Immunological causes of miscarriage

For several decades, with the emergence of new methodological possibilities in immunology, the problem of immunological relationships between the mother and the fetus is given the closest attention. Numerous theories of immunological tolerance during pregnancy have been discussed in the literature, but this issue has not been finally resolved. Without dwelling on this, an extremely important aspect of pregnancy, let's try to summarize the literature data and our own concerning the immunological aspects of miscarriage.

Immunological aspects distinguish autoimmune and alloimmune.

Autoimmune reactions are directed against the mother's own tissues, and the fetus suffers again, either from the reaction of the maternal organism to autoantibodies or from the identity of the antigens to which the mother has autoantibodies. An example of such autoimmune interactions is transient thrombocytopenia of newborns, diffuse-toxic goiter, myasthenia gravis, systemic lupus erythematosus and other autoimmune diseases and conditions in which an unfavorable obstetric anamnesis precedes the development of a clinic for autoimmune disease for many years. An example of such an autoimmune condition is the antiphospholipid syndrome, in which antibodies to phospholipids (AFA) that interfere with phospholipid-dependent coagulation are detected in the blood, without inhibiting the activity of specific coagulation factors. The pathogenetic effect of AFA is associated with the development of recurrent, thromboembolic states.

An example of alloimmune influences is hemolytic disease of newborns due to Rh or ABO sensitization, or with sensitization to other red cell antigens Kell, Duffy, Pp, etc. Another example of alloimmune disorders is the termination of pregnancy due to the fact that the mother can not develop antibodies, Protecting the fetus from its immune aggression, due to compatibility of spouses by the HLA system

On all these issues there is a huge literature, but the positions of some authors are rejected by the data of other researchers. Randomized studies on the importance of certain immunological aspects of miscarriages and various therapies are practically absent.

Features of the immune status in patients with habitual miscarriage

Given the data of the virological and bacteriological examination, it seems that such a persistence is connected with the peculiarities in the immunity system of this patient population. Extremely many studies on this topic, but there are practically no unambiguous results.

The overall assessment of absolute indices of cellular immunity in women with habitual miscarriages and persistent mixed viral infection did not reveal significant differences in these parameters from normative ones.

With a more detailed individual assessment of the indices of the cellular immunity, changes were found in almost every woman. The total number of CD3 + corresponded to the normal level in only 20%, in 50% it was reduced, and in 30% - increased. Almost all women had a change in the number of CD4 +: 47.5% - reduced, and 50% - increased. In 57.5% of women, CD8 + was decreased, in 20% significantly elevated, and in 22.5% corresponded to normative parameters. As a result of these changes, in 30% of women, the immunoregulatory index (CD4 + / CD8 + ratio) was increased and amounted to 2.06 ± 0.08, and in 60% it was reduced to 1.56 + 0.03 and only 10% of women had within the limits of the norm. The content of natural killers CD16 + was within the norm only in 15% of women, significantly reduced in 50% and increased in 35%. The number of CD19 + B-lymphocytes was reduced in 45%, increased in 42.5% of women with habitual miscarriage.

Thus, in the study of the cell link of immunity in all women with habitual miscarriage, changes in the cellular immunity level were revealed in the direction of decreasing all indices.

Comparative analysis of the results of the study of relative indices of lymphocyte subpopulations revealed more significant changes than in the previous group. A statistically significant decrease in CD3 + content was detected. Immunoregulatory subpopulations CD4 +. CD8 +, their total value was within the normal range, as in the control group. However, when comparing them with each other, there was a significant decrease in the relative content of T-helper and T-suppressors in women with habitual miscarriage. The immunoregulatory index was within the norm. The relative content of natural killers (CD16 +) in general in women with habitual miscarriage was higher than normative data. The content of B-lymphocytes was within the normal range.

Thus, a structural analysis of the subpopulation composition of peripheral blood lymphocytes showed abnormalities in more than 50% of women in the direction of reducing T-lymphocyte, T-helper and T-suppressor content and increasing the content of natural killers in almost half of the women in the study group.

Studies of humoral immunity did not reveal any differences from the regulatory parameters. The revealed changes in immune processes at the systemic level as a whole can be characterized as signs of moderately expressed secondary immunodeficiency.

