**5. Opportunistic microflora as a cause of deviations in serum content of embryotropic antibodies**

autoantibodies could lead to multiple deviations in gestation process, miscarriages and still-

A lot of wide spreading conditionally pathogenic or opportunistic viruses and bacteria does not belong to the friendly or normal microflora. These inhabitants of the human organism are the most common ground for deviations of the immune system activity and steady changes in production and serum content of embryotropic autoantibodies. Such microbial agents can activate the different clones of immune competent cells, because members of *Herpesviridae* family (Herpes simplex virus, Epstain-Barr virus, Cytomegalovirus, etc) may implement the role of co-stimulators for CD4+ Т-cells, and in their turn, lead to polyclonal activation of antibody-producing B-lymphocytes. Such intracellular bacteria as *Chlamydia, Mycoplasmae* and other, may activate B-cells directly (T-cell independent activation) by using mechanism of superantigens [Khaitov et al., 2002]. On the other hand the same microbes in one woman will induce immune deviations nearly inevitably, but in other one microbial influence will be minimal or nearly absent. This difference probably depends on individual genetic background, in particular from individual set of MHC molecules [Poletaev, 2008]. Therefore the fact of revealing of Herpes simplex viruses, Cytomegaloviruses, or *Mycoplasma hominis*, etc., by serological methods or by PCR is not the cause for obligatory prescription of treatment, but revealing of infection agents combined with induced immune changes should be. The situation provided the possibility of monitoring for antiviral or antibacterial treatment effectiveness by dynamic measuring of embryotropic autoantibodies [Poletaev, 2008]. In accordance to clinical observations in women suffered from habitual miscarriages [Serova, 2000] treatment directed to etiology can be the most effective if combined with the control on embryotropic autoantibodies in blood; and improvement of according immune parameters indicates for efficacy and sufficiency of used therapy [Serova, 2000]. failure be

Opportunistic microbial flora may induce not only abnormal immune activation, but also become direct cause of pathologic immune suppression, due to usage by microbes multiple molecular instruments for declining general activity of the immune system as important component of strategy of survival in the host-organism [Mayanskiy, 1999]. In their turn prominent maternal immune suppression may influence negatively the pregnancy development and sometimes can be fatal for the fetus [Poletaev, 2010].

Changes in serum content of autoantibodies, if appeared transitory (up to 2-4 weeks), do not influence prominently the fetus development, but long-term or constant prolonged changes may interrupts the pregnancy. Constant abnormal changes in serum content of autoantibodies is typical feature of many women with unexplained infertility (nearly 80-90% of all cases), including ones repeatedly unsuccessfully used IVF [Poletaev, 2010]. In such cases the immune anomalies can interrupt zygote implantation, as well as embryo development. Besides abnormal elevation many of maternal autoantibodies may be reason of pathology in fetus and deviations in child health, because direct action of autoantibodies, or indirectly, by mechanism of maternal immune imprinting (see below) [Lemke & Lange, 1999].

Maternal Immunity, Pregnancy and Child's Health 49

described [Poletaev, 2008]. Two dozen proteins of S100 family take part in regulation of apoptosis, and maturation of primordial nervous system (fetal) [Poletaev, 2008]. Therefore antibody-dependent disturbances of according processes may be related to some forms of malignancy, embryo death cases as well as to malformation of the nervous tube. Consequently the investigation for serum content of autoantibodies against S100 and preventive treatment in necessity should be recommended before pregnancy to each woman

with external marker signs of HPV infection (warts, condylomas with any location).

**7. Non-infection causes of immune deviations in women of fertile ages** 

individual case.

**8. Maternal immune imprinting** 

Bacterial and/or viral infection (acute as well as activation of opportunistic infection) probably is the most often reason of deviations in activity of the immune system of investigated person, monitored by changes in serum content of natural autoantibodies. However other reasons conditioned the long-term immune deviations negatively influencing upon general fertility state, conception, pregnancy course and fetal development may be also important. Tight functional interrelation and prominent mutual influences the immune and neuro-endocrine systems [Poletaev et al., 2002] provides effect of falling dominoes. Any changes in the nervous system or endocrine system will obligatory lead to functional changes in the immune system. For example stroke, or thyroidal pathology, or hypothalamic dysfunction, etc. will be accompanied by changes in production and serum content plurality of autoantibodies, sometimes prominent and long-lasting [Poletaev, 2010]. In this connection even chronic psychogenic stresses may became the reason for immune deviations, negatively influencing upon fertility state [Poletaev, 2010]. Corresponding cases may be effectively treated by specialist in psychotherapy with or without using of antidepressants or similar medicine. Different ecological pollutants also can influence upon the immune state and, mediately, the fertility of investigated patient. The same situation may be provoked by incompetent medication in a course of non-professional "selftreatment". All above mentioned factors indicate for necessity of careful analysis of patient anamnesis: clarification of the main reason(s) leading to immune deviations in observed woman may become the first step in correction of reproductive dysfunction in each

The biological meaning of a maternal organism in the development of a fetus is exclusive and maternal influences upon child's phenotype, have a priority compared to the paternal ones. It is illustrated clearly by the phenomenon of the epigenetic maternal immune imprinting of a system: Mother–Fetus–Child. The essence of this phenomenon is the "inheritance" by the child's organism many of the individual traits of the immune state of the mother, but not the father [Poletaev, 2008]. As a result, specific features of a child's immunity/autoimmunity

The adaptive meaning of maternal immune imprinting is evident. This phenomenon is responsible for the resistance acquisition against infection diseases by any newborn before the first real contact with the widespread viruses and bacteria. A more pronounced antiinfection immunity in the mother provides more potent inborn resistance against the same infection in her child [Lemke & Landor, 1999]. Observations of such kind provide the

against

become more or less an accurate copy (imprint) of the maternal immune state.

As well as opportunistic viruses and bacteria presented in woman organism may trigger for abnormal production of embryotropic autoantibodies, successful anti-microbial treatment of women with chronic infection will lead to normalization the immune parameters in most cases. It is interestingly to note that nearly 30% of recently infertile women had become pregnant during the first six months after anti-bacterial or anti-viral treatment if therapy was accompanied by normalization of serum content of embryotropic autoantibodies [Serova, 2000]. These observations indicate: some women with "unexplained infertility" in essence are fertile, and their pregnancy may happens often but interrupts at early stages (usually before diagnosing) because severe but reversible immune deviations. This deviations has been reflected and may be detected by quantitative measuring of changes in blood serum content of embryotropic autoantibodies.

Obstetricians often arise the question, which seems to be difficult: why did some women with opportunistic infection suffer from repeated miscarriages and other reproductive problems, but reproductive functions of some other women with the same herpetic or mycoplasmic infection was not disturbed? Serova [2000], and Litvak [2001] in observed patients, and Cronise and Kelly [1999] in experiments with laboratory mice show clearly: the cause of opportunistic (potentially pathogenic) microbial factor does induce systemic immune deviations, such situation is usually associated with reproductive problems. On opposite, the situation usually does not influence negatively the pregnancy course if presence of the same microbial factor has not associates with notable immune changes. These empirical data and conclusions are close to aphoristic idea of the founder of the modern microbiology Louis Pasteur: "microbe is nothing, background (that is reactivity of the host-organism) is everything" [Mayanskiy, 1999]. In this context investigation of serum level of embryotropic autoantibodies may became a useful instrument for evaluation of individual risk of pathology in pregnancy if some viruses or bacteria persist in organism of woman. Such observing is suitable for decision on necessity or its contradictions of antimicrobial treatment before planned pregnancy in each individual case.
