Pathogenetic Features of Inflammation and Methods of Its Correction in Remission and Exacerbation of Chronic Herpetic Infection

The dissertation is devoted to the study of the pathogenic features of the inflammatory process and immune response in remission and exacerbation of chronic herpetic infection. The research analyzes the cytokine profile, humoral immune response parameters, autoantibody levels, and circulating immune complexes in patients with chronic HSV infection at various clinical stages of the disease. The author developed and tested a pathogenetically grounded correction scheme employing an inducer of the macrophage phase of the immune response, which allows reducing the activity of the inflammatory process and increasing specific antiviral resistance of the organism regardless of the clinical stage of the pathological process.

Relevance of the Problem. There is no doubt that in modern industrial society, chronic infectious-inflammatory pathological processes, including those of viral etiology, occupy a significant place in the overall structure of morbidity. Many researchers associate the widespread prevalence of chronicization processes with untimely and inadequate treatment of acute infectious-inflammatory processes developing against the background of an imperfect immune response to the etiological factor, which possesses low immunogenic properties and an evolutionarily formed ability to "evade" the control of the immune system. In addition, the constant impact of a complex of negative anthropogenic factors leads to the exhaustion and disruption of adaptive capabilities of the organism, and the human immune system is the most sensitive to the action of xenobiotic factors, which manifests in the disruption of immunoregulatory mechanisms involved in the differentiation of immunocompetent cells and intercellular cooperation (Avtsyin A.P., 1977; Khaityov P.M., Pinegin B.V., 2000; Kevorkov N.N., Cheresev V.A., 2001; Vinokurov M.G., 2002; Trunova I.A. et al., 2003; Mikhailenko A.A., 2004). According to data from the global review of herpesvirus research, infection and morbidity among humanity are increasing year by year, outpacing the rate of population growth on Earth, in connection with which the problem of herpesvirus infection acquires a medical-social character, and the diversity of clinical manifestations, features of causative agents, and the possibility of their spread by virtually all known transmission routes allowed the European Regional Office of the WHO to classify herpesvirus infections in the group of diseases that determine the future of infectious pathology in the current century (Shulzhenko A.E., 2004; Zheleznikova G.F., 2005; Arduino P.G. et al., 2004; Vgyrkonyi V., 2006; Porter S.R., 2006). Of significant importance for science and practical healthcare is the study of the pathogenesis of infectious diseases caused by herpes simplex viruses at the modern scientific-methodological level. The development of this group of diseases occurs against the background of disorders in the immune response, leading to the emergence of a chronic relapsing pathological process with constant exacerbations, the basis of which lies in the prolonged persistence of weakly immunogenic viral antigens (Latysheva T.V., Khutieva L.M., 2001; Shulzhenko A.E., 2004; S.M., Davtyan T.K. et al., 2005; Novikov D.K., 2005; Boswell S.M. et al., 1999; Corey L., Handsfield H.H., 2000; Carrillo-Infante S., 2007). At the same time, it should be noted that there is not only an increase in the number of patients with chronic herpetic infection, but also a significantly more severe course (Latysheva T.V., Khutieva L.M., 2001; Redkin Yu.V. et al., 2006; Samgin M.A., Khaldin A.A., 2002; Ball S.C., 2001; Corey L., 2000, 2002; Hjalmarsson A, 2007). It is known that, once entering the organism, herpes simplex virus (HSV) can remain in it throughout life in an inactive (latent) state, which is associated with mechanisms of persistence, reactivation, and replication of the virus in the presence of normal virus-specific reactions of the organism (Khaldin A.A., 2000, 2002; Shulzhenko A.E., 2004; Ball S.C., 2001; Divito S. et al., 2006; Arena A. et al., 2007; Sheridan B.S. et al., 2007; van den Driessche P. et al., 2007). The mechanism of incomplete elimination of the virus both at primary infection with preserved reactivity of the organism and at HSV infection recurrences under conditions of a full set of anti-HSV immune reactions remains unclear. Presumably, this may be associated with the virus's ability to evade immune surveillance due to low immunogenicity of the virus and, as a consequence, disturbances in the macrophage phase of the immune response, defects in the formation of the specific phase, and the development of synthesis of low-affinity and weakly specific antibodies that do not possess neutralizing properties (Sukhikh G.T. et al., 2000; Barinsky I.F., 2004; Shulzhenko A.E., 2005; Zinkernagel R.M., 2001, 2005; Broketa M.M. et al., 2000; Lavrov V.F. et al., 2006; Lindsay M.K., 2006; Chapman M.D., Thompson E.J. et al., 2007). Despite a sufficiently large number of scientific studies, to date, the mechanisms of protective immunity as the basis for effective cure, as well as the role of disturbances in the cytokine network in the pathogenic mechanisms of chronic herpetic infection development, remain insufficiently studied (Serebryanaya N.B., 2005; Ito M. et al., 1998; LeBlanc R.A., Pesnicak L. et al., 1999; Inagaki-Ohara K., Daikoku T. et al., 2000; Harandr A.M., Svennerholm B. et al., 2001; Deshpande S.P. et al., 2002; Iwasaki A., 2003; Corey