**Maternal Immunity, Pregnancy and Child's Health**

Alexander B. Poletaev

*P.K. Anokhin Research Institute of Normal Physiology Russian Acad. Med. Sci., Medical Research Ctr. "Immunculus", Moscow, Russia* 

#### **1. Introduction**

40 From Preconception to Postpartum

Wilcox, A.J. & Skjaerven, R. (1992). Birth weight and perinatal mortality: the effect of

Wiles, N.J.; Peters, T.J.; Leon, D.A. & Lewis, G. (2005). Birth weight and psychological

distress at age 45-51 years: Results from the Aberdeen Children of the 1950s cohort

gestational age. *Am J Public Health*, Vol. 82(3): 378-382.

study. *Br J Psychiatry*, Vol. 187: 21-8.

Why do women live longer, than men? Is gender-connected lifespan related to woman's ability to give a new life and partly depend on persistence of fetal cells in maternal tissues (microchimerism) [O'Donoghue, 2008]? On opposite side, childlessness leads to shortening of an average lifespan of women (http://www.moscowuniversityclub.ru/home.asp ?artId=5742). Some believes, that pregnancy (if happens not too often) leads to mobilizing of the biologic reserves in woman organism and improves the general health state. The phenomenon could be related to positive influence of fetal and placental trophic factors, and besides, to receiving of fetal stem-cell powerful reparative-regenerative potencies. In any case, if result of pregnancy is appearance of a new life (child) and strengthening of the woman's health and longevity, then this phenomenon principally can not be considered from viewpoint of pathology. Accordingly, it seems quite incorrect to habitual using some of "fetal invasion", "maternal aggression", or similar terms, semantically associated with rather negative (pathological) events. Normal pregnancy should not be considered from confrontational positions, because such approach distort the biological sense of pregnancy. Maternal organism does not struggle against new life, but helps embryo with implantation, growth, development and maturation of the last. Moira Howes provides refined arguments for idea that maternal immune influences upon the fetus are principally lacking of aggressiveness, because during gestation mother and fetus are in essence not two but rather one complicated organism [Howes, 2007]. Pregnancy seems to be peculiar example of mutually beneficial co-assistance of two biological systems temporally functioning in frame of united super-organism.

Ideology of this kind may became very useful for explanation of many not yet explained facets of pregnancy, including immune phenomena related to maternal-fetal interactions. First of all, we should decline an habitual attitude to the pregnancy as situation of immune conflict between mother and fetus. From such point of view any forms of mutual aggression should be considered as the pathology which may lead to pregnancy losses.

Is any absurd in this view? Hardly so. Besides we have other bright and widespread phenomena, similar to some extend. For example, any healthy human organism together with its obligatory inhabitants (permanently presented variants of normal micro-flora:

Maternal Immunity, Pregnancy and Child's Health 43

Historically, immunology emerged as a branch of applied microbiology, therefore "microbiological" approaches and accents have persisted for decades due to the fact that generations of specialists in immunology have been educated by microbiologists. From habitual (microbiological) point of view the pregnancy is a paradox. For solution of this puzzle more than half of century ago Peter Medawar proposed the hypothesis about inability to adequate recognize the "alien" fetus by the immune system of pregnant women – Medawar proposed that this phenomenon could be based upon combined mechanisms of maternal immune suppression and maternal-fetal immune tolerance [Medawar, 1953]. Unfortunately this speculation was too seriously perceived by many obstetricians as rather elevated activity of the immune system during pregnancy [Sacks et al., 1999; Kaštelan et al., 2010]. In his review Entrican specially noted, that pregnancy is accompanied by changes in different components of the immune system, but these changes should not be considered as

Evidently at early 50th Medawar could not think out of frames of traditional views – that is about activity of the immune system aimed to and restricted by searching and destruction of aliens. But now many immunologists re-evaluate the main predestination of the immune system. Nearly half of century ago Pierre Grabar proposed a homeostatic function of the immune system mediated by the natural autoantibodies [Grabar, 1968]. Some earlier, in thirtieths, an idea of the regulatory autoantibodies was mentioned by Karl Landsteiner [Landsteiner, Scher, 1936]. However the main prophet of the new immunological views became Elia Metchnikoff. He had claimed that it would be wrong to consider the immune system mainly as a gendarme of an organism. Its participation in a constant struggle Hostagainst-Parasite is no more a particular case of much more wide biological predestination of the immune system – dynamic participation in self-maintenance, self-reparation, selfoptimization, and maintenance of organism' harmony state under the constant pressure of the Environment [Metchnokoff, 1901]. Not *War but Peace* – or providing general homeostasis or "harmony" in Mechnikoff terms seems to be the main feature the immune activity [Matzinger, 2002; Poletaev, 2010]. Developing fetus is not inspected by the immune system as something hazard and does not became an object for attack in spite of evident nonselfness, but is considered by maternal organism as an object for integration. In this connection active maternal immune recognition of the fetus is an important and necessary condition for normal development of pregnancy [Howes, 2007]. In opposite side, if "the rate of recognition" of embryo and fetus by maternal immune system is too low - it may be reason for pregnancy losses. The last is typical for women with immune suppression related to different causes [Nyukhnin, 2007]. Moreover frequency of miscarriages is directly related

to intensity of maternal immune suppression [Poletaev & Morozov, 2000].

