**3. Natural autoantibodies and the health state of the human organism**

In recent twenty years clinical immunology was characterized by emerge of paradoxes *sui generis* contradicting to adopted positions of many physicians. As an example, puzzle of natural serum autoantibodies may be noted. The generation of autoantibodies against selfantigens is a common phenomenon in humans. Elevated autoantibody level earlier has been associated directly and exclusively with the pathogenesis of autoimmune diseases. Now it is common place that the rise of serum content of many autoantibodies also occur in the context of other diseases, not belonging to autoimmune ones, including strike, cancer, or complicated pregnancy [Backes et al., 2011; Poletaev, 2010]. Moreover, it was clearly demonstrated that natural a-Abs of IgG, and IgM classes against very different self-antigens had been permanently presented in the blood serum of any healthy person [Lacroix-Desmazes et al., 1998]. Experimental data indicates for roughly equal serum content of a-Abs with the same specificity in the vast majority of healthy individuals [Lacroix-Desmazes et al., 1998], and conversely, indicates notably deviations in production and serum content of particular a-Abs, related to primary molecular changes in the certain cell populations in different tissues and organs, accompanying the plurality of diseases [Poletaev & Churilov, 2010]. It is proved that production and secretion of natural a-Abs is regulated directly by the quantity/availability of respective antigens (by feed-back principle [Kovaliov & Polevaya, 1985]. It is based on the fact, that although expression/degradation rates of any cytoplasmic, membrane, or nuclear antigens in any specialized cells are individual, but at the same time they are similar and represent same relative level/pattern in any healthy person (with slight variation between individuals). Only minor variability in serum level of a-Abs with different specificity is typical for humans in the normal (healthy) state, but not for cases of pathology. Plurality of very different chronic diseases has been connected directly to steady abnormal changes in rates of apoptotic, necroptotic, or necrotic events, as well as to abnormalities in expression/secretion of multiple autoantigens. Such events lead to the changes in a-Abs serum content with according specificity (feed-back principle).

In other words versatile set of natural autoantibodies with different specificity, can be considered as immune fingerprints of molecular content of an entire organism, and mirrors the functional state of the different populations of cells. The general system of autoantibodies has been named earlier as "Immunologic Homunculus" [Cohen & Young, 1991], or "Immunculus" [Poletaev & Osipenko, 2003; Poletaev & Churilov 2010]. Immunculus can be considered as an internal image of the current functional-metabolic state of the body expressed in the terms (language) of quantitative alterations in the content of different autoantibodies. To some extent the Immunculus concept is similar to the concept of Neurological Homunculus, which is an internal image of the body's anatomical/physiological state reflected by the nervous system in the language of the spikes activity of the brain's neuronal nets [Cohen & Young, 1991]. However, in contrast to the dimensionally fixed and morphologically structured neuronal nets, the Immunculus is a dissipative system constructed not by the cellular but by the highly mobile molecular elements: very different autoantibodies presented in the blood, lymph, and interstitial fluid

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

In recent twenty years clinical immunology was characterized by emerge of paradoxes *sui generis* contradicting to adopted positions of many physicians. As an example, puzzle of natural serum autoantibodies may be noted. The generation of autoantibodies against selfantigens is a common phenomenon in humans. Elevated autoantibody level earlier has been associated directly and exclusively with the pathogenesis of autoimmune diseases. Now it is common place that the rise of serum content of many autoantibodies also occur in the context of other diseases, not belonging to autoimmune ones, including strike, cancer, or complicated pregnancy [Backes et al., 2011; Poletaev, 2010]. Moreover, it was clearly demonstrated that natural a-Abs of IgG, and IgM classes against very different self-antigens had been permanently presented in the blood serum of any healthy person [Lacroix-Desmazes et al., 1998]. Experimental data indicates for roughly equal serum content of a-Abs with the same specificity in the vast majority of healthy individuals [Lacroix-Desmazes et al., 1998], and conversely, indicates notably deviations in production and serum content of particular a-Abs, related to primary molecular changes in the certain cell populations in different tissues and organs, accompanying the plurality of diseases [Poletaev & Churilov, 2010]. It is proved that production and secretion of natural a-Abs is regulated directly by the quantity/availability of respective antigens (by feed-back principle [Kovaliov & Polevaya, 1985]. It is based on the fact, that although expression/degradation rates of any cytoplasmic, membrane, or nuclear antigens in any specialized cells are individual, but at the same time they are similar and represent same relative level/pattern in any healthy person (with slight variation between individuals). Only minor variability in serum level of a-Abs with different specificity is typical for humans in the normal (healthy) state, but not for cases of pathology. Plurality of very different chronic diseases has been connected directly to steady abnormal changes in rates of apoptotic, necroptotic, or necrotic events, as well as to abnormalities in expression/secretion of multiple autoantigens. Such events lead to the changes in a-Abs serum content with according specificity (feed-back principle).

In other words versatile set of natural autoantibodies with different specificity, can be considered as immune fingerprints of molecular content of an entire organism, and mirrors the functional state of the different populations of cells. The general system of autoantibodies has been named earlier as "Immunologic Homunculus" [Cohen & Young, 1991], or "Immunculus" [Poletaev & Osipenko, 2003; Poletaev & Churilov 2010]. Immunculus can be considered as an internal image of the current functional-metabolic state of the body expressed in the terms (language) of quantitative alterations in the content of different autoantibodies. To some extent the Immunculus concept is similar to the concept of Neurological Homunculus, which is an internal image of the body's anatomical/physiological state reflected by the nervous system in the language of the spikes activity of the brain's neuronal nets [Cohen & Young, 1991]. However, in contrast to the dimensionally fixed and morphologically structured neuronal nets, the Immunculus is a dissipative system constructed not by the cellular but by the highly mobile molecular elements: very different autoantibodies presented in the blood, lymph, and interstitial fluid

**3. Natural autoantibodies and the health state of the human organism** 

the later.

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 homeostasis and mitigates very different metabolic and functional deviations.

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 background for autoimmune disease [Poletaev, 2010]. any

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?

Maternal Immunity, Pregnancy and Child's Health 47

If we will take in mind that autoantibodies are biologically active regulatory molecules it will be evident, not only excessive production, but also shortages in many (any?) 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

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

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

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

indicates for efficacy and sufficiency of used therapy [Serova, 2000].

development and sometimes can be fatal for the fetus [Poletaev, 2010].

of maternal immune imprinting (see below) [Lemke & Lange, 1999].

birth formation [Poletaev, 2008].

**embryotropic antibodies** 
