Features of Immunoinflammatory Processes in Pregnant Women with Chronic Pyelonephritis in Remission

The dissertation is devoted to the study of features of the immunobiochemical status in pregnant women with chronic pyelonephritis in stage of clinical remission. The relevance of the work is conditioned by the high prevalence of infectious-inflammatory diseases in women of reproductive age and their role in the development of complications of pregnancy. In the first trimester of pregnancy, it is necessary to ensure a balance of the neuroimmunoendocrine system, microelement metabolism, and cytokine profile for the successful course of pregnancy and normal development of the fetus. During the investigation, the content of biometals (copper, zinc, manganese, selenium), proinflammatory cytokines (IL-1β, IL-6), cytokines mediating humoral and cellular immunity (IL-4, IFN-γ), as well as concentrations of immunoglobulins and circulating immune complexes in the serum of pregnant women with chronic pyelonephritis in stage of remission was studied in comparison with «practically healthy» pregnant women. The obtained data made it possible to identify systemic secondary microelementosis, cytokine imbalance, and activation of the humoral link of the immune system in the examined patients, which is of significance for the prevention of pregnancy complications.

Relevance of the Topic. In the context of the modern industrialized society, characterized by processes of population aging, declining birth rates, and others, one of the most important socio-medical problems urgently requiring resolution is the improvement of the quality of reproductive health of women and the health of newborn children. (Kulakov V.I. et al., 2004.) It is known that a high prevalence rate of infectious-inflammatory diseases of various organs and systems in women of reproductive age constitutes a significant factor leading to complications of physiological pregnancy, such as spontaneous abortion, threat of pregnancy interruption, development of late gestosis, intrauterine growth retardation, antenatal fetal death, birth of a sick child, and a number of others (Abramchenko V.V., 1994; Aylamazyan E.K., 1995; Kulakov V.I., Vikhlyaeva E.M., 1995; Shekhtman M.M., 1999; Savelieva G.M., Panina O.B., Sinichava L.G. et al., 2000; Savelieva G.M., Kurzer M.A., 2000; Serov V.N., Kuzmin V.N., Muzykatova B.S., 2000; Bozhin E.Yu., 2000; Rassaeva L.Sh., 2003; Gibbs R.S., Duff P., 1991; Froen J.F., Moyland R.A., Saugstad O.D. et al., 2002). Analysis of scientific literature data allows the conclusion that the share of infectious-inflammatory processes in the structure of causes of maternal mortality in the Russian Federation amounts to 13–15% (Ankirkovskaya A.E., 1989, 1995; Beznoshchenko G.B., Beznoshchenko A.B., 2000; Kulakov V.I., Frolova O.G. et al., 2004). Among the most frequently encountered infectious-inflammatory diseases leading to complications of pregnancy, pyelonephritis rank foremost, the main etiological factor of which at present is considered to be conditionally pathogenic microflora that, under the influence of ecological factors, unbalanced nutrition, antibiotic therapy, and other factors, has increased its virulence and developed resistance to pharmacological effects (Bashmakova M.A., Kosheleva N.G., Kalashnikova E.P., 1995; Pytel Yu.A., Loran O.B., 1996; Voropaeva S.D., 1997; Bukharin O.V., 1999; Shekhtman M.M., 1999; Tikhonova O.V., 2001, Rassaeva L.Sh., 2003). (Batyrova A.K., Stamkulova T.A., 1991; Bashmakova M.A., Kosheleva N.G., Kalashnikova E.P., 1995; Pytel Yu.A., Loran O.B., 1996; Shekhtman M.M., 1999). (Bashmakova M.A., Kosheleva N.G., Kalashnikova E.P., 1995; Voropaeva S.D., 1997; Bukharin O.V., Boyko A.B., Zhuravleva L.A., 1998; Bukharin O.V., 1999; Tikhonova O.V., 2001). For the successful realization of a genetically determined program of conception, preservation, and physiological development of pregnancy, a significant restructuring of the state of the neuroimmunoendocrine system, the activity of lipid peroxidation processes and antioxidant protection, the state of the microelement balance of the body, and others must occur in the female organism. There is no doubt that the presence of foci of infectious-inflammatory diseases in a pregnant woman can lead to a disruption of the delicate intersystem relationships in the body, resulting in pathological course of pregnancy and its complications. (Kevork N.N., Shilov Yu.I., Shirshev S.V. et al., 1993; Kozlova V.I., Pukhner A.F., 1997; Sukhikh G.T., Van'ko