From the foregoing it becomes clear that systemic changes in the cellular and humoral links of the immune system can not be regarded as determining factors affecting the course of the gestational process and its outcome. There is a need to search for new more sensitive tests than indicators of the subpopulation composition of lymphocytes, which could become markers of the functional state of cells of the immune system. In the regulation of inflammatory response, including chronic, mediators of intercellular interactions play a central role - cytokines.

Among the immunological causes of miscarriage in recent years are the activation of CD19 + 5 + cells, the main purpose of which is associated with the production of autoantibodies to hormones that are crucial for the normal development of pregnancy: estradiol, progesterone, chorionic gonadotropin.

The normal level of CD19 ⁺ 5 ⁺ cells is from 2 to 10%. The level above 10% is considered pathological. With pathological activation of CD19 + 5 +, due to the increased content of autoantibodies to hormones, the patients are deficient in luteal phase, inadequate response to ovulation stimulation, "resistant ovaries" syndrome, premature "aging" of the ovaries and premature menopause. In addition to directly influencing the listed hormones in the pathological activity of these cells, there is a lack of preparatory reactions for implantation in the endometrium and decidual tissue. This is expressed in decidual inflammation and necrosis, in violation of the formation of fibrinoid and excessive deposition of fibrin. There is a slow increase in chorionic gonadotropin, damage to the yolk sac, subchorial hematomas during pregnancy.

For more than 20 years, according to the WHO program, studies have been conducted aimed at creating an acceptable contraceptive vaccine based on chorionic gonadotropin. To successfully create the vaccine, it was necessary to solve the problems associated with low immunogenicity of the chorionic gonadotropin molecule and high cross-reactivity with molecules of LH, TSH, FSH. Two mechanisms of action of a vaccine based on chorionic gonadotropin are described. First, the binding of antibodies to the chorionic gonadotropin leads to a disruption in the interaction of the hormone with the receptor, which leads to a regression of the yellow body and to the expulsion of the blastocyst. Secondly, antibodies to the chorionic gonadotropin are able to enhance the antibody-dependent cytotoxicity of T-lymphocytes, directed at trophoblast cells producing chorionic gonadotropin. However, the vaccine for chorionic gonadotropin was found to be ineffective due to cross-reactivity with gonadotropic hormones and primarily with LH. There was an attempt to create a vaccine based on the production of antibodies to the beta subunit of chorionic gonadotropin, which determines the unique biological activity and immunological specificity of this hormone. The effectiveness of a vaccine based on chorionic gonadotropin is quite high. According to TalwarG. Et al. (1994), with titer of antibodies to chorionic gonadotropin more than 50 ng / ml in 1224 cycles, only one pregnancy was noted. Fertility was restored with antibody titer below 35 ng / ml. However, the vaccine did not find use, because to maintain a certain titer of antibodies it is necessary to introduce chorionic gonadotropin 3-5 times a year; almost monthly monitoring of the level of antibody titer is required; the cross-development of hypothyroidism with long-term use of the vaccine, cross-reacting of chorionic gonadotropin and TSH, autoimmune aggression against cells containing receptors for chorionic gonadotropin in ovaries, fallopian tubes has been reported. Data on the course of pregnancy after use of the vaccine in animal and female experiments are very few and contradictory.

Antibodies to chorionic gonadotropin were detected using gonadotropins in the treatment of infertility and in IVF programs. According to Sokol R. Et al. (1980), in the course of 3 courses of treatment with drugs with chorionic gonadotropin, the development of resistance to the therapy was established. At the same time, antibodies with greater tropicity to the chorionic gonadotropin, LH and lower to FSH were detected. Baunstein G. Et al., (1983), after using menopausal gonadotropin and chorionic gonadotropin to treat infertility in the serum of women, found antibodies with low affinity and high specificity for the chorionic gonadotropin. It has been suggested that these antibodies can lead to subclinical abortions, which is masked in the form of infertility of an unknown genesis.

According to Pala A. Et al. (1988), antibodies to chorionic gonadotropin were determined for several months after spontaneous abortion. The study noted that antibodies to the chorionic gonadotropin may interfere with the formation of the hCG receptor complex and block its biological effect. According to Tulppala M. Et al. (1992), antibodies to the chorionic gonadotropin are detected after abortions - spontaneous and artificial. The authors note that these antibodies were not inhibited by the addition of chorionic gonadotropin, and with artificial vaccine sensitization, the antibodies are inactivated by the addition of chorionic gonadotropin; In addition, they believe that the presence of antibodies to the chorionic gonadotropin does not necessarily lead to miscarriage.

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