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In which cases are immunology tests recommended? When and how are they performed?
Immunology tests are appointed after a consultation with clinical immunologist in cases where it is impossible to achieve pregnancy, repeated miscarriages or pregnancy complications.

In cases of impossibility to achieve pregnancy and recurrent miscarriages, the immunology tests include both blood and endometrium parameters. After achieving pregnancy, monitoring of the immune indicators is performed using peripheral blood samples.

Indicators

Indicators of cell immunity

Immunophenotyping of lymphocyte populations, determination of Treg cells, determination of CD34 stem cells; functional cell tests – for cell activity and proliferation.

Indicators of humoral immunity

Serum immunoglobulins, complement fractions, autoantibodies.

Indicators of tissue compatibility

Cross-match reaction through flow cytometry.

Endometrial implantation indicators

Immunophenotyping of endometrial cells from biopsy material through flow cytometry -

Serum factors of angiogenesis - PlGF, sFLT-1

Immunology tests – in case of inability to conceive and in recurrent miscarriages

The inability to conceive is frequently related to problems causing rejection of the embryo, in many cases before the pregnancy is detected even by the most sensitive tests. Approximately 15-20% of all pregnancies end up in a miscarriage and the risk increases with each subsequent miscarriage. American Society for Reproductive Immunologyspecifies five scientifically proven causes for a miscarriage: infections (1%), anatomical defects (5-10%), hormonal disorders (20%), chromosome defects (7-50%), immunology reasons (50%); in about 15% of the cases no reason can be revealed.

Until the last decade, nothing could be done to help such couples where no anatomical or chromosomal defects, or hormonal disorders were detectable. New researches proved that immunological factors play a role in about 80% of those so called "unexplained" cases, and new therapeutic approaches allow full-term pregnancy in more than 80% of these cases.

Immunological problems fall into the category of causes related to the environment where the pregnancy occurs. The possibility of a successful pregnancy depends to a great extent on the complex interaction of complicated immunological attitudes aimed at making the uterus an adequate environment for the development of the embryo, the growing fetus and the placenta. Sometimes these immune mechanisms can proceed in the wrong direction and depending on how or when this happens, a woman may miscarry or she cannot get pregnant, or cannot conceive after an IVF.

The immune system - one of the most complicated and complex systems in the body

The immune system is one of the most complicated and complex systems in the body that functions as a first defense line against antigens. Antigens are proteins on the cell surface that identify the cell as "self" or "non-self". The immune system differentiate proteins as self and non-self, it neutralizes or destroys the non-self ones by an immune response, thus preserving the homeostasis of the body.

The immunological problems associated with recurrent miscarriages and implantation failure are caused by disorders in the antibody response, which fall into two categories:autoimmune and alloimmune. Autoimmune is the immune response of the mother to the pregnancy. In autoimmune disorders the woman rejects her own proteins, i.e. she accepts them as occurring disease and the auto-antibodies are antibodies that attack her own antigens. In alloimmune disorders the mother responds with an immune response to the genetic components of the father during the pregnancy, i.e. she rejects the proteins of the man. Both disorders can be identified through blood tests.

Autoimmune factors

There are a variety of autoimmune disorders that can lead to recurrent miscarriages or to failure of implantation: antiphospholipid antibodies, antithyroid antibodies, antinuclear antibodies. Approximately in 30% of women with the so called "unexplained" recurrent miscarriages, the blood tests show an autoimmune problem. A woman can have one or more of these disorders.

Antiphospholipid antibodies

In pregnancy, phospholipids act as adhesive that keeps together dividing cells and are necessary for the growth of the placenta in the uterine wall. They also filter the nutrition medium from maternal blood to the fetus, as well as the waste substances from the fetus through the placenta. The antibodies themselves do not cause miscarriages, but their presence indicates that an abnormal autoimmune process can lead to impaired function of phospholipids, and hence the risk of a miscarriage, intrauterine fetal growth retardation and preeclampsia.

A panel of tests for detection of IgG, IgM and IgA isotypes of antibodies against seven phospholipids is recommended: anticardiolipin, phosphoethanolamine, phosphoinositol, phosphatidic acid, phosphoglycerol, phosphoserine, phosphocholine. A positive test for one or more of these types of antiphospholipid antibodies is an indication that the woman has an immune response which can cause recurrent miscarriages. For a definite detection of the presence of antiphospholipid antibodies, it is necessary to establish the persistence of positive levels by repeating the test after 6-8 weeks. As some women become positive only after they become pregnant, a second testing in the early period of pregnancy in women with a history of recurrent miscarriages is recommended.

When applying an appropriate treatment in women with antiphospholipid antibodies, successful outcome of the pregnancy is achieved in 70-80% of the cases.

Antinuclear antibodies

Antinuclear antibodies (ssDNA, dsDNA, Sm, RNP, SS-A, SS-B, Scl-70, Jo-1, Histone) react against normal components of the cell nucleus. They are found in a number of immunological diseases such as systemic lupus erythematosus, progressive systemic sclerosis, Sjögren's syndrome, dermatomyositis, rheumatoid arthritis, etc. A positive test for the presence of antinuclear antibodies is an indication that the woman probably has an autoimmune process which may cause disturbances in the development of the placenta and lead to early pregnancy loss.