L.V., Kulakov V.I., 1997; Dzutseva V.V., 2000; Abramchenko V.V., 2001; Trunov A.N., Efremov A.B., Trunova L.A. et al., 2002; Jauniaux E., Jurkovic D., Gulbis V. et al., 1995; Ekerfelt S., Matthiesen L., Berg G., 1997; Kuttle W.H., Franklin R.D., 2001; Ng S.C., Gilman-Sachs A., Thaker P. et al., 2002; Peng B., Liu S., 2002). In recent years, considerable attention from researchers has been devoted to studying the significance of the balance of cytokines—mediators of intercellular relationships—for the biological realization of the fertilization program, the physiological course of pregnancy, and the formation of adequate relationships in the mother-placenta-fetus system, as well as changes in their content in the presence of complications of its course. It has been demonstrated that during normally developing pregnancy, changes occur in the balance of interleukins that should lead to the activation and predominance of the T-lymphocyte-mediated helper type 2 immune response with the synthesis of blocking antibodies, which is one of the leading mechanisms of fetal protection. At the same time, in various complications of pregnancy, many authors have identified multidirectional changes in interleukin concentrations leading to a reduction in the expression of the protective T-helper type 2 response and the loss of its dominant role (Kozlova S.N., Loginova I.M., Berdygina N.Yu., 2002; Panova I.A., Tsarkova R.Kh., Sotnikova N.Yu. et al., 2002; Szereday L., Spath P., Szekeres-Bartho J., 1999; Wilczynski J.R., Banasik M., Tchorzewski H. et al., 2000; Ho H.N., Chao K.H., Chen H.F. et al., 2001; Ng S.C., Gilman-Sachs A., Thaker P. et al., 2002; Ng S.C., Gilman-Sachs A., Thaker P. et al., 2002). It is known that disturbances of electrolyte metabolism can lead to the development of arterial hypertension, spontaneous abortions, congenital malformations, fetal hypotrophy (Svigris A.Yu. et al., 1986; Krotenko N.M. et al., 1989; Marku G.A. et al., 1991; Egorova O.A., 1992; Wathen N.C. et al., 1995). In recent years, interest in the influence of essential microelements (EM) on the reproductive function of women and the course of physiological pregnancy has grown (Avtsyn A.P. et al., 1991; Krivoruchko I.V., 1995), especially against the background of intensifying ecological pressure (Kulikov V.Yu., 1998). At the same time, it has been established that during pregnancy, both the mother and the fetus require adequate supply of such EM as iron, copper, selenium, fluorine, cobalt, and zinc (Agadjanyan N.A. et al., 1994). If questions of the physiological effects of EM have been studied to a sufficient degree, then the significance of such EM as manganese and selenium has remained until recently unexplored (Sasina 1995; Tym K.E. et al., 1995; Vagapova M.E. et al., 1996), as have the correlational relationships between biometals in plasma blood in women with complicated course of pregnancy. Even the physiological bases of the interaction of macro- and microelements are poorly studied, not to mention possible violations of these correlations under pathological conditions. Undeniable interest is the influence of biometal imbalance on the state of immunoregulatory systems of the organism (for example, the cytokine profile), the activation of which is characteristic of pregnancy (Pak I.V. et al., 1989). Despite the sufficient quantity of scientific publications devoted to the study of the cytokine profile, immunological parameters reflecting the state of the humoral and cellular links of immunity in various complications of physiological pregnancy, investigations dedicated to studying their changes in chronic infectious-inflammatory diseases in stage of clinical remission in pregnant women are represented by isolated works, although the aforementioned pathological processes can lead to imbalance in homeostatic systems of the organism and the development of complications of pregnancy and deterioration of newborn health (Avtenschlus A.I., Ivanova O.V., Konovalova T.N., 1998; Bozhin E.Yu., 2000; Rassaeva L.Sh., 2003). Furthermore, it is relevant and highly significant to study the metabolism of biometals playing a significant role in maintaining homeostasis and general resistance of the organism in interrelation with immunoregulatory parameters during physiological pregnancy and its complications. All of the above has made it possible to formulate the goal and objectives of the present investigation. Goal of the investigation: to study the features of the immunobiochemical status in pregnant women with chronic pyelonephritis