Нарушение баланса провоспалительных цитокинов и Т-регуляторных клеток у больных хроническим гломерулонефритом
DOI: 10.26442/00403660.2020.06.000671
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Chebotareva N.V., Vinogradov A.A., Gindis A.A., et al. The balance of proinflammatory cytokines and Treg cells in chronic glomerulonephritis. Therapeutic Archive. 2020; 92 (6): 46–52. DOI: 10.26442/00403660.2020.06.000671
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Цель. Определить клиническое значение цитокинов Th17, Th1 и Тreg в моче для оценки активности и прогрессирования ХГН с нефротическим синдромом (НС).
Материалы и методы. В исследование включены 98 больных ХГН – 37 женщин и 61 мужчина. В зависимости от степени активности ХГН пациенты разделены на 2 группы. 1-я состояла из 51 пациента с НС. У 21 исследуемого выявлено снижение скорости клубочковой фильтрации ниже 60 мл/мин. Во 2-й группе – 47 пациентов с протеинурией от 1 до 3 г/сут без НС. У 26 больных наблюдалось снижение скорости клубочковой фильтрации ниже 60 мл/мин/1,73 м2. Проведена биопсия почки и верифицирован морфологический диагноз 65 пациентам: у 20 – мезангиопролиферативный гломерулонефрит, 16 – мембранозная нефропатия, 18 – фокально-сегментарный гломерулосклероз (ФСГС), 11 – мембранопролиферативный гломерулонефрит. Группа контроля состояла из 15 здоровых людей. Уровни интерлейкинов – ИЛ-6, ИЛ-10, ИЛ-17, фактора некроза опухоли a (ФНО-a) в моче определяли с помощью иммуноферментного анализа. У 39 пациентов в биоптате выявили количество FoxP3-положительных клеток в воспалительном интерстициальном инфильтрате коркового слоя на участке 1,5 мм2.
Результаты. В общей группе больных ХГН отмечалось повышение уровня цитокинов Th17, Th1 и Treg в моче: ФНО-a и ИЛ-10 по сравнению со здоровыми лицами. Повышение уровня ИЛ-6 в моче больных с высокой клинической активностью ХГН (с НС и дисфункцией почек) более выражено, чем у пациентов с НС и сохранной функцией почек. У больных ХГН с НС по сравнению с пациентами без НС отмечены уменьшение количества T-рег клеток в интерстиции почки и снижение продукции противовоспалительного ИЛ-10. Наиболее значимые изменения цитокинового профиля с повышением провоспалительных цитокинов и снижением Т-рег в ткани почки и противовоспалительного ИЛ-10 в моче зафиксированы у больных ФСГС с НС.
Заключение. У больных ХГН с НС, особенно при ФСГС, отмечается дисбаланс цитокинов, характеризующийся повышенным уровнем в моче провоспалительных ИЛ-17, ИЛ-6, ФНО-a, сниженным уровнем противовоспалительного ИЛ-10 и Т-рег лимфоцитов в ткани почки. Нарушение баланса цитокинов отражает высокую активность ХГН и риск его прогрессирования.
Ключевые слова: интерлейкин-17, интерлейкин-6, интерлейкин-10, фактор некроза опухоли αa, Т-регуляторные клетки, хронический гломерулонефрит.
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Chronic glomerulonephritis (CGN) is a disease with a steadily progressing course, which is based on inflammation with the activation of immune cells. The severity of the inflammatory reaction in the kidney tissue is determined by the balance of locally pro-inflammatory factors and protective mechanisms, which include anti-inflammatory cytokines and T-regulatory lymphocytes (Treg). The study of processes that can modulate the severity of inflammation in the kidney is of particular interest for understanding the basic patterns of CGN progression.
Aim. To determine the clinical significance of the Th17, Th1, and Treg cytokines in urine to assess the activity and progression of chronic glomerulonephritis with nephrotic syndrome (NS).
