zhong Wang, and Xin-Bo Sun. “Assessment of sperm antigen specific T regulatory cells in women with recurrent miscarriage.” Early human development 89.2 (2013): 95-100.