in stage of clinical remission. Objectives of the investigation: 1. To study the content of biometals (copper, zinc, manganese, and selenium) in the serum of «practically healthy» pregnant women and pregnant women with chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy. 2. To determine the content of proinflammatory cytokines IL-1β and IL-6 in the serum of «practically healthy» pregnant women and pregnant women with chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy. 3. To study the concentrations of IL-4 and gamma-interferon—inducers of humoral and cellular immune response—in the serum of «practically healthy» pregnant women and pregnant women with chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy. 4. To study the content of IgM, IgA, IgG and levels of circulating immune complexes in the serum of «practically healthy» pregnant women and pregnant women with chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy. 5. To identify features of interrelationships between parameters of microelement metabolism and immunological parameters in the examined groups. SCIENTIFIC NOVELTY For the first time it has been demonstrated that in women with chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy, a systemic secondary microelementosis develops, manifested as a deficiency of selenium, copper, zinc, and manganese. The work demonstrates the interrelationship between violations of microelement content, the expression of inflammatory reactions, and the activation of the humoral link of the immune system of women with chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy, which is confirmed by correlational interrelationships among them. It has been established that in chronic pyelonephritis in stage of clinical remission in the first trimester of pregnancy, a cytokine imbalance is tested in the examined women, manifested by a reliable increase in the concentrations of the proinflammatory interleukin IL-6 and the inducer of cellular immunity IFN-γ against the background of a reliable decrease in IL-4—a cytokine possessing anti-inflammatory properties. The obtained data indicate the significance of inflammatory reactions in the pathogenesis of chronic pyelonephritis in stage of clinical remission during pregnancy, as well as a reduction in the expression of the T-helper type 2 response, the activation of which is necessary for the physiological course of pregnancy and fetal development. Reliably high concentrations of immunoglobulin A and levels of circulating immune complexes have been determined in the serum of pregnant women with chronic pyelonephritis in stage of clinical remission, indicating the presence of antigenic stimulation of the organism in the examined patients, leading to the activation of the humoral link of the immune system. PRACTICAL SIGNIFICANCE The obtained data have made it possible to assess the contribution of violations of biometal content in plasma blood to the pathogenesis of chronic pyelonephritis during pregnancy, defining them as a systemic secondary microelementosis. The interrelationship of the latter with the expression of inflammatory reactions and the activation of the humoral link of the immune system has provided the basis for recommending the use of preparations containing the aforementioned microelements with the aim of preventing the occurrence and treating complications of pregnancy associated with the studied pathological process. It has been demonstrated that, in order to improve the quality of examination of pregnant women for detecting activation of the focus of chronic inflammation in pregnant women with chronic pyelonephritis in stage of clinical remission, it is advisable to use testing of circulating immune complex levels as a screening method, the elevation of which reflects the degree of antigenic stimulation of the organism. The most indicative criterion for determining the expression of inflammatory reactions in the body of pregnant women with chronic pyelonephritis in stage of clinical remission is testing the concentrations of the proinflammatory cytokine IL-6. PROPOSITIONS FOR DEFENSE 1. In pregnant women with chronic pyelonephritis in stage of clinical remission, «systemic secondary microelementosis» develops. 2. Stage of clinical remission in pregnant women with chronic pyelonephritis is characterized by the activation of immunoinflammatory processes. 3. Changes in immunometabolic parameters in pregnant women with chronic pyelonephritis in stage of clinical remission are accompanied by an imbalance of microelements.