Нетоз при волчаночном нефрите

Решетняк Т.М., Нурбаева К.С., Пташник И.В., Кудряева А.А., Белогуров А.А., Лила А.М., Насонов Е.Л. Нетоз при волчаночном нефрите. Терапевтический архив. 2024;96(5):453–458.
DOI: 10.26442/00403660.2024.05.202699

© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.

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Reshetnyak TM, Nurbaeva KS, Ptashnik IV, Kudriaeva AA, Belogurov AA, Lila AM, Nasonov EL. NETosis in lupus nephritis. Terapevticheskii Arkhiv (Ter. Arkh.). 2024;96(5):453–458. DOI: 10.26442/00403660.2024.05.202699

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Аннотация

Цель. Оценить уровень комплекса миелопероксидаза (МПО)-ДНК в крови у пациентов с системной красной волчанкой (СКВ) и его связь с волчаночным нефритом (ВН).
Материалы и методы. В исследование включены 77 пациентов с СКВ – 30 с СКВ без антифосфолипидного синдрома, 47 с СКВ + антифосфолипидный синдром и 20 практически здоровых человек в качестве контрольной группы. Комплекс МПО-ДНК исследован в сыворотке крови методом иммуноферментного анализа.
Результаты. Уровень комплекса МПО-ДНК в сыворотке крови оказался достоверно выше у больных СКВ по сравнению со здоровым контролем (p=0,001). Среди пациентов с СКВ 30 (39%) имели повышенный уровень комплекса МПО-ДНК. Повышение уровня комплекса МПО-ДНК оказалось достоверно связано с ВН в анамнезе (p=0,009). Среди пациентов, включенных в исследование, 20 имели активный ВН, и вероятность наличия активного ВН у пациентов с повышенным уровнем комплекса МПО-ДНК оказалась выше, чем у пациентов без повышения концентрации комплекса МПО-ДНК: 12 (40%) из 30 против 8 (17%) из 47 (χ²=5,029; p=0,034). Обнаружена ассоциация между повышенными уровнями комплекса МПО-ДНК и наличием протеинурии, гематурии, цилиндрурии, асептической лейкоцитурии. Выявлена прямая корреляция комплекса МПО-ДНК с индексом SLEDAI-R у пациентов с активным ВН (r_s=0,497; p=0,026).
Заключение. У 39% больных СКВ выявлены повышенные уровни комплекса МПО-ДНК. Эти пациенты чаще имели ВН в анамнезе и на момент включения в исследование. Корреляция между уровнем комплекса МПО-ДНК и активностью ВН согласно SLEDAI-R указывает на потенциальную роль комплекса МПО-ДНК в качестве биомаркера для оценки активности поражения почек при СКВ.

Ключевые слова: системная красная волчанка, волчаночный нефрит, NETs, нетоз, комплекс МПО-ДНК

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Aim. To evaluate the levels of MPO-DNA complex in patients with systemic lupus erythematosus (SLE) and its association with the presence of lupus nephritis (LN).
Materials and methods. The study included 77 patients with SLE, of whom 30 had SLE without anti phospholipid syndrome (APS), 47 had SLE with APS, and 20 were healthy individuals serving as the control group. The MPO-DNA complex in the serum was investigated using ELISA.
Results. The levels of MPO-DNA complex in serum were significantly higher in patients with SLE compared to healthy controls (p=0.001). Among the patients with SLE, 30 (39%) had elevated levels of MPO-DNA complex. The presence of elevated MPO-DNA complex was significantly associated with the presence of a history of LN (p=0.009). Moreover, among the patients included in the study, 20 had active LN, and patients with elevated MPO-DNA complex levels were more likely to have active LN than patients without elevated MPO-DNA complex concentrations [12 (40%) of 30 vs 8 (17%) of 47, χ²=5.029; p=0.034]. An association was found between elevated levels of MPO-DNA complex and the presence of proteinuria, hematuria, cellular hematic/granular casts and aseptic leukocyturia. A direct correlation of MPO-DNA complex with SLEDAI-R was found in patients with active LN (r_s=0.497; p=0.026).
Conclusion. Elevated levels of MPO-DNA complex were detected in 39% of patients with SLE. These patients had a higher prevalence of LN in their medical history and at the time of inclusion in the study. The correlation between MPO-DNA complex levels and the activity of LN according to SLEDAI-R indicates the potential role of MPO-DNA complex as a biomarker for assessing the activity of renal damage in SLE.

