Reproductive immunology
Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously unexplained infertility or recurrent miscarriage.
Immune system in pregnancy
The immunological system of the mother plays an important role in pregnancy considering the embryo's tissue is half foreign and unlike mismatched organ transplant, is not normally rejected. During pregnancy, immunological events that take place within the body of the mother are crucial in determining the health of both mother and fetus. The mother must develop immunotolerance to her fetus since both organisms live in an intimate symbiotic situation. Progesterone-induced-blocking factor 1 is one of several known contributing immunomodulatory factors to play a role in immunotolerance during pregnancy.The placenta also plays an important part in protecting the embryo for the immune attack from the mother's system. Secretory molecules produced by placental trophoblast cells and maternal uterine immune cells, within the decidua, work together to develop a functioning placenta. Studies have proposed that proteins in semen may help a person's immune system prepare for conception and pregnancy. For example, there is substantial evidence for exposure to partner's semen as prevention for pre-eclampsia, a pregnancy disorder, largely due to the absorption of several immune modulating factors present in seminal fluid, such as transforming growth factor beta.
Insufficient immune tolerance
An insufficiency in the maternal immune system where the fetus is treated as a foreign substance in the body can lead to many pregnancy-related complications.- Rh disease, or Rh isoimmunization, occurs when the maternal immune system develops antibodies that recognizes fetal red blood cells as foreign. This can lead to a number of potentially dangerous consequences to the fetus including hemolytic disease due to the destruction of red blood cells, kernicterus, or even death. Treatment with anti-D immunoglobulin has been studied extensively on the prevention of Rh disease. However, there has been no conclusive evidence that treatment with anti-D immunoglobulin is beneficial to the mother or fetus when it comes to Rh isoimmunization.
- Pre-eclampsia is a disorder prevalent in 5% to 10% of all pregnancies that can lead to vascular health issues such as hypertension which can lead to other complications such as seizures, hemolytic disease, damage to the placenta, and inhibition of the growth and development of the fetus. Risk factors for pre-eclampsia include older maternal age, obesity, and history of vascular disease. Monocyte activation in pregnancy is mediated by pregnancy hormones to prevent monocytes from becoming pro-inflammatory by inducing apoptosis. However, if there is dysfunction in this process, the activation of monocytes can potentially lead to damage and dysfunction in endothelial cells, which is thought to lead to the hallmark inflammation that is seen in pre-eclampsia. Prevention for those at risk for pre-eclampsia may include calcium supplementation, Vitamin C and E supplementation, low-dose aspirin, unfractionated heparin and low-molecular-weight heparin, and magnesium sulfate. Treatment goals include lowering the mother's blood pressure using antihypertensive medications that are safe to administer in pregnancy.
- Advances in single-cell RNA sequencing have led to the discovery of new insights into how immune system dysfunction could contribute to recurrent pregnancy loss. Due to this technological advancement, individual immune cells in the uterine environment can be identified, allowing researchers to detect and identify specific cell populations. Using these methods, studies have identified that women with recurrent pregnancy loss exhibit altered patterns among their decidual natural killer cells. This includes limited supportive dNK cells as well as abnormal development among the cells. Along with that, the T-cell population in recurrent pregnancy loss display more inflammatory and cytotoxic gene expressions compared to a healthy pregnancy. Single-cell analysis has identified miscommunications between natural killer cells, T-cells and macrophages which all contribute to breaking down the maternal-fetal tolerance. These findings suggests that an imbalance between tolerance-promoting immune responses and the pro-inflammatory activity is where the cause of recurring pregnancy loss occurs. Continued advances in single cell analysis hold diagnosing and treating immune-related infertility.
- According to ESHRE guidelines, recurrent miscarriage is defined as 3 or more pregnancy losses before the third trimester and has many etiologies, including many that stem from immune dysfunction, most of which can be treated with immunosuppressive medications
- *An increase in the prevalence of antiphospholipid antibodies can be found in many recurrent miscarriage patients. However, there is no evidence that the increase in antiphospholipid antibodies harms the pregnancy, but it is thought to be indicative of immune dysfunction and proinflammatory responses in regards to the pregnancy.
- *An increase in prevalence of proinflammatory cells and natural killer cells can be found in women experiencing a miscarriage. However, there has been no evidence that the prevalence of these proinflammatory cells can predict pregnancy outcomes, including risk of a miscarriage.
- *Maternal HLA class II allele presence has been found to be potentially linked to predisposed immune attacks against male embryos. Proposed treatments for this immune dysfunction include corticosteroids, allogeneic lymphocyte immunization, intravenous immunoglobulin infusion, and tumor necrosis factor α antagonists.
Microbiology
Uterine natural killer cells
The maternal immune system, specifically within the uterus, changes to allow for implantation and protect a pregnancy from immune attack. While natural killer cells, part of the innate immune system, are cytotoxic and responsible for attacking pathogens and infected cells, one subtype, uterine natural killer cells is modified during pregnancy. Despite the fetus containing foreign paternal antigens, uNK cells do not recognize it as "non-self", so that their cytotoxic effects do not target the developing fetus. The number and type of uNK cells and receptors change during a healthy pregnancy; the uNK profile differs in an abnormal pregnancy. In the first trimester of pregnancy, uNK cells are among the most abundant leukocytes present, but the number slowly declines up until term. It has even been proposed that uNK contributes to the protection of extravillous trophoblast, important cells that contribute to the growth and development of a fetus. The uNK cells secrete transforming growth factor-β which is believed to have an immunosuppressive effect through modulation of leukocyte response to trophoblasts.KIRs and human leukocyte antigen
s are expressed by the uNK cells of the mother. Both polymorphic maternal KIRs and fetal human leukocyte antigen -C molecules are variable and specific to a particular pregnancy. In any pregnancy, the maternal KIR genotype could be AA, AB, or BB and the HLA-C ligands for KIRs are divided into two groups: HLA-C1 and HLA-C2. Studies have shown that there is poor compatibility between specifically maternal KIR AA and fetal HLA-C2, which leads to recurrent miscarriage, preeclampsia and implantation failures. In assisted reproduction, these new insights could have an impact on the selection of single embryo transfer, oocyte, or sperm donor selection according to KIRs and HLA in patients with recurrent miscarriages.Cancer and tumours in pregnancy
In both cancer and pregnancy, cells grow and divide at fast rates without being effectively targeted by the human immune system. There is a parallel immunomodulatory mechanism in pregnancy and cancer: T helper cell expression differs based on cytokine levels; in pregnancy, Type 1 is up-regulated, whereas in cancer Type 2 is up-regulated. In pregnancy, regulatory T cells allow the body to accept the fetus. Tregs perform a similar task with tumors. Cancer treatment aims to lower Treg activity, while treatment for pregnancy complications aims to increase Treg activity. This can cause complications in a person with cancer who is pregnant, since the goal is to decrease Tregs to eliminate the cancer, while that could also harm the fetus. Careful use of Treg-modifying immunotherapy is required to ensure the safety of the pregnant person and the fetus.Common in women of reproductive age, with an incidence approaching 80% by age 50, uterine fibroids are benign smooth muscle tumours. They are generally asymptomatic, although they can cause pain, sometimes severe, especially if large, or subjected to torsion or impaction. Between 10 and 30% of women with fibroids develop complications during pregnancy. While their relationship to adverse outcomes is unclear, fibroids are associated with early pregnancy bleeding and loss, premature rupture of membranes and labor, and caesarean sections.