More often general immune suppression in fertile women can be induced by chronic opportunistic infections (such as *Herpes viridae, Chlamidia*, etc.), and besides – by prolonged usage of some medicines, chronic intoxications, and chronic psychogenic stresses [Poletaev, 2008]. Situation of immune suppression may be associated with incomplete or insufficient fetal recognition by maternal immune system and with pregnancy loss. Frequent miscarriages are also common for women with genetical similarities to her spouse (in cases of marriage between relatives) because excessive similarities in MHC genes between spouses do not permit maternal immune system to recognize clearly the fetal-paternal antigens [Roberts et al., 1996]. Thus (in case of similarities in MHC patterns of mother, father

signs of immune suppression [Entrican, 2002].

"domestic" microbes) also may be considered as super-organism, whose biologically antigenic components function for mutual benefit. Commensal microflora of gut play principal role in digestion and utilization of food as well as in production of vitamins [Grubb et al., 1989]. It is worth mentioning, that only allied microorganisms provide us with vitamin B12, which plays a key role in the normal functioning of the brain and nervous system, and plays great role for the formation of blood. Vitamin B12 is normally involved in the metabolism of every cell of the body, especially affecting no only DNA synthesis and regulation, but also fatty acid synthesis and energy production [Lieberman, & Marks, 2008; Zaichik, & Churilov, 2008]. Interestingly, B12 can be produced only through bacterial fermentation-synthesis in digestive tract of animals and humans [De Baets et al., 2000]. 

Today we don't know the most of important details about mechanisms and principles of coexistence with our micro-inhabitants, in spite of fact that symbiotic microorganisms compose nearly 10% of human body weight [Levinson, & Jawetz, 2000]. Fortunately, genetic and antigenic foreignness of such "components" of our body per se, does not imply obligatory mutual struggle [Pradeu T., Carosella, 2006]. Moreover, biologic non-relative organism (normal microflora and host-organism), as well as partly relative (mother and fetus) components forms a new entity – quasi-united superorganism. Of special interest is the fact, that immune system provides the main instrument not for rejection, but for peaceful and mutually useful integration of different and autonomous organisms under the guidance of alive host super-organism [Parnes, 2004].

Due to the system mother-fetus could be considered as peculiar and specialized example of super-organism there is no immunological or any other conflict between integrated components (maternal and fetal compartments) *in normal condition*. In case of united superorganism there is no "foreignness" of integrated components. Nevertheless, in some pathological situations maternal-fetal interactions can become abnormal and can lead to pathology of pregnancy development. Unfortunately obstetricians meet with such pathological cases too often, and comprehension of the main aspects of maternal-fetal interactions from immunological point of view may be practically important.

#### **2. Maternal immunity and pregnancy**

Probably up to 40% of all desired pregnancies is interrupted spontaneously during initial 1- 3 weeks after fertilization [Radhupathy, 1997]. Additionally 10-15% loss of pregnancies occurs later. Many pregnancies, interrupted at the initial stages, can be related to genetic aberrations [Balakhonov, 2001], but further losses seems related mostly to epigenetic reasons [Poletaev, 2008]. In general most of authors believe that genetic abnormalities are reasonable for nearly 5-13% of unfavorably results and nearly 90% of such cases is based upon other reasons, including changes in immune mechanisms [Radhupathy, 1997; Poletaev, 2008; Sukhikh & Van'ko, 2003]. Participation of the immune mechanisms in regulation of pregnancy is far from being fairly understood yet. However it should be noted that many of cytokines (interleukins, interferons, chemokines) and autoantibodies seem to be important factors involved in mechanisms of tissue's regeneration, growth and cells differentiation [Khaitov, 2002; Poletaev, 2010]. These observations may become a key for the future understanding of the issue from viewpoint of constructive (not destructive) impact of immunity in pregnancy development and fetus formation and maturation.

