CHANGES IN SERUM LEVELS OF PRO- AND ANTI-INFLAMMATORY CYTOKINES IN WOMEN WITH PAPILLOMAVIRUS INFECTION BEFORE AND AFTER THERAPY



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The group of papillomaviruses is one of the most common viral infections among sexually transmitted diseases in the young population. A long, sluggish inflammatory process significantly worsens adequate pre-gravidar preparation. Along with papillomavirus infection, herpesvirus and chlamydia infections are the most frequent associations. Many authors believe that PVI reveals dysregulation of pro- and anti-inflammatory cytokines in the blood serum. Currently, there are no uniform standards for the management and treatment of women with papillomavirus infection without pronounced clinical manifestations to prevent morphofunctional disorders of the genitourinary system leading to reproductive disorders. But most authors believe that the use of antiviral and immunomodulatory drugs is the main method of therapy against the proliferation of pathogens in the body. The aim of the study was to compare changes in the levels of IL-17, IL-12 p70, IL-12 p40, IL-13 and TFR-β1 in the blood serum of women with papillomavirus infection before and after therapy with Inosine pranobex (IP) and Solanum tuberosum (ST). Materials and methods: a survey of 137 patients with papillomavirus infection treated with drugs with the active substance Inosine pranobex and Solanum tuberosum was conducted. The levels of IL-17, IL-12 p70, IL-12 p40, IL-13, and TFR-β1 in blood serum were determined using specific reagents from R&D Diagnostics Inc. (USA). Results. Changes in pro- and anti–inflammatory cytokines before therapy: decrease - IL–12 p70, p40, increase - IL-13, IL-17 and TFR-β1. After therapy, the following changes were revealed in the group of patients exclusively with PVI infection when using the drug of synthetic origin IP: the levels of IL-12 p70, IL-12 p40 and a decrease in IL-13 and TFR-β1 increased, while with ST therapy: an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TFR-β1. With IP therapy, patients with HPV+HVI registered an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13, while TFR-β1 did not change, and with ST therapy, IL-12 p70, IL-12 p40 also increased and IL-13 decreased, TFR-β1 remained unchanged. In the group of women with HPV+chlamydia infection, an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TFR-β1 with IP therapy, and an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TFR-β1 with ST therapy were shown. In all groups of patients, IL-17 remained high after therapy without a statistically significant difference between the subgroups. In the groups of patients treated with IP, a predominant normalization of the degree of immune disorders was recorded.