Antithyroid antibodies

Women with elevated thyroid antibodies (Anti-TG Ab and Anti-TPO Ab) are subject to twice as greater risk of a miscarriage compared to those where these are absent. Testing with highly sensitive tests for the presence of these antibodies is mandatory in women with a history of two or more miscarriages or with an abnormal thyroid function.

Treatment of autoimmune risk factors

Treatment of autoimmune risk factors includes treatment regimens with low doses of heparin, corticosteroids and/or aspirin. Another method used successfully in recent years is the intravenous administration of high doses of immunoglobulin (IVIg). An adequate therapy can lead to a successful pregnancy in over 70% of women with immune disorders.

Alloimmune factors

There are two possible reasons for alloimmune response that lead to pre-term loss of the fetus: either the immune system does not recognize the pregnancy or the woman is develops an abnormal immune response to the pregnancy.

In the early stages of the pregnancy, the immune system of the mother receives signals from the fetus, some of which are genetically inherited by the father. Some of these signals are due to the difference between maternal and paternal antigens on the white blood cells, the so called HLA antigens, which are specific for each individual, and the fetus inherits half of mother’s and half of father’s antigens. When a woman becomes pregnant, her immune system usually recognizes father’s antigens as non-self and can form circulating cytotoxic antibodies. Recurrent miscarriages and chorioamnionitis are associated with the presence of such antibodies. The presence of circulating cytotoxic HLA antibodies can be detected by flow cytometric test (cross-match reaction). Treatment is required when such antibodies are detected.

Natural killer cells

Natural killer cells or NK cells are a population of lymphocytes that mediate the cytotoxic activity against malignant, virus-infected cells and produce immune-active substances, the so called cytokines in immune stimulation. In pregnancy, a specific NK cells population (CD3-CD16-CD56+) in the placenta contributes to cell growth, secretes growth molecules for the placenta and reduces local immune response at the border of maternal body and the placenta. Conversely, another population of NK cells (CD3-CD16+CD56+), when activated by IL-2 is cytotoxic to the placental trophoblast. These cells secrete tumor necrosis factor (TNF), which can destroy the placenta. Women with over 12% of CD16+CD56+ NK cells are at higher risk of miscarriage and embryo implantation failure.

The percentage of NK cells is determined via flow cytometric immunophenotyping. Women with high activity of NK (CD16+CD56+) cells respond well to therapy with intravenous immunoglobulin (IVIg) - over 90% efficiency.

Immunophenotyping of endometrial cells from biopsy material

NK cells are the primary lymphocyte population (up to 70%) in the uterine lining during implantation and in the early period of the pregnancy. They produce immunoregulatory cytokines and play a major role in the regulation of the maternal immune response to fetal allograft, the implantation and the maintenance of the pregnancy.

Decidual NK cells are separated into 2 subpopulations that play a different role in the trophoblast migration process and the implantation. In early period of pregnancy, 56+bright16- NK cells that are prevalent (up to 99%) in a normal pregnancy, release Th2 associated cytokines which assist implantation and play a major role in the regulation of the normal trophoblastic migration and the implantation.

The proper function of NK cells in the endometrium is an integral part of any successful pregnancy. Therefore it is necessary to monitor peripheral NK cells and subpopulations up to the 6-th lunar month.

LIF (leukemia inhibitory factor) and its gp130 receptor

LIF (leukemia inhibitory factor) and its gp130 receptor have important functions for the development of the blastocysts and the implantation. The endometrium of infertile women produces significantly less LIF during the implantation period, as well as a lower gp130 expression.

Expression of Mucin 1 (MUC1) in the endometrium is essential during the implantation period.

Autologous peripheral blood mononuclear cells (PBMC) for local immunomodulation in women with reproductive problems are used to induce endometrial differentiation and to facilitate the process of implantation of the embryo into the uterus.

Serum factors of angiogenesis

Improper development and function of the placenta are at the core of a number of complications during pregnancy, such as preeclampsia, eclampsia, fetal growth retardation, premature birth or stillbirth. The placental development is carried out by coordinating a set of processes of the angiogenesis. Disturbance in these processes may lead to decrease in blood flow to the fetus, increased blood pressure of the mother and premature birth. Therefore, biomarkers of angiogenesis have been proposed as potential predictors of pregnancy outcome.

Soluble tyrosine kinase (sFlt-1) is an anti-angiogenic protein inhibiting vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). In the course of a normal pregnancy the levels of sFlt-1, PlGF and the sFlt-1/PlGF ratio in the serum of the mother vary within a certain normal range for each gestation week. Deviations in the levels of circulating sFlt-1 and PlGF, along with the conventional methods for monitoring the pregnancy allow the gynaecologist to diagnose and prevent, by adjusting the therapy, any unwanted complications before the onset of their clinical symptoms.

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