The interface between the reproductive and immune system is an important one that I have studied for years and was trained in by the late Prof Alan Beer of Chicago.
The interface between these two systems is controlled by several mechanisms and pathways.
When defects in these mechanisms happen, they can result in pathological conditions in reproduction. That can manifest in pregnancy and also in gynaecology in the form of various conditions.
Within the mechanisms of immunology and related obstetric complications, a vital role is played by natural killer (NK) cells and T cells, as well as other cells, such as dendritic cells and B cells, which are important both in the establishment and maintenance of pregnancy. While uterine NK cells have a role in implantation, an imbalance of NK Cells and T cells can lead to miscarriage, female infertility and embryonic implantation restriction.
Trophoblast invasion and immunological evasion
Uterine NK cells are lymphocytes belonging to the broader natural killer cell lymphocyte class. However, uterine natural NK cells have a unique phenotype. As the predominant uterine immune cell, uterine NK cells peak at the time of embryonic implantation.
Many hypotheses have been proposed to explain the mechanisms of maternal-foetal immune tolerance with the trophoblast and placenta being the main targets for immunological attack. For successful embryonic implantation into the luminal epithelium of the endometrium, trophoblast cells invasion is essential. The presence of uterine cells around the extravillous trophoblast is also important. Invading trophoblasts establish uteroplacental circulation and further invade the endometrial spiral arteries requiring a cooperation with uterine NK cells as the foetal trophoblast cells come into maternal contact.
This process of uterine invasion of the extravillous trophoblast cells is well balanced and finely controlled. There are delicate interactions at the implantation site with uterine NK cells, macrophages and CD3-T cells. The balance of pro-inflammatory cytokines and chemokines controls the extent of trophoblast infiltration and ultimately determines reproductive success. Over-invasion of the trophoblast endangers the mother, while under-invasion leads to reproductive failure or complications.
Another finely balanced relationship for controlled resolution of the inflammatory process at the implantation site is that of embryonic related apoptotic cell clearance by maternal macrophages with paternal allo-antigen release. Further to this, immune evasion also occurs through the destruction of tryptophan from maternal T cells. Indoleamine 2,3-dioxygenase (IDO) causes a drop in tryptophan thereby protecting the foetus through substantial T-cell suppression.
Others include: modulation of maternal decidual NK cells through classical and non-classical human leukocyte antigens (HLA-G, HLA-E, HLA-C), which bind to NK cell receptors to inhibit uterine NK target killing of trophoblast cells; immunogenetic factors involving MHC genes or genetic regions which confer protection to the foetus; maternal recognition of paternal allo-antigens allowing pregnancy and establishment of the placenta; the role of male antigens themselves as well as seminal plasma in inducing a tolerant environment and preparing for implantation; immune-modulatory proteins such as early pregnancy factor that protect the pregnancy; and the role of hormones (HCG and progesterone) which both increase in early pregnancy and have immune-suppressive properties.
Miscarriages and other complications
In a remarkable series of events, implantation and placental development occur connecting the embryo with the mother. The invading trophoblast expresses paternal proteins and interacts directly with the maternal immune system, but uses several mechanisms to avoid rejection. There is active bidirectional dialogue between the embryo, trophoblast and immune system cells. A balanced interaction results in a successful pregnancy.
Recurrent miscarriage occurs in 2 to 5% of women of reproductive age and is defined as two or more consecutive pregnancy losses. It has long been recognised that the preimplantation endometrium shows increased numbers of uterine NK cells in women with idiopathic recurrent miscarriage and high numbers of uterine NK cells in women with recurrent miscarriage have also been linked to miscarriage in subsequent pregnancy. There is evidence linking both T Helper cell 1 and T Helper cell 2 to pregnancy loss, with high TH1 cytokines and low TH2 cytokines both seen in recurrent miscarriage patients.
Various pathways and mechanisms involving TH1 bias, cytokine networks imbalance, NK cell and T cell imbalance and immunogenetic and hormonal factors are involved.
Preeclampsia and premature labour and IUGR have also been linked to NK cells. There are modifying factors involved in preeclampsia including various cytokines, proteins and growth factors. Placental oxidative stress may lead to increased shedding of necrotic syncytiotrophoblast debris in the maternal circulation leading to the production of pro-inflammatory cytokines.
Moreover, dominant TH1 immune responses have been linked to premature labour subgroups as have innate immune responses to microorganisms at the maternal-foetal interface through the expression of Toll-like receptors (TLR).
At Sydney Reproductive Immunology we provide complete innovative testing for immune reproductive interactions and offer a tailored monitoring and whole range of treatments as appropriate to individual patients.
The following are examples of conditions we cater for and treat at our Sydney Reproductive Immunology Specialised Centre:
Repeated implantation failures and IVF failures
Repeated pelvic and vaginal infections
High risk pregnancy with complications or history of complications such as preeclampsia, IUGR, stillbirth, pregnancy loss in mid trimester
Patients with autoimmune conditions such as Crohn’s Disease, ulcerative colitis, MS, rheumatoid arthritis, SLE etc who are pregnant or considering pregnancy.
Associate Professor Gamal Matthias is an Obstetrician and Gynaecologist and Reproductive Immunologist and Fertility Specialist who has trained and worked in England, USA and Australia.
Having trained under Professor Alan Beer, A / Prof Matthias introduced learned concepts and reproductive immunology services with the formation of Sydney Reproductive Immunology in 1995.
A / Prof Matthias delivers high risk obstetric patients. He provides specialist care for women with reproductive immune issues, endometriosis, PCOS and sub fertility. He performs advanced laparoscopic and hysteroscopic surgery.
A / Prof Matthias also provides subspecialised services for women who suffer miscarriages, repeated IVF failures, pregnancy loss and other fertility conditions.
A / Prof Matthias’ wide experience ensures safety and choice for women. He is heavily involved in training medical students, registrars and new specialists. His gynaecology interests include gynaecology, laparoscopic, pelvic floor surgery, colposcopy and gynaecological endocrinology.
A / Prof Matthias has academic and research interests and has authored several publications. He lectures widely on reproductive immunology both nationally and internationally. A / Prof Matthias is a Senior Examiner with the Australian Medical Council.
A / Prof Matthias has rooms in Miranda and Condell Park and operates regularly at Hurstville Private Hospital.
T (02) 9709 4700
83 Gallipoli Street
Bankstown, NSW, 2200
Suite 7 / 26-28
Miranda, NSW, 2228
1. Matthias G. Immune interactions and tolerance between mother and embryo. An overview of mechanisms and related obstetric complications. O&G Magazine. The Royal Australian College of Obstetricians and Gynaecologists. Vol 9 No 4 Summer 2007.