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ORIGINAL ARTICLE
DOI: 10.24412/2707-6180-2021-63-63-69 UDC 616.613-007.63-002.1:612.017.1-053.2 SCSTI 76.29.36
INNATE AND ADAPTIVE IMMUNITY STATE DETERMINATION IN CHILDREN WITH PYELONEPHRITIS ON CONGENITAL HYDRONEPHROSIS BACKGROUND IN ACTIVE STAGE OF THE DISEASE
M.MISHYNA1, V. DAVYDENKO2, I. MARCHENKO1, YU. MOZGOVA*1, S.MALANCHUK2, O.DUBOVIK\ YU. MISHYN
iKharkiv national medical university, Kharkiv, Ukraine 2V.N. Karazin Kharkiv national university, Kharkiv, Ukraine
Myshina M. - https://orcid Mozgova Yuliya - https://orcid Malanchuk Svitlana - https://orcid Mishyn Yuriy - https://orcid
Citation/
Библиографияльщ сттеме/ Библиографическая ссылка: Mishyna M, Davydenko V, Marchenko
I, Mozgova Yu, Malanchuk S, Dubovik O, Mishyn Yu. Innate and adaptive immunity state determination in children with pyelonephritis on congenital hydronephrosis background in active stage of the disease.
West Kazakhstan Medical Journal. 2021;63(2):63-69. DOI: 10.24412/27076180-2021-63-63-69
Мишина М, Давыденко В, Марченко И, Мозгова Ю, Маланчук С,Дубовик Е, Мишин Ю. Аурудын белсендi сатысында туа бiткен гидронефроз фонында пиелонефрит бар балалардаFы иммунитетпн iшкi жэне бешмделу жаFдайын аньщтау. West Kazakhstan Medical Journal.2021;63(2): 63-69. DOI: 10.24412/2707-6180-2021-63-63-69
Мишина М, Давыденко В, Марченко И, Мозгова Ю, Маланчук С,Дубовик Е, Мишин Ю. Определение внутреннего и адаптивного состояния иммунитета у детей с пиелонефритом на фоне врожденного гидронефроза на активной стадии заболевания.West Kazakhstan Medical Journal. 2021;63(2): 63-69. DOI: 10.24412/2707-6180-202163-63-69
org/ 0000-0001-9348-7804 org/ 0000-0001-6770-9397 org/ 0000-0002-9376-3693 org/ 0000-0003-4955-3522
Innate and adaptive immunity state determination in children with pyelonephritis on congenital hydronephrosis background in active stage of the disease M.Mishyna1, V. Davydenko2, I. Marchenko1, Yu. Mozgova*1, S.Malanchuk2, O.Dubovik1, Yu. Mishyni
iKharkiv national medical university, Kharkiv, Ukraine 2V.N. Karazin Kharkiv national university, Kharkiv, Ukraine
Purpose: to determine the state of adaptive and innate immunity depending on the age of children and the etiological factor of pyelonephritis on congenital hydronephrosis background in active stage of the disease.
Methods: The research was performed by using of conventional methods. It was found that the leading causative agents of secondary pyelonephritis on congenital hydronephrosis background in young children were Escherichia coli, Enterococcus faecalis and Staphylococcus epidermidis; in middle-aged group were Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Candida albicans, and in elder children were Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Candida albicans. There was detected that a decrease in CD95+ lymphocytes in young children and a significant increase of this index in middle-aged and elder children took place. A potent elevation of pro-inflammatory cytokines production was shown, and in middle-aged and elder children with Enterococcus faecalis pyelonephritis the level of IL-1ß was in 3.8 and 5.2 times, respectively, higher than in young children, and in Escherichia coli pyelonephritis in 3.4 and 5.9 times, respectively. A decreased neutrophils phagocytic activity was detected that may contribute to insufficient elimination of circulating immune complexes as evidenced by their significant increase in serum. The highest rates were determined in elder children, where the leading pathogens were mainly Enterococcus faecalis, Escherichia coli and Klebsiella pneumoniae. Conclusions: Thus, there is no doubt about the presence of immune mechanisms in children with pyelonephritis on congenital hydronephrosis background, autoimmune syndrome is developed by damage of own cells membranes and sensitization to cell components mimicking the infectious agent antigens. Post-infectious autoimmune syndrome in combination with secondary immunodeficiency is a more severe condition because involves not only autoaggression, but also a lack of factors and components of immune response, manifested by severe course of pyelonephritis in children with congenital hydronephrosis. The existing immunodeficiency creates conditions for disease progression, stimulates other pathogenetic factors, and as the infectious inflammatory process is developing, an immunological insufficiency is worsening and associated not only with the persistence of microorganisms, their toxins, but also with depletion of immune system reserves.