"domestic" microbes) also may be considered as super-organism, whose biologically antigenic components function for mutual benefit. Commensal microflora of gut play principal role in digestion and utilization of food as well as in production of vitamins [Grubb et al., 1989]. It is worth mentioning, that only allied microorganisms provide us with vitamin B12, which plays a key role in the normal functioning of the brain and nervous system, and plays great role for the formation of blood. Vitamin B12 is normally involved in the metabolism of every cell of the body, especially affecting no only DNA synthesis and regulation, but also fatty acid synthesis and energy production [Lieberman, & Marks, 2008; Zaichik, & Churilov, 2008]. Interestingly, B12 can be produced only through bacterial fermentation-synthesis in digestive tract of animals and humans [De Baets et al., 2000].

Today we don't know the most of important details about mechanisms and principles of coexistence with our micro-inhabitants, in spite of fact that symbiotic microorganisms compose nearly 10% of human body weight [Levinson, & Jawetz, 2000]. Fortunately, genetic and antigenic foreignness of such "components" of our body per se, does not imply obligatory mutual struggle [Pradeu T., Carosella, 2006]. Moreover, biologic non-relative organism (normal microflora and host-organism), as well as partly relative (mother and fetus) components forms a new entity – quasi-united superorganism. Of special interest is the fact, that immune system provides the main instrument not for rejection, but for peaceful and mutually useful integration of different and autonomous organisms under the

Due to the system mother-fetus could be considered as peculiar and specialized example of super-organism there is no immunological or any other conflict between integrated components (maternal and fetal compartments) *in normal condition*. In case of united superorganism there is no "foreignness" of integrated components. Nevertheless, in some pathological situations maternal-fetal interactions can become abnormal and can lead to pathology of pregnancy development. Unfortunately obstetricians meet with such pathological cases too often, and comprehension of the main aspects of maternal-fetal

Probably up to 40% of all desired pregnancies is interrupted spontaneously during initial 1- 3 weeks after fertilization [Radhupathy, 1997]. Additionally 10-15% loss of pregnancies occurs later. Many pregnancies, interrupted at the initial stages, can be related to genetic aberrations [Balakhonov, 2001], but further losses seems related mostly to epigenetic reasons [Poletaev, 2008]. In general most of authors believe that genetic abnormalities are reasonable for nearly 5-13% of unfavorably results and nearly 90% of such cases is based upon other reasons, including changes in immune mechanisms [Radhupathy, 1997; Poletaev, 2008; Sukhikh & Van'ko, 2003]. Participation of the immune mechanisms in regulation of pregnancy is far from being fairly understood yet. However it should be noted that many of cytokines (interleukins, interferons, chemokines) and autoantibodies seem to be important factors involved in mechanisms of tissue's regeneration, growth and cells differentiation [Khaitov, 2002; Poletaev, 2010]. These observations may become a key for the future understanding of the issue from viewpoint of constructive (not destructive) impact of

interactions from immunological point of view may be practically important.

immunity in pregnancy development and fetus formation and maturation.

guidance of alive host super-organism [Parnes, 2004].

**2. Maternal immunity and pregnancy** 

Historically, immunology emerged as a branch of applied microbiology, therefore "microbiological" approaches and accents have persisted for decades due to the fact that generations of specialists in immunology have been educated by microbiologists. From habitual (microbiological) point of view the pregnancy is a paradox. For solution of this puzzle more than half of century ago Peter Medawar proposed the hypothesis about inability to adequate recognize the "alien" fetus by the immune system of pregnant women – Medawar proposed that this phenomenon could be based upon combined mechanisms of maternal immune suppression and maternal-fetal immune tolerance [Medawar, 1953]. Unfortunately this speculation was too seriously perceived by many obstetricians as rather elevated activity of the immune system during pregnancy [Sacks et al., 1999; Kaštelan et al., 2010]. In his review Entrican specially noted, that pregnancy is accompanied by changes in different components of the immune system, but these changes should not be considered as signs of immune suppression [Entrican, 2002].

Evidently at early 50th Medawar could not think out of frames of traditional views – that is about activity of the immune system aimed to and restricted by searching and destruction of aliens. But now many immunologists re-evaluate the main predestination of the immune system. Nearly half of century ago Pierre Grabar proposed a homeostatic function of the immune system mediated by the natural autoantibodies [Grabar, 1968]. Some earlier, in thirtieths, an idea of the regulatory autoantibodies was mentioned by Karl Landsteiner [Landsteiner, Scher, 1936]. However the main prophet of the new immunological views became Elia Metchnikoff. He had claimed that it would be wrong to consider the immune system mainly as a gendarme of an organism. Its participation in a constant struggle Hostagainst-Parasite is no more a particular case of much more wide biological predestination of the immune system – dynamic participation in self-maintenance, self-reparation, selfoptimization, and maintenance of organism' harmony state under the constant pressure of the Environment [Metchnokoff, 1901]. Not *War but Peace* – or providing general homeostasis or "harmony" in Mechnikoff terms seems to be the main feature the immune activity [Matzinger, 2002; Poletaev, 2010]. Developing fetus is not inspected by the immune system as something hazard and does not became an object for attack in spite of evident nonselfness, but is considered by maternal organism as an object for integration. In this connection active maternal immune recognition of the fetus is an important and necessary condition for normal development of pregnancy [Howes, 2007]. In opposite side, if "the rate of recognition" of embryo and fetus by maternal immune system is too low - it may be reason for pregnancy losses. The last is typical for women with immune suppression related to different causes [Nyukhnin, 2007]. Moreover frequency of miscarriages is directly related to intensity of maternal immune suppression [Poletaev & Morozov, 2000]. in