L., 2007; Uchakin P.N. et al., 2007). Many aspects of the pathogenesis of chronic herpetic infection remain not fully elucidated, and research on the pathogenic features of the mechanisms of clinical remission of the pathological process, which largely determines the further development of the disease, has practically not been conducted. Increasing importance is being attributed to the use in treatment not only of antiviral chemopreparatives, but also of pathogenetically grounded treatment methods capable of regulating the balance of mediators of intercellular relationships — cytokines — and participating in the normalization of the functional state of the immune system (Gladko O.V. et al., 2002; Hengge U.R., Ruzicka T., 2004; Miller R.L. et al., 2002; Patel R. et al., 2007; Tempesta M. et al., 2007). For these purposes, stimulators of the macrophage phase of the immune response are fairly widely used (Percival S.S., 2000; Kislova L.K., 2003; Naser V. et al., 2005; Raduner S. et al., 2006; McCann D.A. et al., 2007). However, the authors present contradictory data on the mechanisms of influence of drugs of this group on the activity of the destructive-inflammatory process in herpetic infection (Vonau V. et al., 2001; Schwarz E. et al., 2005; Matthias A. et al., 2007), and data on their use in patients with clinical remission of the pathological process are practically absent. The above determined the relevance of further in-depth study of the mechanisms of development of the immunoinflammatory process in the pathogenesis of exacerbation and clinical remission of chronic herpetic infection and the development of new pathogenetically grounded approaches to treatment and rehabilitation, and allowed formulating the goal and objectives of the present research. Goal of the Work. To study the features of the inflammatory process and immune response in the pathogenesis of remission and exacerbation of chronic herpetic infection and to develop new pathogenetically grounded approaches to their correction. Objectives of the Research: 1. To study the activity of the inflammatory process in patients with remission and exacerbation of chronic herpetic infection by determining in serum the concentrations and balance of proinflammatory and anti-inflammatory cytokines, levels of autoantibodies to antigens of native and denatured DNA. 2. To assess the functional state of the immune system by determining the concentrations of regulatory cytokines; levels of specific anti-herpetic antibodies and their avidity, content of circulating immune complexes in the serum of patients with remission and exacerbation of chronic herpetic infection. 3. To conduct a comparative analysis of clinical-immunological indicators of the activity of the inflammatory process and immune response in patients during remission and at exacerbation of chronic herpetic infection. 4. To develop a pathogenetically grounded scheme of correction of identified disturbances using an inducer of the macrophage phase of the immune response and to study its influence on clinical-immunological manifestations of inflammation in chronic herpetic infection at various periods of the disease after conducted correction. 5. To develop a diagnostic complex for examination of patients with chronic herpetic infection for assessment of the initial status and effectiveness of the conducted correction. Scientific Novelty. For the first time in patients with remission of chronic herpetic infection, an increase was established in the serum, relative to normative indicator values, of concentrations of proinflammatory cytokines IL-1β, IL-6, content of markers of cellular destruction, autoantibodies to antigens of native and denatured DNA, concentrations of inducers of the humoral and cellular branches of the immune system IL-2, IL-4, interferon-u, content of circulating immune complexes, and specific anti-herpetic antibodies. The obtained data indicate that, despite the absence of clinical manifestations of chronic herpetic infection, the organism of the examined patients retains activity of destructive-inflammatory processes, stimulation of immune response, and anti-herpetic protection, which is low-efficiency, as it does not lead to complete elimination of the etiological factor. The above is confirmation of the postulate of the continuity of development of the pathological process even in the period of clinical well-being. It has been shown that the main distinguishing feature of the exacerbation stage of chronic herpetic infection from the clinical remission of the pathological process is a 2-3 fold increase in the concentrations of the main proinflammatory cytokine IL-1β in the serum, which determines the severity of the inflammatory process at this stage of the disease: For the first time, it has been demonstrated that the use in patients with clinical remission and exacerbation of chronic herpetic infection of an inducer of the macrophage phase of the immune response according to the proposed scheme (1 capsule twice daily — 1 day and 1 capsule once daily — 4 days) leads to a reduction in the activity of the inflammatory process and stimulation of the specific antiviral resistance of the organism, regardless of the clinical stage of the pathological process. This is confirmed by a decrease on days 7, 14, and 21 after completion of the correction course in the content of the main proinflammatory cytokine IL-1β, markers of cellular destruction, autoantibodies to antigens of native and denatured DNA, an increase in the concentrations of interferon-u, an increase in the levels of specific anti-herpetic IgG