Keywords: children, pyelonephritis, etiological factor, immunity, pro-inflammatory cytokines, immunoglobulins.
О
Mozgova Yu.
e-mail: yumozgova19SG@ gmail.com
Received/ Келт tyctí/ Поступила: 23.12.2020.
Accepted/
Басылымра к,абылданды/ Принята к публикации: 22.04.2021
ISSN 2707-6180 (Print) © 2021 The Authors Published by West Kazakhstan Marat Ospanov Medical University
Аурудыц белсендi сатысында туа б™ен гидронефроз фонында пиелонефритi бар балалардаFы иммунитеттщ шю жэне бейiмделу жаFдайын аньщтау
М.Мишина1, В. Давыденко2, И. Марченко1, Ю. Мозгова*1, С. Маланчук2, Е. Дубовик1, Ю. Мишин1
1Харьков ^лттык медицина университета, Харьков, Украина
2В.Н. Каразин атындагы Харьков ^лттык университета, Харьков, Украина
Мак;саты: балалардыц жасына жэне аурудьщ белсендi сатысында туа бпкен гидронефроз фонында пиелонефриттщ этиологиялы; факторына байланысты адаптивта жэне туа бгткен иммунитеттщ жагдайын аныктау. Эд^ер. Зерттеу жалпы кабылданган эдiстермен ЖYргiзiлдi. Ерте жастагы балаларда туа бiткен гидронефроз аясында кайталама пиелонефриттщ жетекшi коздыргыштары Escherichia coli, Enterococcus faecalis жэне Staphylococcus epidermidis болып табылатыны аныкталды; орта жастагы топта Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Candida albicans, ал ересек балаларда - Proteus mirabilis, Klebsiella pneumoniae, Enteracocociae pneumoniae, E. coli. Albicans сацыраук^ла; микроорганизмдерг Нэтижелер. Жас балаларда CD95 + лимфоциттердщ тeмендеуi жэне орта жэне ересек жастагы балаларда б^л керсетюштщ едэуiр артуы аныкталды. ^абынуга карсы цитокиндер eндiрiсiнiц KYШтi жогарылауы байкалды, ал пиелонефритi бар орта жэне ересек балаларда Enterococcus faecalis il-1ß децгеш жас балаларга Караганда тшсшше 3,8 жэне 5,2 есе жогары жэне Escherichia coli тудырган пиелонефрит кезiнде тиiсiнше 3,4 жэне 5,9 есе жогары болды. Нейтрофилдердщ фагоцитарлы; белсендiлiгiнiц тeмендеуi аныкталды, б^л айналымдагы иммунды; кешендердiц жеткiлiксiз жойылуына ык;пал етуi MYмкiн, б^л олардыц сарысудагы айтарлыктай ^лгаюымен дэлелденедi. Ец жогары керсеткштер ересек жастагы балаларда аныкталды, онда жетекшi коздыргыштар непзшен Enterococcus faecalis, Escherichia coli жэне Klebsiella pneumoniae болды. Е^орытынды. Осылайша, туа бiткен гидронефроз фонында пиелонефрита бар балаларда иммундык механизмдердщ болуы KYмэн тудырмайды, аутоиммундык синдром ез жасушаларыныц мембраналарыныц закымдануы жэне инфекциялык агенттiц антигендерiн имитациялык жасуша компоненттерiне сенсибилизация нэтижесiнде дамиды. Инфекциядан кейiнгi аутоиммунды синдром кайталама иммун тапшылыгымен бiрге ауыр жагдай болып табылады, eйткенi ол аутоагрессияны гана емес, сонымен бiрге туа бпкен гидронефрозы бар балалардагы пиелонефриттщ ауыр агымымен кeрiнетiн иммундык жауаптыц факторлары мен компоненттерiнiц болмауын да камтиды.Б^л иммун тапшылыгы аурудыц eршуiне жагдай жасайды, баска патогенетикалык факторларды ынталандырады, ал инфекциялык-кабыну процесi дамыган сайын иммунологиялык жеткiлiксiздiк KYшейедi, б^л микроорганизмдердщ, олардыц токсиндерiнiц сакталуына гана емес, сонымен бiрге иммундык жуйенщ резервтерiнiц саркылуына да байланысты.
