Reproductive immunology

Pregnant women experience many physiological changes before implantation of the early embryo (blastocyst) takes place. Ovulation, copulation, and fertilization directly or indirectly induce dramatic changes in uterine physiology that resemble classical inflammation at the mucosal surfaces of the female reproductive tract, and it is quite likely that these changes impact the maternal immune system well before the blastocyst implants in the uterus. Consequently, the outcome of the immune response differs during pregnancy, when compared to outcomes in nonpregnant women. Thus, the uterus may be preconditioned to accept the blastocyst.

Blastocyst implantation is a crucial point in the process of reproduction because it is the moment of highest spontaneous embryo loss for humans. It is characterized by the invasion of trophoblastic cells in the maternal decidua, a mucosal tissue derived from the endometrium. Antigenically, the fetus and placenta have half of the histocompatibility genes because of the paternal origin of the conceptus. The reasons why the fetus and placenta are accepted by the maternal immune system are still largely unknown. It is, however, a harmonic equilibrium among maternal cells of the immune system. Originally, British immunologist Peter Medawar proposed three broad hypotheses to explain the paradox of maternal immunological tolerance to the fetus: (a) physical separation of mother and fetus; (b) antigenic immaturity of the fetus; and (c) immunologic inertness of the mother. At the present time, several factors have been included in the mechanisms of fetal protection: (1) general aspecific immunosuppression due to hormonal and proteic patterns of pregnancy, (2) reduced fetal immunogenicity by alteration of expression of fetal MHC antigens by placental trophoblast cells, (3) IgG production toward paternal lymphocyte antigens and toward maternal lymphocytes (blocking antibodies), also called trophoblast-lymphocyte cross-reactive antigens (TLX) for their cross reactivity with antigens of the trophoblast. These blocking antibodies could bind and protect fetal antigens from maternal lymphocytes, and (4) modification of the cellular mediated response driven by cytokines . Cytokines are produced in the feto-placental unit and have a positive activity on the development of pregnancy.

Spontaneous human fetal loss is a significant clinical problem. Studies on recurrent spontaneous abortion syndromes are dominated by suggestions of immunologic causation. This evidence includes genetic (epidemiological) analyses, anatomical, physiological, and evidence for cytokine dysregulation linked to inappropriate activation of the innate and adaptive immune systems during human pregnancy. However, it is difficult to discriminate whether abnormalities of pregnancies are causes or effects of immune dysfunction.

Autoimmunity is defined as the pathologic condition where humoral or cellular immune response is also directed against self-antigens, leading to severe and debilitating clinical conditions. Systemic autoimmune conditions such as systemic lupus erythematosus (SLE) are associated with higher risk for pregnancy loss. In the general population, about 15% of clinical pregnancies are spontaneously aborted, and about 50% of fertilized eggs fail implantation as a blastocyst. The higher rate of fetal loss in women with SLE occurs in association with antiphospholipid antibodies (aPL), which are also associated with miscarriage in otherwise healthy women. Clinical relevance is also given to lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and antinuclear antibodies (ANA). These are associated with several medical conditions the description of which is beyond the aim of this article.

Association of LAC with recurrent miscarriage has been described in the past twenty years. The lupus anticoagulant test (LAC) is a clotting time test used to detect women's antibodies against components of the blood clotting system, such as negatively charged phospholipids or prothrombin. These antibodies cause a prolongation in the clotting time.The aCL test measures 3 different species of antibodies to the phospholipid cardiolipin. This test is essentially an antiphospholipid antibody test, with all features similar to those of the aPL. ANA are antibodies against one or more elements within a biological cell, involved in the machinery of translating genomic message into proteins. These antibodies can destroy cells, and their effect usually leads to SLE.

When the immune system is the cause of miscarriage, the mother has a 30% chance of having a successful pregnancy without intervention after three miscarriages, a 25% chance after four miscarriages, and a 5% chance after five miscarriages. More epidemiological studies report a 90% chance of failure in untreated patients, whereas, in the presence of aPL, a 70% chance of reproductive failure was reported. Prevalence of LA in women with recurrent miscarriage has been quoted in a range between five and fifteen percent of fetal loss. Pathogenesis of fetal loss in the presence of aPL includes the presence of extensive infarction and necrosis in the placenta due the recurrent thrombosis of the placental vascular bed. In particular, intraluminal thromboses of the uterine spiral arteries and necrotizing decidual vasculopathy, histologically characterized by fibrinoid necrosis, atherosis, and intimal thickening have been observed.

Among immune system causes of miscarriage are the inability to properly detect fetal antigens and the lack of producing blocking antibodies. Another cause is maternal production of anti-sperm antibodies (IgG and IgA).

Endometriosis is a disease in which abnormal endometrial tissue grows in the abdomen and other places in the body. It causes internal bleeding, inflammation, scarring, severe pain, fatigue, and sometimes infertility. Endometriosis is related to the functional deficit of NK cells and cytoplasmic granules of cytotoxic lymphocytes (CTL) that allow the development of autoantibodies. In premature ovarian failure, autoantibodies against ovarian tissue and against gonadothropin receptors have been found. Oocyte reduction has been detected in women affected with premature ovarian failure.

Several male factors can influence the ability of successful fertilization, including the presence of male anti-sperm antibodies (IgG and IgM) that bind to the surface of the spermatozoa and may mask receptors or other functionally important proteins, thus interfering with the sperm-egg interaction, and reducing the probability for successful fertilization. Male anti-sperm antibody production is more likely to occur after vasectomy, or with undescended testicles, or epididymitis.

See also Autoimmunity and autoimmune diseases; Immunochemistry; Immunologic therapies; Immunological analysis techniques