At the time of implantation, a complex immunological interaction takes place between the embryo and immune cells of the endometrium “cross talk”. This is important for successful implantation and for continuation of the pregnancy. The interaction is done through exchange of cytokines.
Disorders of the Immune system may lead to reproductive failure at different stages of reproductive process: unexplained infertility, recurrent IVF or ICSI failures and recurrent miscarriage.
The T cells are immune cells that produce substances known as cytokines (immune molecules that control both immune and other cells). There are two types of T cells; Th1 (cytotoxic T cells) produce cytokines that pro inflammatory such as interleukin 2, interferon and tumour necrosis factor alpha (TNF ), attack cells infected by viruses and tumour cells. Th2 (helper T cells) produce cytokines that oppose the effect of ctyokines produced by Th1 (anti inflammatory)such as interleukins it also release growth factors that regulate other immune cells. Th2 and Th1 are normally in balance. In normal pregnancy the balance is tilted toward excess Th2 while excess Th1 may result in pregnancy failure.
Natural killer T cells are characterised by their expression of the cell surface antigens. All NK cells originate from stem cells in the bone marrow and after maturation will either circulate in the blood or migrate and reside in tissues such as endometrium. N K cells play an important role in protecting the body from tumors and virus infection. They distinguish these from normal cells by recognizing a surface molecules known as MHC. N K cells are activated when their surface receptor bind to this specific antigen complex with the MHC. When NK cells are activated they release cytotoxic cytokines such as tumour necrosis factor (TNF) alpha which destroy cells infected by viruses.
Antibodies are substances produced by B lymphocytes in response to pathogens such as bacteria. The antibodies circulate into the blood and body tissues. Antibodies normally protect the body from invasion by foreign bodies such as bacteria and viruses. For unknown reasons the body may develop antibodies to its own cells.
- Antisperm antibodies can be present in either or both partners. It can be present either in the blood or in the genital tract secretions such as cervical mucus and ejaculate. There are different types of antibodies e.g. IgG, IgA and IgM. Antisperm antibodies in the ejaculate will make the sperm ineffective by making them stick together and preventing them from being released. In the female, antisperm antibodies in the cervical mucous may interfere with the process of sperm transport and antibodies in the fallopian tubes may affect fertilization. The incidence in female are 1-2% in fertile women and 8-10% and in infertile women. The incidence in men are 2-4% in fertile men, 8-10% in infertile men and 20-30% in homosexual men. The cause of antisperm antibodies is unknown, but there are associations with genital infection, trauma to the testicles, varicocele, vasectomy and after reversal of vasectomy.
- DQ alpha matching in the couple: Each person inherits two DQ numbers from his or her prospective parents. A pregnancy is recognised as foreign because the fathers Human leukocyte antigen (HLA) antigen is different from that of the mother. The mother makes blocking antibodies that attach to and camouflage the placenta (protecting antibodies). If the fathers HLA is too similar to that of the mother, the embryo will not be protected because it will not be able to differentiate itself from that of the mother, leading to lack of blocking antibodies to protect the fetus and the pregnancy may fail.
- Antiphospholipids antibodies syndrome: Phospholipids are present on the cell membranes of all cells; they are glue molecules which play an important role in embryo implantation. Antiphospholipid antibodies (anticardiolipins and Lupus anticoagulant) cause the womans blood to clot quickly cutting off blood supply to the baby. Inherited thrombophilias (Factor V Leiden, prothrombin mutation, protein C, protein S, antithrombin deficiency etc) are associated with an increased risk of recurrent miscarriage and probably recurrent IVF failure .
- A mother may develop antibodies to her baby's DNA or DNA breakdown products such as ANA.
- Excess or hyperactive Natural Killer cells can damage the cells which
make the placenta and the endocrine system that produce hormones essential
for pregnancy. Some laboratories define the presence of more than 12% of NK cells in blood of woman with recurrent failed IVF as abnormal.