Негiзгi свздер: балалар, пиелонефрит, этиологиялыц фактор, иммунитет, цабынуга царсы цитокиндер, иммуноглобулиндер.
Определение внутреннего и адаптивного состояния иммунитета у детей с пиелонефритом на фоне врожденного гидронефроза в активной стадии заболевания
М. Мишина1, В. Давыденко2, И. МарченюУ, Ю. Мозгова*1, С. Маланчук, Е. Дубовик1, Ю. Мишин1
1Харьковский национальный медицинский университет, Харьков, Украина 2Харьковский национальный университет имени В. Н. Каразина, Харьков, Украина
Цель исследования - определить состояние адаптивного и врожденного иммунитета в зависимости от возраста детей и этиологического фактора пиелонефрита на фоне врожденного гидронефроза в активной стадии заболевания.
Методы. Исследование проводилось общепринятыми методами.Установлено, что ведущими возбудителями вторичного пиелонефрита на фоне врожденного гидронефроза у детей раннего возраста являются Escherichia coli, Enterococcus faecalis и Staphylococcus epidermidis; в группе среднего возраста возбудителями были Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis,
Candida albicans, а у детей более старшего возраста - Proteus mirabilis, Klebsiella pneumoniae, Enteracocociae pneumoniae, кишечные палочки, грибковые микроорганизмы альбиканс. Выявлено снижение CD95 + лимфоцитов у детей раннего возраста и значительное увеличение этого показателя у детей среднего и старшего возраста. Показано сильное повышение продукции провоспалительных цитокинов, у детей среднего и старшего возраста с пиелонефритом Enterococcus faecalis уровень IL-1ß был в 3,8 и 5,2 раза соответственно выше, чем у детей раннего возраста, и при пиелонефрите, вызванном Escherichia coli в 3,4 и 5,9 раза соответственно. Обнаружена пониженная фагоцитарная активность нейтрофилов, что может способствовать недостаточной элиминации циркулирующих иммунных комплексов, о чем свидетельствует их значительное увеличение в сыворотке. Самые высокие показатели были определены у детей старшего возраста, где ведущими возбудителями были, в основном, Enterococcus faecalis, Escherichia coli и Klebsiella pneumoniae.
Выводы. Таким образом, не вызывает сомнений наличие иммунных механизмов у детей с пиелонефритом на фоне врожденного гидронефроза, аутоиммунный синдром развивается в результате повреждения мембран собственных клеток и сенсибилизации к компонентам клеток, имитирующих антигены инфекционного агента. Постинфекционный аутоиммунный синдром в сочетании со вторичным иммунодефицитом является более тяжелым состоянием, поскольку включает в себя не только аутоагрессию, но и отсутствие факторов и компонентов иммунного ответа, что проявляется тяжелым течением пиелонефрита у детей с врожденным гидронефрозом. Имеющийся иммунодефицит создает условия для прогрессирования заболевания, стимулирует другие патогенетические факторы, а по мере развития инфекционно-воспалительного процесса усиливается иммунологическая недостаточность, связанная не только с сохранением микроорганизмов, их токсинов, но и с истощением резервов иммунной системы. Ключевые слова: дети, пиелонефрит, этиологический фактор, иммунитет, провоспалительные цитокины, иммуноглобулины.
Introduction
Pyelonephritis is the most common childhood disease [1, 2] with a tendency to chronic inflammation and recurrence. At the same time, there is an increase in the frequency of secondary pyelonephritis in children associated with congenital anomalies of urinary tract, such as congenital hydronephrosis, which can lead to the development of chronic renal failure [3, 4, 5]. Despite the constantly increasing number of antibacterial drugs and administration according sensitivity of the pathogen, it is not always possible to provide effective antimicrobial therapy [6, 7].