Materials and methods. The study included 98 patients with CGN – 37 women and 61 men. Patients were divided into two groups according to the degree of CGN activity. Group I consisted of 51 patients with NS. In 21 subjects, a decrease in GFR<60 ml/min was revealed. Group II included 47 patients with proteinuria from 1 to 3 g/day without NS. GFR<60 ml/min/1.73 m2 was observed in
26 patients. A kidney biopsy was performed in 65 patients and the hystological diagnosis was verified: 20 had mesangioproliferative GN, 16 had membranous nephropathy, 18 had focal segmental glomerulosclerosis, and 11 had membranoproliferative GN. The control group consisted of 15 healthy people. The levels of IL-6, IL-10, IL-17, tumor necrosis factor a (TNF-a) in the urine were determined using enzyme-linked immunosorbent assay. The number of FoxP3-positive cells in the inflammatory interstitial infiltrate of the cortical layer was determined in 39 patients (in a biopsy sample in a 1.5 mm2 area).
Results. In group of patients with CGN, there was an increase in the levels of Th17, Th1, and Treg cytokines in urine – TNF-a and IL-10 compared with healthy individuals. An increase in the levels of IL-6 in the urine of patients with high clinical activity of CGN (with NS and renal dysfunction) was more pronounced than in patients with NS and normal renal function. There was a decrease in the number of Treg cells in the interstitium of the kidney and a decrease in the production of anti-inflammatory IL-10 in CGN patients with NS, compared with patients without NS. The most pronounced changes in the cytokine profile were observed in patients with FSGS with an increase in pro-inflammatory cytokines and a decrease in Treg in the kidney tissue/anti-inflammatory IL-10 in the urine.
Conclusion. An imbalance of cytokines characterized by an increased levels of pro-inflammatory IL-17, IL-6, TNF-a, and a reduced levels of anti-inflammatory IL-10 and T-regulatory cells in the kidney tissue is noted in patients with NS, especially with FSGS. Imbalance of cytokines reflects the high activity of CGN and the risk of the progression of the disease.
Keywords: interleukin-17, interleukin-6, interleukin-10, tumor necrosis factor αa, Treg cells, chronic glomerulonephritis.
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1. Araya C, Diaz L, Wasserfall C, et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol. 2009;24(1):1691-8. doi: 10.1007/s00467-009-1214-x
2. Stangou M, Bantis C, Skoularopoulou M, et al. Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis. Indian J Nephrol. 2016;26(3):159. doi: 10.4103/0971-4065.159303
3. Turner JE, Paust HJ, Steinmetz OM, Panzer U. The Th17 immune response in renal inflammation. Kidney Int. 2010;77(12): 1070-5. doi: 10.1038/ki.2010.102
4. Mosmann TR, Coffman RL. TH1 and TH2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties. Annu Rev Immunol. 1989;7(1):145-73. doi: 10.1146/annurev.iy.07.040189.001045
5. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123-32. doi: 10.1038/ni1254
6. Lai Kwan Lam Q, King Hung Ko O, Zheng BJ, Lu L. Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis. Proc Natl Acad Sci USA. 2008;105(39):14993-8. doi: 10.1073/pnas.0806044105
7. Maloy KJ. The Interleukin-23/Interleukin-17 axis in intestinal inflammation. J Intern Med. 2008;263(6):584-90. doi: 10.1111/j.1365-2796.2008.01950.x
8. Molet S, Hamid Q, Davoineb F, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001;108(3):430-8. doi: 10.1067/mai.2001.117929
9. Chen DY, Chen YM, Wen MC, et al. The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis. Lupus. 2012;21(13):1385-96. doi: 10.1177/0961203312457718