> More often general immune suppression in fertile women can be induced by chronic opportunistic infections (such as *Herpes viridae, Chlamidia*, etc.), and besides – by prolonged usage of some medicines, chronic intoxications, and chronic psychogenic stresses [Poletaev, 2008]. Situation of immune suppression may be associated with incomplete or insufficient fetal recognition by maternal immune system and with pregnancy loss. Frequent miscarriages are also common for women with genetical similarities to her spouse (in cases of marriage between relatives) because excessive similarities in MHC genes between spouses do not permit maternal immune system to recognize clearly the fetal-paternal antigens [Roberts et al., 1996]. Thus (in case of similarities in MHC patterns of mother, father

Maternal Immunity, Pregnancy and Child's Health 45

in any spatial compartment of the body. Therefore, the content of autoantibodies with the different antigenic specificity may be considered as roughly the same in various compartments of the bloodstream. This feature permits us (at least potentially) to evaluate the functional-metabolic state of any organ (the heart, brain, liver, etc.) by measuring the content of autoantibodies with respected AG specificity (directed against cordial, brain, or hepatic AGs), presented in the same sample of the serum. Besides natural autoantibodies interacting with molecular structures of the self organism, represent one of the main instruments by which the immune system takes part in the control upon organism's homeostasis [Poletaev & Osipenko, 2003; Poletaev & Churilov 2010]. That is reflected by set of autoantibodies not only as passive "mirror" of the organism's state, but also as an active participator in tuning of the different physiologic functions, including clearance of organism from excessive producing molecular components and debris of dying cells [Poletaev, 2010]. The active regulatory function of the Immunculus has been clearly demonstrated by its participation in the mechanisms of regeneration of injured tissues [Poletaev, 2010]. The control and "tuning" functions of the Immunculus have been visible also in the processes of cellular differentiation and morphogenesis during early (fetal) ontogenetic development [Poletaev, 2008]. Regulatory, reparatory, and/or managerial functions of the Immunculus are illustrated by positive effects of the IVIG therapy in different pathologies (oncology, infection diseases, intoxications, neurology diseases, etc.) [Poletaev, 2008]. This kind of treatment, based on massive administration to the patient of immunoglobulines (autoantibodies), obtained from thousands of healthy donors, leads to the correction of the

the

homeostasis and mitigates very different metabolic and functional deviations.

background for autoimmune disease [Poletaev, 2010].

Serum content of various different autoantibodies is maintained in relatively common ranges (different for autoantibodies with each defined antigenic specificity) in any healthy person – in men and women. In opposite side, constant abnormal elevation or decreasing of some autoantibodies may be secondary reflection of primary tissue or organ pathology and may be used for estimation of clearance effectiveness in injured organ [Poletaev & Churilov, 2010]. More rarely primary abnormal rise of definite autoantibodies may become the

Bearing in mind the systemic (not summative) organization of autoantibody Network (Immunculus), it may be easily to comprehend, how it may reflect innumerable multiplicity of functional states of whole organism and its compartments. In this way, we would assume that reflection-recognition process of changeable and innumerable "antigenic images" of the body is based not upon changes of independent elements, but upon the whole immune network (Immunculus). In this context I would like to appeal to only two of quotations: "…The initial paradigm "one autoantibody for one disease" does not appear to be useful any longer. An autoantibody profile does seem to offer more diagnostic and prognostic power than the determination of single autoantibody specificity. The consequence is the use of new assays to detect different autoantibodies" [Meroni et al., 2007]. Backes C. and other [2011] wrote: "Instead of allocating single antigens to a specific group of diseases and even to a specific disease, it appears more appropriate to allocate seroreactivity patterns". This idea identification of autoantibody reactivity patterns, also addressed as autoantibody signatures that are highly specific for various diseases as shown by us and others". The main question is: how soon we will begin to learn very specific language which used the

immune system for telling the wonderful story of dynamic changes of ours bodies?

and fetus) women's immune system turns out to be lacking of full-fledged recognition of the fetus as well as an ability to provide an active maintenance for growth and development of the later.