The recurrent nature of pyelonephritis in children, resulting from congenital hydronephrosis, the absence of etiotropic therapy effect are explained not only by the presence of highly virulent microflora [8], but also by complex pathogenetic mechanisms [9, 10, 11], in the development of which immune system plays an important role [12, 13].
The role of immune mechanisms in the pathogenesis of secondary pyelonephritis in children becomes especially important due to immune system immaturity and imperfection of its many functions in the child's body [14], and also in children with congenital hydronephrosis, secondary pyelonephritis occurs on the background of already existing immunological body restructuring according to impaired differentiation of the urinary tract tissues [15].
The available literature data show a low level of local immune defense in urinary tract that creates favorable
conditions forbacterial colonization [16, 17]. Inflammation in the urinary system appears due to the interaction of two main factors such as child's immunity characteristics and the pathogenic characteristics of pyelonephritis causative agent [18].
However, the literature analysis revealed that such issues as the intensity of phagocytosis, the role of apoptosis, the nature of the cytokine response are insufficiently studied and debatable, there are also no data on the phenotyping of T- and B-lymphocyte subpopulations, their activation during pyelonephritis in children with congenital hydronephrosis.
Therefore, the aim of this research was to determine the state of adaptive and innate immunity depending on the age of children and the etiological factor of pyelonephritis on congenital hydronephrosis background in active stage of the disease.
Methods
24 children aged 1 month to 18 years ill with pyelonephritis, who were in the Municipal Non-Profit Enterprise «Regional Clinical Children's Hospital № 1» were examined. 10 somatically healthy children formed a control group.
Collecting the material from children and bacteriological investigation were performed by conventional methods [19, 20].
Immunological methods included determination of levels of immunoglobulins main classes (A, M, G), cytokines, general complement, circulating immune complexes by using of enzyme-linked immunosorbent assay. Determination of lymphocyte subpopulations
were done by immunofluorescence using Fits-labeled monoclonal antibody kits. Phagocytic activity of neutrophils was determined by the number of phagocytic cells [21].
The work was carried out in accordance with the requirements of the Law of Ukraine «About Medical Products», 1996, articles 7, 8, 12, to the management of ICHGSP (2008), GLP (2002), in accordance with the requirements and norms, standard provisions on ethics of the Ministry of Health of Ukraine J№ 690 dated 23/09/2009. The research was performed with minimal psychological losses from sick children. Parents were fully informed about the methods and volume of the study.
Statistical analysis was performed using StatSoft STATISTICA Version7 [22, 23].
Results
Analysis of the research data revealed that the leading pathogens of secondary pyelonephritis on the background of congenital hydronephrosis in young children (1 group -children under 3 years) were Escherichia coli, Enterococcus faecalis and Staphylococcus epidermidis; in middle-aged (2 group - children from 4 to 7 years) were Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Candida albicans, and in elder children (3 group - children from 8 to 18 years) were Proteus mirabilis, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis, Candida albicans (Fig. 1).
Figure 1. Leading pathogens of pyelonephritis in children with congenital hydronephrosis in the active stage of the disease.
Immunological studies in children with pyelonephritis on the congenital hydronephrosis background detected that the parameters of cellular immunity versus reference values appeared variable in children of different ages. Statistically significant changes regardless to child's age and the pathogen were observed in quantity of CD3+, CD4+, CD8+ and CD25+, indexes of which were decreased. There was found a reduced level of lymphocytes subpopulation with a marker of CD95+ differentiation in young children and a significant increase of this index in middle-aged and elder children (Fig. 2).
Analysis of immunoglobulin levels in children with pyelonephritis on congenital hydronephrosis background revealed that the serum IgA did not differ significantly from the reference values in young children, and in middle-aged and elder children there was a suppression of IgA production. There was a significant increase in IgM in children of group 1, in children of group 2 this index did not differ from the reference values, and in children of group 3 there was a tendency to elevation (Fig. 3).
Candida albicans
Klebsiella pneumoniae
Enterococcus faecalis
Candida albicans
Proteus mirabilis
Pseudomonas aeruginosa Enterococcus faecalis
Staphylococcus epidermidis
Escherichia coli
0 20 40 60 80 100 120 140 160 CD3 □ CD4 CD8 ■ CD25 ■ CD95
Figure 2. Parameters of the cellular immune system in children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease.