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Changes in serum levels of pro- and anti-inflammatory cytokines in women with papillomavirus infection before and after therapy
The group of papillomaviruses is one of the most common viral infections among sexually transmitted diseases in the young population [1]. A long, sluggish inflammatory process significantly worsens adequate pre-gravidar preparation. However, if pregnancy does occur, a number of obstetric and perinatal problems arise: infertility, miscarriage, fetal development disorders, premature birth, etc. [25].
Along with papillomavirus infection (PVI), the most frequent associations are herpesvirus (HVI) and chlamydia infections, which not only aggravates the violation of a woman's reproductive potential, but also increases the likelihood of oncogenesis [13]. Herpes simplex virus types 1 and 2 (HSV1/2) has the ability to infect the endometrium, which, against the background of an existing PVI infection, can prevent implantation of the fetal egg in the uterine cavity [3]. It was also hypothesized that PVI is stimulated by a herpetic infection that promotes the integration of the human papillomavirus (HPV) genome into the host cell [9, 3, 16, 17]. A feature of chlamydia infection is asymptomatic productive inflammation with damage to the epithelial membrane of the pelvic organs, which leads to adhesions, including fallopian tubes, contributing to the development of infertility by the tubal factor [14]. In a study by S. Bellaminutti et al. (2014), it was shown that chlamydia infection is most often detected in young patients under 25 years of age in a monovariant (22%), and in association with PVI, the indicator reached 45.8% [24]. These data were also confirmed by D. Panatto et al. (2015), who noted a frequent combination of chlamydia and HPV at a younger age: if in the general population this combination was found in 57% of patients, then among women under 25 years of age - in 69.7% [21].
Many authors believe that PVI reveals dysregulation of pro- and anti-inflammatory cytokines in the blood serum [11, 15]. In the recurrent course of PVI, an increase in IL-10, IL-13 and protein causing degradation of the intercellular matrix with a predominance of a mixed (T1/T2) type of immune response was detected. With a non-recurrent course, T1 type of immune response was detected [7]. In 2019, T.B. Poston at al. It was determined that CXCL10, TNF-α and IL-17A are cytokines associated with increased chances of endometrial infection in chlamydia infection. It has been demonstrated that the transmission of type I IFN signals in mice stimulates the production of CXCL10, prolonging chlamydia infection, which contributes to the pathology of the fallopian tubes [20, 23].
Currently, there are no uniform standards for the management and treatment of women with PVI without pronounced clinical manifestations to prevent morphofunctional disorders of the genitourinary system leading to reproductive disorders. But most authors believe that the use of antiviral and immunomodulatory drugs is the main method of therapy against the reproduction of pathogens in the body [2, 6].
Further studies of immunological disorders in papillomavirus infection will expand the understanding of the immunopathogenesis of the disease and evaluate the mechanisms of therapy effectiveness.
The purpose of the work. To compare changes in the level of IL-17, IL-12 p70, IL-12 p40, IL-13 and TFR-β1 in the blood serum of women with papillomavirus infection before and after therapy with Inosine pranobex and Solanum tuberosum.
The methods used. The study included 137 people divided into the main group – 107 women and the control group – 30 practically healthy women.
At the first stage of the study, the main group was divided into 3 groups depending on the etiology - group I with PVI, group II - association of PVI and HVI and group III - association of PVI and chlamydia infection. At the second stage of the study, 3 groups, by random sampling, were divided into subgroups - I subgroup (A) of women received therapy with the drug with the active substance Inosine pranobex (IP), II subgroup (B) - with the active substance Solanum tuberosum (ST) and the main therapy in groups II and III of patients - with HVI b in combination with Valacyclovir and in the group with chlamydia infection – Doxycycline. The study was conducted twice. Initially – before therapy and 1 month after therapy. Determination of the levels of IL-17, IL-12 p70, IL-12 p40, IL-13, TFR-β1 in blood serum was carried out using specific reagents from R&D Diagnostics Inc. (USA) by the sandwich variant of solid-phase enzyme immunoassay. The results were taken into account using the enzyme immunoassay "Multiscan" (Finland). Calculations of the amount of cytokine were carried out by constructing a calibration curve using a computer program. The amount was expressed in pg/ml and ng/ml. The degree of immune disorders (INS) was calculated according to A.M. Zemskov et al. (1994) [4, 8].
The analysis of the obtained results was carried out using the SPSS v.22 program by the method of variational statistics using the Student's two-sample t-test and the Mann-Whitney test with Bonferroni correction. Quantitative features that do not have a normal distribution were evaluated using nonparametric methods and are presented in the form of median (Me), lower and upper quartile (Q25% Q75%). The significance level p<0.05 was considered statistically significant.
The main results. When analyzing the level of the studied pro- and anti-inflammatory cytokines in the blood serum of patients before and 1 month after therapy, patterns and differences were demonstrated (Table 1).