10. Mansouri M, Mansouri P, Raze AA, Jadali Z. The potential role of Th17 lymphocytes in patients with psoriasis. An Bras Dermatol. 2018;93(1):63-6. doi: 10.1590/abd1806-4841.20186123
11. McGeachy MJ, Cua DJ. Th17 Cell Differentiation: The Long and Winding Road. Immunity. 2008;28(4):445-53. doi: 10.1016/j.immuni.2008.03.001
12. Rodrigues-Díez R, Rodrigues-Díez RR, Rayego-Mateos S, et al. The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response. Lab Invest. 2013;93(7):812-24. doi: 10.1038/labinvest.2013.67
13. Zhu S, Qian Y. IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin Sci. 2012;122(11):487-511. doi: 10.1042/cs20110496
14. Kolls JK, Lindén A. Interleukin-17 Family Members and Inflammation. Immunity. 2004;21(4);467-76. doi: 10.1016/j.immuni.2004.08.018
15. Ley K, Smith E, Stark MA. IL-17A-producing neutrophil-regulatory Tn lymphocytes. Immunol Res. 2006;34(3):229-42. doi: 10.1385/ir:34:3:229
16. Stark MA, Huo Y, Burcin TL, et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005;22(3):285-94. doi: 10.1016/j.immuni.2005.01.011
17. Niemir ZI, Ondracek M, Dworacki G, et al. In situ upregulation of IL-10 reflects the activity of human glomerulonephritides. Am J Kidney Dis. 1998;32(1):80-92. doi: 10.1053/ajkd.1998.v32.pm9669428
18. Ouyang W, Rutz S, Crellin NK, et al. Regulation and functions of the
IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol. 2011;29(1):71-109. doi: 10.1146/annurev-immunol-031210-101312
19. Zhang R, Li Q, Chuang PY, et al. Regulation of pathogenic Th17 cell differentiation by IL-10 in the development of glomerulonephritis. Am J Pathol. 2013;183(2):402-12. doi: 10.1016/j.ajpath.2013.05.001
20. Kalavrizioti D, Gerolymos M, Rodi M, et al. T helper (Th)-cytokines in the urine of patients with primary glomerulonephritis treated with immunosuppressive drugs: Can they predict outcome? Cytokine. 2015;76(2):260-9. doi: 10.1016/j.cyto.2015.08.002
21. Wang L, Li Q, Wang L, et al. The role of Th17/IL-17 in the pathogenesis of primary nephrotic syndrome in children. Kidney Blood Press Res. 2013;37(1):332-45. doi: 10.1159/000350161
22. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Ann Rev Immunol. 2009;27(1)6:485-517. doi: 10.1146/annurev.immunol.
021908.132710
23. Ogura H, Murakami M, Okuyama Y, et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity. 2008;29(4):628-36. doi: 10.1016/j.immuni.2008.07.018
24. Matsumoto K, Kanmatsuse К. Increased Urinary Excretion of Interleukin-17 in Nephrotic Patients. Nephron. 2002;91(1):243-9. doi: 10.1159/000058399
25. Velden J, Paust HJ, Hoxha E, et al. Renal IL-17 expression in human ANCA-associated glomerulonephritis. Am J Physiol Renal Physiol. 2012;302(1):1663-73. doi: 10.1152/ajprenal.00683.2011
26. Strehlau J, de Haij S, Boonstra JG, et al. Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation. Proc Natl Acad Sci USA. 1997;94(2):695-700. doi: 10.1073/pnas.94.2.695
27. Kawaguchi M, Kokubu F, Kuga H, et al. Modulation of bronchial epithelial cells by IL-17. J Allergy Clin Immunol. 2001;108(5):804-9. doi: 10.1067/mai.2001.119027
28. Von Vietinghoff S, Ley K. Homeostatic regulation of blood neutrophil counts. J Immunol. 2008;181(8):5183-8. doi: 10.4049/jimmunol.181.8.5183
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1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России
(Сеченовский Университет), Москва, Россия;
2 ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова», Москва, Россия
________________________________________________
N.V. Chebotareva1, A.A. Vinogradov2, A.A. Gindis1, I.N. Bobkova1, W. Cao1, L.V. Lysenko1
1 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
2 Lomonosov Moscow State University, Moscow, Russia