Candida albicans 0 9^ь-
u' I O'b
CO Klebsiella pneumoniaeU, *3 O'b
CO Ob
Enterococcus faecalis 1,( 1
Candida albicans 1 Ow
0, I« °'b
Proteus mirabilis 1
r-N no O'4
Pseudomonas aeruginosa 1
1 12 °'t
Enterococcus faecalis 1 13 O'b
1,
Staphylococcus epidermidis 1 1I 'I I
1 12 O's
Escherichia coli 0, I 'I
IgA IgM IgG
Figure 3. Immunoglobulins indexes in children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease.
The main role in the immunopathogenesis of pyelonephritis on congenital hydronephrosis background belongs to the mediators of inflammation, which are formed in the body in response to the influence of aggression factors produced by causative agents. Cytokines are able to modulate the regulatory and effector functions of cells. In a healthy body, there is a balance between cytokines with pro-inflammatory and anti-inflammatory activity. A normally functioning immune system prevents the uncontrolled release of inflammatory mediators and provides an adequate response in macroorganism against microbial invasion.
Study of pro-inflammatory cytokine status in children with pyelonephritis on congenital hydronephrosis
O
2
4
б
I
1O 12
background showed a significant increase in the production of IL-1P, IL-6 and TNFa, versus reference values, in all groups of children independently on leading pathogen (Fig. 4).
Thus, cytokine status parameters according to levels of pro-inflammatory cytokines indicate the active stage of inflammation, and a prolonged rising in TNFa leads to the development of autoallergic reactions, which in turn lead to depletion of the immune system, inhibition of non-specific defense. These processes are crucial in the formation of immunopathological mechanisms of cellular immunity suppression at the stages of T-cell differentiation and proliferation.
Candida albicans
Proteus mirabilis
со Klebsiella pneumoniae
со Staphylococcus epidermidis
Enterococcus faecalis
Escherichia coli
Candida albicans
Klebsiella pneumoniae
Proteus mirabilis 24,2 14,2 2
Proteus vulgaris
Pseudomonas aeruginosa
Staphylococcus epidermidis
У -r
Enterococcus faecalis
Escherichia coli
Staphylococcus epidermidis
2 Enterococcus faecalis ,8L0,8 4,2
Escherichia coli ,4
ILlß
IL6
TNFa
0 20 40 60 80 100 120
Figure 4. Proinflammatory cytokine status parameters in children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease.
Phagocytosis is one of the important nonspecific immunity parameters that provides the protective properties of the body. The course of phagocytosis is manifested by time, however, at the present stage the process itself is not studied, but its results such as the fate of phagocytic cells, the number of absorbed by cells particles, its intensity is analyzed. Therefore, the study of phagocytosis allows to establish the quality of the immune nonspecific response.
It was found that the phagocytic number of neutrophils and their absorption capacity were below control values. Thus, significant changes were observed in the phagocytic activity of neutrophils. The percentage of phagocytic cells in children of different groups was significantly lower than the reference values, indicating a lack of effector functions of phagocytosis in children with pyelonephritis on congenital hydronephrosis background in the active stage, and is one of the mechanisms of low quality inflammatory response. The identified changes indicate the suppression of the body's defense systems (phagocytic chain), which can cause persistence of infection (including intracellular), weak immunogenicity and lack of intense immunity, which is clinically reflected in the torpid course of the disease and recurrent illnesses (Fig. 5).
Low efficiency of phagocytosis may contribute to insufficient elimination of circulating immune complexes, as evidenced by their significant increase in serum of
children with pyelonephritis on congenital hydronephrosis background in all age groups, regardless of the pathogen and versus control group. The highest rates were found in children of elder group, where the leading pathogens were mainly Enterococcus faecalis, Escherichia coli and Klebsiella pneumoniae (Fig. 6).
Candida albicans H -2 i г|.,1
w Klebsiella pneumoniae 1
CO i -о i
Enterococcus faecalis i -11
i -6i i26,1
Candida albicans i -9--1— 8-
3
Proteus mirabilis ,8 '
К 4
Pseudomonas aeruginosa
-6 —'
Enterococcus faecalis -5,6 -'
1
Staphylococcus epidermidis ,-
о 8,2 —'
Escherichia coli s V ^ ) í'19,1 J -r
F
CH50
Figure 5. Indexes of phagocytosis in children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease.