antibodies and their degree of functional maturity (avidity) in the serum, relative to data obtained before the use of the proposed correction scheme. For the first time, it has been established that the inducer of the macrophage phase of the immune response used in the study possesses a modulating effect on the course of the immunoinflammatory process at remission and exacerbation of chronic herpetic infection and allows the formation of an optimal balance of pro- and anti-inflammatory cytokines, contributing to the reduction of the activity of the inflammatory-destructive process, which is confirmed by data of variance analysis indicating that the character and direction of changes in the concentrations of IL-1β, interferon-u, IL-6, and CIC in the serum of examined patients on days 7, 14, and 21 after conducted correction depend on their initial concentration before its commencement. It has been established that a more intensive increase in interferon-u concentrations occurs in patients with chronic herpetic infection with initially low values of its levels in the serum before conducting correction by the inducer of the macrophage phase of the immune response, compared to patients with initially high values, however, by day 21 after the conducted course, its concentrations are equalized in the serum of the examined persons. For the first time, it has been established that the change in the content of specific anti-herpetic IgG antibodies, as well as their degree of avidity, was a significant factor of the phase of immunoglobulin production and CIC formation, in which the inducer of the macrophage phase was applied. It has been shown that the most effective is the beginning of correction in the 1st and 3rd phases of immunoglobulin production and CIC formation, in this case, an increase in the content of specific anti-herpetic antibodies and their degree of avidity was noted throughout the entire observation period (days 7, 14, and 21), whereas in persons whose correction course was conducted in the 2nd phase, by day 21 after its completion, a decrease in the levels of specific anti-herpetic IgG antibodies and their degree of avidity was observed. Scientific and Practical Significance. The pathogenetic groundlessness and clinical efficacy of the proposed correction scheme based on the use of a stimulator of the macrophage phase of the immune response (1 capsule twice daily — 1 day and 1 capsule once daily — 4 days) have been demonstrated; its use allows reducing the activity of the inflammatory process and stimulating specific antiviral resistance of the organism in patients with exacerbation and clinical remission of chronic herpetic infection, which is clinically confirmed by a reduction in the duration of exacerbation by an average of 2.2 times, a decrease in the frequency of their occurrence by an average of 2.25 times, as well as an increase in the duration of remission by an average of 2.2 times regardless of the period of treatment initiation, that is, an improvement in the quality of life of patients. The obtained results made it possible to develop criteria for determining the effectiveness of treatment of chronic herpetic infection based on the determination before and on days 7, 14, 21 after completion of treatment conducted in the stage of remission, of the content in serum of specific IgG antibodies to herpes simplex virus types I and II, the degree of avidity of specific IgG antibodies; content of circulating immune complexes; (Trunov A.N., Obukhova O.O., Shvaik A.P., Gorbenko O.M., Trunova I.A. Method for Assessing the Efficacy of Treatment of Chronic Herpetic Infection // Russian Federation Patent for Invention No. 2331886, registration (publication) date 2008.08.20, priority date 2007.03.20, invention application: No. 2007110276/15). Theoretical and practical provisions developed in the dissertation research have been introduced into the scientific-pedagogical activity of the Department of Pathophysiology with a course of clinical pathophysiology of Novosibirsk State Medical University of Roszdrav (section on pathogenesis of inflammation) and into the practical activity of the City Immunological Center MUZ GP No. 1. Propositions to be Defended: 1. The absence of clinical manifestations in patients with chronic herpetic infection during remission is not associated with the absence of activity of the destructive-inflammatory process. 2. For clinical remission and exacerbation of chronic herpetic infection, activation of immune response processes and specific anti-herpetic protection is characteristic, which is low-efficiency, as it does not lead to complete elimination of the etiological factor. 3. The proposed correction scheme using an inducer of the macrophage stage of the immune response is pathogenetically grounded and clinically effective, as it leads to a reduction in the activity of the destructive-inflammatory process, stimulation of antiviral resistance of the organism, reduces the duration and frequency of occurrence of exacerbations of the pathological process, and prolongs the duration of remission. 4. In patients with remission and exacerbation of chronic herpetic infection, the effectiveness of the inducer of the macrophage phase of the immune response on the synthesis of specific anti-herpetic antibodies and their degree of avidity depends on the phase of synthesis of immunoglobulins and formation of circulating immune complexes, in which its use was initiated, and its influence on the content of proinflammatory cytokines and interferon-u depends on their initial level before the commencement of correction.