Immunologic causes of non-pregnancy

For several decades, with the emergence of new methodological possibilities in immunology, the problem of immunological mother-fetus relationships has received 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 extremely important aspect of pregnancy, we will try to summarize the literature data and our own regarding the immunological aspects of miscarriage.

Among the immunological aspects, a distinction is made between autoimmune and alloimmune.

Autoimmune reactions are directed against the mother's own tissues, and the fetus suffers secondarily, either from the mother's reaction to autoantibodies, or from the identity of the antigens to which the mother developed autoantibodies. Examples of such autoimmune interactions are transient thrombocytopenia of newborns, diffuse toxic goiter, myasthenia, systemic lupus erythematosus and other autoimmune diseases and conditions in which an unfavorable obstetric history precedes the development of the clinical picture of the autoimmune disease by many years. An example of such an autoimmune condition is antiphospholipid syndrome, in which antibodies to phospholipids (APA) are detected in the blood, preventing phospholipid-dependent coagulation without inhibiting the activity of specific coagulation factors. The pathogenetic effect of APA is associated with the development of repeated thromboembolic conditions.

An example of alloimmune effects can be hemolytic disease of the newborn due to Rh or ABO sensitization, or sensitization to other erythrocyte antigens Kell, Duffy, Pp, etc. Another example of alloimmune disorders is termination of pregnancy due to the fact that the mother cannot produce antibodies that protect the fetus from her immune aggression, due to compatibility of the spouses according to the HLA system.

There is a huge literature on all these issues, but the positions of some authors are rejected by the data of other researchers. Randomized studies on the significance of certain immunological aspects of miscarriage and different treatment options are practically absent.

Features of the immune status in patients with habitual miscarriage

Taking into account the data of virological and bacteriological examination, it seems that such persistence is associated with the peculiarities of the immune system in this contingent of patients. There are an extremely large number of studies on this topic, but there are practically no unambiguous results.

The total assessment of absolute indices of cellular immunity in women with habitual miscarriage and persistent mixed viral infection did not reveal any significant differences between these indices and the normative ones.

A more detailed individual assessment of the cellular immunity indicators revealed changes in almost every woman. The total CD3+ count corresponded to the normal level only in 20%, in 50% it was decreased, and in 30% it was increased. Almost all women had changes in the CD4+ count: in 47.5% it was decreased, and in 50% it was increased. In 57.5% of women, CD8+ was decreased, in 20% it was significantly increased, and in 22.5% it corresponded to the standard 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 decreased and amounted to 1.56+0.03, and only in 10% of women it was within the normal range. The content of natural killers CD16+ was within the normal range only in 15% of women, significantly reduced in 50% and increased in 35%. The number of B-lymphocytes CD19+ was reduced in 45% and increased in 42.5% of women with habitual miscarriage.

Thus, when studying the cellular link of immunity in all women with habitual miscarriage, changes in the cellular link of immunity were revealed towards a decrease in all indicators.

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 the CD3+ content was revealed. Immunoregulatory subpopulations CD4+.CD8+, their total value was within the normal range, as in the control group. However, when comparing them with each other, a significant decrease in the relative content of T-helpers and T-suppressors was seen in women with habitual miscarriage. The immunoregulatory index was within the normal range. The relative content of natural killers (CD16+) in women with habitual miscarriage was generally higher than the normative data. The content of B-lymphocytes was within the normal range.

Thus, the structural analysis of the subpopulation composition of peripheral blood lymphocytes showed deviations from the norm in more than 50% of women towards a decrease in the content of T-lymphocytes, T-helpers and T-suppressors and an increase in the content of natural killers in almost half of the women in the study group.

Humoral immunity studies did not reveal any differences from the normative parameters. The revealed changes in immune processes at the systemic level can generally be characterized as signs of moderate secondary immunodeficiency.

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

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

The normal level of CD19 ⁺ 5 ⁺ cells is from 2 to 10%. The level above 10% is considered pathological. In case of pathological activation of CD19+5+ due to increased content of autoantibodies to hormones, patients experience luteal phase deficiency, inadequate response to ovulation stimulation, “resistant ovary” syndrome, premature “aging” of the ovaries and premature menopause. In addition to the direct effect on the listed hormones, pathological activity of these cells is accompanied by insufficient reactions in the endometrium and decidual tissue preparatory to implantation. This is expressed in decidual inflammation and necrosis, disruption of fibrinoid formation and excessive fibrin deposition. During pregnancy, a slow increase in chorionic gonadotropin, damage to the yolk sac, and subchorionic hematomas are observed.

For over 20 years, studies have been conducted in accordance with the WHO program to create an acceptable contraceptive vaccine based on human chorionic gonadotropin. To successfully create a vaccine, it was necessary to solve the problems associated with the low immunogenicity of the human chorionic gonadotropin molecule and high cross-reactivity with LH, TSH, and FSH molecules. Currently, two mechanisms of action of the human chorionic gonadotropin-based vaccine have been described. First, the binding of antibodies to human chorionic gonadotropin disrupts the interaction of the hormone with the receptor, which leads to regression of the corpus luteum and blastocyst expulsion. Second, antibodies to human chorionic gonadotropin are capable of enhancing antibody-dependent cytotoxicity of T-lymphocytes directed at trophoblast cells producing human chorionic gonadotropin. However, the vaccine to human chorionic gonadotropin was considered ineffective due to cross-reaction with gonadotropic hormones, primarily with LH. An attempt was made to create a vaccine based on the production of antibodies to the beta subunit of human chorionic gonadotropin, which determines the unique biological activity and immunological specificity of this hormone. The effectiveness of the vaccine based on human chorionic gonadotropin is quite high. According to Talwar G. et al. (1994), with a titer of antibodies to human chorionic gonadotropin over 50 ng/ml, only one pregnancy was noted in 1224 cycles. Fertility was restored with an antibody titer below 35 ng/ml. However, the vaccine has not found application, since in order to maintain a certain antibody titer, human chorionic gonadotropin must be administered 3-5 times a year; almost monthly monitoring of the antibody titer is necessary; There are reports of cross-development of hypothyroidism with long-term use of the vaccine, due to cross-reaction of chorionic gonadotropin and TSH, autoimmune aggression against cells containing receptors to chorionic gonadotropin in the ovaries and fallopian tubes. Data on the course of pregnancy after use of the vaccine in animal experiments and in women are very few and contradictory.

Antibodies to human chorionic gonadotropin were detected when using gonadotropins in the treatment of infertility and in IVF programs. According to Sokol R. et al. (1980), resistance to the therapy was established during 3 courses of treatment with drugs containing human chorionic gonadotropin. In this case, antibodies were detected that had a high affinity for human chorionic gonadotropin, LH, and a lower affinity for FSH. Baunstein G. et al. (1983) detected antibodies with low affinity and high specificity for human chorionic gonadotropin in the serum of women after using menopausal gonadotropin and human chorionic gonadotropin for the treatment of infertility. It was suggested that these antibodies may lead to subclinical abortions, which are masked as infertility of unknown genesis.

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

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