Candida albicans
Klebsiella pneumoniae
Enterococcus faecalis
Candida albicans
Proteus mirabilis
Pseudomonas aeruginosa
Enterococcus faecalis
Staphylococcus epidermidis
Escherichia coli
36,7
40 60 80 100 120 140
Figure 6. Circulating immune complexes index in children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease.
In the comparative analysis of immunological parIn the comparative analysis of immunological parameters of cellular, humoral immune factors, phagocytic immune system and pro-inflammatory cytokine profile in children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease, studying their participation and the importance of each contribution to the development of the pathological process certain peculiarities of immunopathogenesis were detected. A deficiency of complement system activity index (CH50) in middle-aged and elder children groups was established. In the 1st group (young children) the participation of CH50 in the mechanisms of elimination of circulating immune complexes which prevents their excessive accumulation and, consequently, damage of organs and tissues, was reliably shown. Therefore, this defect of the immune response in children of groups 2 and 3 can be regarded as a result of impaired secretory function of macrophages that produce CH50.
Cytotoxic effect of causative agents on lymphocytes
0
20
40 60
80 100
0
20
that lead to lymphopenia, may be indicative for suppression and functional disagreement of cellular immune response in general.
In addition, the state of immune cells apoptosis was studied indirectly by the value of the specific surface receptor CD95+. In middle-aged and elder children with pyelonephritis on congenital hydronephrosis background in the active stage of the disease a severe imbalance in cellular immunity was detected and characterized by a significant exceeding of the level of T-lymphocytes containing CD95+ receptors on their membrane surface versus reference values that indicates an activation of lymphocytes apoptosis. And elevated apoptosis leads to further profound changes and progression of existing T-lymphocyte deficiency, as well as imbalance of all immune system links.
At the same time, a decrease in the expression of the marker CD25+ on the surface of T cells was established. The revealed decrease in the level of immunoregulatory CD4+ and CD25+ T- regulating lymphocytes in the peripheral blood of children with pyelonephritis on congenital hydronephrosis background may indicate the development of autoimmune inflammation. Thus, the processes of activation of apoptosis in severe T-cell deficiency is an important pathogenetic aspect in pyelonephritis on congenital hydronephrosis background in middle-aged and elder children.
It should be noted that changes in cellular immune factors in children with pyelonephritis on congenital hydronephrosis background correspond to the inflammation processes of microbial origin in general, and are characterized by severe deficiency in absolute quantity of leukocytes, lymphocytes, cells with phenotypes CD3+, CD4+ CD8+, CD18+; decreased immunoregulatory index (CD4+ / CD8+), which is an important indicator of the harmonious function of the immune system.
Discussion
Disturbances in the composition of the cellular, humoral, phagocytic link and pro-inflammatory cytokine balance were noted, which were caused by antigenic factors of the leading pathogens of pyelonephritis on congenital hydronephrosis background. Therefore, it can be established that in such children a complex defect of the phagocytic link of the immune system took place, leading to insufficiency of this component of immunity. And also the high level in blood of pro-inflammatory IL-1P, IL-6, TNFa cytokines was found.
The formation of pyelonephritis on congenital hydronephrosis background is accompanied by a violation of adaptive immunity mechanisms, so the monitoring of immunological parameters showed a decrease in cellular immunity by functional activity of T-lymphocytes, absolute number of T-lymphocytes (CD3+), T-helpers (CD4+), natural regulatory cells for excluding of autoaggression
(CD4+), T-cytotoxic cells (CD8+) in all age groups independently on the pathogen. According to the common view, after infecting of the urogenital tract an acute pyelonephritis is developing and in which T-lymphocytes actively migrate from the peripheral bloodstream to the area of primary inflammation. The strains of Enterococcus faecalis, Escherichia coli and Klebsiella pneumoniae have the most aggressive potential. In children with pyelonephritis on congenital hydronephrosis background such changes in the humoral immune system were detected and characterized by imbalance of CD22+, immunoglobulins A, M, G. Reduction in the absolute number of B-lymphocytes (CD22+), IgG and IgA levels in 2nd and 3rd groups, with normal IgM level in the 2nd group and a slight increase in the 3rd group. At the same time in the 1st group the rising in the number of B-lymphocytes, IgA, IgM and IgG levels in the active phase of the process was revealed.