A multidirectional change in pro- and anti-inflammatory cytokines in the blood serum of patients in the study groups before treatment was established. The level of IL-17A was increased in comparison with the control group (p<0.05) in patients of all major groups. At the same time, there was no statistically significant difference in its content in blood serum between the groups.
In the main groups of women, a decrease in IL 12 subtype p70 was revealed with a deficiency of IL 12 p40 in comparison with the control group. At the same time, in group II patients (with PVI and HVI), IL-12 p70 deficiency was determined (p<0.01) both in comparison with the control group and with groups with bacterial infection (p2-3=0.003) and monoinfection (p1-2=0.002). IL-12 p40 in Group II was also the lowest in relation to both the control group (p<0.001) and the groups with chlamydia infection (p2-3=0.002) and group I (p1-2=0.004).
IL-13 values were elevated in blood serum in all groups of patients compared to the control group (p<0.05 - 0.01). The highest rates were registered in the group with viral and bacterial association in comparison with the I (p1-3=0.002) and II (p2-3=0.003) groups of patients. There were no intergroup differences between groups I and II.
TFR-β1 was increased 1.5-2 times in the blood serum of women in all the main study groups compared with the control group (p<0.01).
When analyzing pro- and anti-inflammatory cytokines in the blood serum of patients 1 month after therapy, a number of changes were demonstrated. In group I, in both subgroups, there was a general tendency to recover, but without reaching the control values. With IP therapy (subgroup IA), an increase in the levels of IL-12 p70 was determined by an average of 2 times, IL-12 p40 by 2.5 times and a decrease in IL-13 and TFR-β1 by 1.5 times, relative to the values before therapy. Patients of subgroup IIB had a similar tendency, but more pronounced and different from subgroup IA in terms of IL-12 subtypes: IL-12 p70 – 5 times, IL-12 p40 – 3 times. IL-13 and TFR-β1, on average, became 1.5 times lower in comparison with the values before therapy, to the same extent and without significant differences from the results of subgroup IA. The control values of IL-12 p40, IL-13, TFR-β1 were not achieved in both subgroups, the values of IL-12 p70 were significantly higher, both in subgroup IA and in subgroup IB compared with reference values.
In group II, an almost identical picture of the dynamics of all cytokines in the blood serum was established, except for the absence of dynamics in the content of TFR-β1, which did not change after therapy and remained above the control values. In subgroup IIA, a significant increase in IL-12 p70 was documented – an average of 13 times, IL-12 p40 - 77 times. Whereas the level of IL-13, on the contrary, decreased and became 1.4 times less, and TFR-β1 in the blood serum did not change in comparison with the indicators before therapy. In subgroup IIB, similar changes in cytokine levels were also recorded in patients receiving ST therapy in the form of an increase, on average - IL-12 p70 – 33 times, IL-12 p40 – 63 times, IL-13, on the contrary, decreased, on average 1.3 times, and TFR-β1 in dynamics the treatment has not changed. Significant differences between the subgroups were revealed only in the content of IL-12 p70 and IL-12 p40. Cytokine levels corresponding to the values of the control group were not reached.
In group III, the changes in the cytokine content in the blood serum were somewhat different, and differences between the subgroups were also revealed. In the blood serum of subgroup IIIA after IP therapy, changes were recorded in the form of an increase in the content of IL-12 p70 by an average of 3.2 times, IL-12 p40 by 1.4 times, IL–13 decreased by an average of 1.9 times and TFR-β1 decreased by 1.7 times. While in the serum of patients from subgroup IIIB, the level of IL-12 p70 increased by an average of 10 times, IL-12 p40 – 1.2 times, and the values of IL-13 decreased by 1.2 times and TFR-β1 - 1.3 times. When comparing the subgroups with each other, higher values of IL-12 p70 were recorded in subgroup IIIB and IL-12 p40 in subgroup IIIA, and a decrease in the content of IL-13 in subgroup IIIA. Only in subgroup IIIA, the value of TFR-β1 was achieved, which did not differ from the similar indicator of volunteers from the control group.
Assessing the content of IL-17 in the blood serum of patients of all groups, no dynamic changes were detected: the cytokine remained at an elevated level, relative to the control values, regardless of the therapy performed and the nature of the infection.

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About the authors

T. Nevezhkina

ФГБОУ ВО ТГМУ Минздрава России

Email: www.tanya.ru9292@mail.ru

ассистент кафедры нормальной и патологической физиологии

Russian Federation

E. V. Markelova

"Pacific state medical University" Vladivostok, Russia

Email: markev2010@mail.ru

MD, Professor, Head of the department of normal and pathological physiology

Russian Federation

С. Knysh

Email: www.tanya.ru9292@mail.ru

M. Tulupova

Paracelsus LLC

Email: www.tanya.ru9292@mail.ru

Ph.D. (medicine), Chief Physician

L. Matyshkina

«Pacific state medical university», Vladivostok, Russian Federation (FSBEI HE PSMU MOH Russia, Vladivostok, Russia)

Author for correspondence.
Email: www.tanya.ru9292@mail.ru

Ph.D. (medicine), associate professor, head of obstetrics and gynecologist department

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