An increase in the concentration of the circulating immune complexes is an indirect evidence of disease activity and severity. Thus, there is no doubt about the presence of immune mechanisms in children with pyelonephritis on congenital hydronephrosis background, autoimmune syndrome is developed by damage of own cells membranes and sensitization to cell components mimicking the infectious agent antigens. Post-infectious autoimmune syndrome in combination with secondary immunodeficiency is a more severe condition because it involves not only autoaggression, but also a lack of factors and components of various forms of immune response, manifested by severe course of pyelonephritis in children with congenital hydronephrosis. The existing immunodeficiency creates conditions for disease progression, stimulates other disease pathogenetic factors, and as the infectious inflammatory process is developing an immunological insufficiency is worsening and associated not only with the persistence of microorganisms, their toxins, but also with depletion of immune system reserves.
Conclusion
Thus, due to the etiological feature of secondary pyelonephritis on congenital hydronephrosis background, in the implementation of immune protection in this pathology innate immune factors participate greatly than the mechanisms of adaptive immunity, although, as in most diseases of infectious-inflammatory origin; the division is often quite conditional due to the close interaction and commonality of their mechanisms. Manifestation of innate immune functions in secondary pyelonephritis in children with congenital hydronephrosis in the active stage of the disease is carried out during an inflammatory reaction, which is a response to cell membranes damage by alteration and penetration of foreign agents, pathogenic or opportunistic bacteria.
References:
1. Kurihara S, Miyazaki Y, Kohno S. Acute bacterial pyelonephritis: Pathogenesis, pathophysiology, and therapy. Nippon Rinsho. 2006;64(2):572-75.
2. Grabe M, Bishop MC, Bjerklund-Johansen TE, et al. Guidelines on Urological Infections. European Association of Urology. 2012:110 -8.
3. Цыгин А. Инфекция мочевыводящих путей у детей. Педиатрическая фармакология. 2010;7(6):39-43.
Tsygin A.N. Urinary tract infections in children. Pediatric pharmacology. 2010;7(6):39-43. (InRussian)
4. Леонова ЛВ.Патологическая анатомия врожденных обструктив-ных уропатий у детей [автореферат диссерт]. Moсква; 2009.55 с.
Leonova LV. Pathological anatomy of congenital obstructive uropathy in children [dissertation abstract]. Moscow; 2009. 55 p. (In Russian)
5. Музыченко ЗН.Осложненные инфекции мочевыводящих путей у детей.
Muzychenko ZN. Complicated infections of urinary tract in children. (In Russian)
6. Ермоленко ВМ, Филатова НН, Малкоч АВ. Инфекция мочевых путей и ее лечение в возрастном аспекте. Лечащий врач 2012;8:8-11.
Ermolenko VM, Filatova NN, Malkoch AV. Infection of urinary tracts and its treatment in the aspect of age. Lechaschi Vrach Journal. 2012;8:8—11.(In Russian)
7. Gallegos J, Márquez S, Morales K, Peña A. Etiologic and antibiotic susceptibility profile of the first episode of febrile urinary tract infection. Chilena Infectol. 2013;30(5):474 -9.
8. Cheng CH, Tsau YK, Kuo CY, Su LH, Lin TY. Comparison of extended virulence genotypes for bacteria isolated from pediatric patients with urosepsis, acute pyelonephritis, and acute lobar nephronia. Pediatr Infect Dis J. 2010 Aug;29(8):736-40. D0I:10.1097/INF.0b013e3181dab249
9. Tittel AP, Heuser C, Ohliger C, Knolle PA, Engel DR, Kurts C. Kidney dendritic cells induce innate immunity against bacterial pyelonephritis. J Am Soc Nephrol. 2011 Aug;22(8):1435-41. DOI: https://doi.org/10.1681/ASN.2010101072
10. Desai J, Kumar SV, Mulay SR, Konrad L, Rimoli S, Schauer C, et al. PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling. Eur J Immunol. 2016;46(1):223-9.
11. Mak R.H., Kuo H.J. Pathogenesis of urinary tract infection: an update. Curr Opin Pediatr. 2006;18:148-52.
12. Кириллов ВИ,Зайцева ОВ, Богданова НА.Эффективность им-мунокоррекции с помощью синтетического дипептида при пиелонифрите у детей. Вопросы современной педиатрии 2013;12(1):24-9. DOI: https://doi.org/10.15690/vsp.v12i1.555 Kirillov VI, Zaitseva OV, Bogdanova NA. Efficacy of immunocorrective treatment with synthetic dipeptide in children with pyelonephritis. Current Pediatrics. 2013;12(1):24—9. DOI: https://doi.org/10.15690/vsp.v12i1.555. (InRussian)
13. Пекарева НА, Чупрова АВ, Лоскутова СА, Пантелеева ЕЮ. Трунов АН. Патогенетическое значение динамики цитокинов
при хроническом обструктивном пиелонефрите у детей. Педиа-трия.2008; 87(3):23-7.
Pekareva NA, Chuprova AV, Loskutova SA, Panteleeva EY, Trunov AN. Pathogenetic value of studying the cytokines dynamics in chronic obstructive pyelonephritis in children . Pediatria. 2008; 87(3):23—7. (InRussian)
14. Щеплягина ЛА, Круглова ИВ. Возрастные особенности иммунитета у детей. РМЖ. 2009;17(23):1564.
Scheplyagina LA, Kruglova IV. Age features of immunity in children. RMJ. 2009;17(23):1564. (In Russian)
15. Bartoli F, Gesualdo L, Paraies G, Caldarulo E. Renal expression of monocyte chemotactic protein-1 epidermal growth factor in children with obstructive hydronephrosis. J Pediatr Surg. 2000;35(4):569 -72.
16. Hilbert DW, Paulish-Miller TE, Tan CK, Carey AJ, Ulett GC, Mordechai E, et al. Clinical Escherichia coli isolates utilize alpha-hemolysin to inhibit in vitro epithelial cytokine production. Microbes Infect. 2012 July;14(7-8):628-38. DOI: https://doi.org/10.1016/j. micinf.2012.01.010
17. Хаитов РМ,Пинегин БВ,Ярилин АА.Руководство по клинической иммунологии.Диагностика заболеваний иммунной систе-мы:Руководство для врачей. Москва, »ГЭОТАР - Медиа» 2009. 352 с.
Khaitov RV, Pinegin BV, Yarilin AA. Guide on clinical immunology. Diagnosis of immune system diseases: guide for doctors. Moskow: Geotar-Media; 2009. 352 p.(In Russian)
18. Bidet P, Bonarcorsi S, Bingen E. Virulence factors and pathophysiology of extraintestinal pathogenic Escherichia coli. Arch. Pediatr. 2012 Nov;19(3):80-92. DOI: https://doi.org/10.1016/ S0929-693X(12)71279 - 4
19. Bilko IP. Requirements for the collecting and transport of material for microbiological investigation. Suchasni infectsii. 2001;3:106-9.
20. Methodical instructions on application of the unified microbiological (bacteriological) methods of research in clinical diagnostic laboratories. Appendix I to the Order of the Ministry of Health № 535;1985. 123p.
21. Lefkovits I, Pernis P. Immunologic methods of research. Switzerland: Basel institute of immunology; 1988. 527 p.
22. Лапач СН, Чубенко АВ, Бабич ПН. Статистические методы в медико-биологических исследованиях с использованием Excel. Морион.2000. 320 с
Lapach SN, Chubenko AV, Babich PN. Statictic methods in medical-biological research using Excel. Kyiv: Morion; 2000. 320 p. (In Russian)
23. Осипов ВП, Лукьянова ЕМ, Антипкин ЮГ, Бруслова ЕМ,Ма-рушко РВ. Методика статистической обработки медицинской информации в научных исследованиях. Планета людей. 2002. 200 с.
Osipov VP, Lukyanova EM, Antipkin YG, Bruslova EM, Marushko RV. Methods of statistical processing of medical information in scientific research. Kyiv: Planeta lyudey; 2002. 200 p. (In Russian)