Keywords: systemic lupus erythematosus, lupus nephritis, NETs, NETosis, MPO-DNA complex

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Список литературы

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4. Juha M, Molnár A, Jakus Z, et al. NETosis: an emerging therapeutic target in renal diseases. Front Immunol. 2023;14:1253667. DOI:10.3389/fimmu.2023.1253667
5. Vorobjeva NV, Chernyak BV. NETosis: Molecular Mechanisms, Role in Physiology and Pathology. Biochemistry. 2020;85:1178-90. DOI:10.1134/S0006297920100065
6. Schultz BM, Acevedo OA, Kalergis AM, et al. Role of Extracellular Trap Release during Bacterial and Viral Infection. Front. Microbiol. 2022;13:798853. DOI:10.3389/fmicb.2022.798853
7. Насонов Е.Л., Авдеева А.С., Решетняк Т.М., и др. Роль нетоза в патогенезе иммуновоспалительных ревматических заболеваний. Научно-практическая ревматология. 2023;61(5):513-30 [Nasonov EL, Avdeeva AS, Reshetnyak TM, et al. The role of NETosis in the pathogenesis of immunoinflammatory rheumatic diseases. Rheumatology Science and Practice. 2023;61(5):513-53 (in Russian)]. DOI:10.47360/1995-4484-2023-513-530
8. Wang M, Ishikawa T, Lai Y, et al. Diverse Roles of NETosis in the Pathogenesis of Lupus. Front Immunol. 2022;13:895216. DOI:10.3389/fimmu.2022.895216
9. Chen SY, Wang CT, Chen CY, et al. Galectin-3 Mediates NETosis and Acts as an Autoantigen in Systemic Lupus Erythematosus-Associated Diffuse Alveolar Haemorrhage. Int J Mol Sci. 2023;24:9493. DOI:10.3390/ijms24119493
10. Gestermann N, Di Domizio J, Lande R, et al. Netting Neutrophils Activate Autoreactive B Cells in Lupus. J Immunol. 2018;200:3364-71. DOI:10.4049/jimmunol.1700778
11. Leffler J, Martin M, Gullstrand B, et al. Neutrophil Extracellular Traps That Are Not Degraded in Systemic Lupus Erythematosus Activate Complement Exacerbating the Disease. J Immunol. 2012;188:3522-31. DOI:10.4049/jimmunol.1102404
12. Lande R, Ganguly D, Facchinetti V, et al. Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA-Peptide Complexes in Systemic Lupus Erythematosus. Sci Transl Med. 2011;3:73ra19. DOI:10.1126/scitranslmed.3001180
13. Garcia-Romo GS, Caielli S, Vega B, et al. Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus. Sci Transl Med. 2011;3:73ra20. DOI:10.1126/scitranslmed.3001201
14. Reshetnyak T, Nurbaeva K. The Role of Neutrophil Extracellular Traps (NETs) in the Pathogenesis of Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Int J Mol Sci. 2023;24(17):13581. DOI:10.3390/ijms241713581
15. Masuda S, Nakazawa D, Shida H, et al. NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta. 2016;459:89-93. DOI:10.1016/j.cca.2016.05.029
16. Kessenbrock K, Krumbholz M, Schönermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623-5. DOI:10.1038/nm.1959
17. Wang W, Peng W, Ning X. Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis. Int J Rheum Dis. 2018;21(2):415-21. DOI:10.1111/1756-185X.13226
18. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. DOI:10.1002/art.1780400928
19. Gladman DD, Ibanez D, Urowitz MB. Systemic Lupus Erythematosus Disease Activity Index 2000. J Rheumatol. 2002;29(2):288-91.
20. Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39(3):363-9. DOI:10.1002/art.1780390303
21. Dooley MA, Aranow C, Ginzler EM. Review of ACR renal criteria in systemic lupus erythematosus. Lupus. 2004;13(11):857-60. DOI:10.1191/0961203304lu2023oa
22. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521-30.
DOI:10.1111/j.1523-1755.2004.00443.x
23. Mina R, Abulaban K, Klein-Gitelman MS, et al. Validation of the Lupus Nephritis Clinical Indices in Childhood-Onset Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 2016;68(2):195-202. DOI:10.1002/acr.22651
24. Reshetnyak T, Nurbaeva K, Ptashnik I, et al. Markers of NETosis in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Int J Mol Sci. 2023;24(11):9210. DOI:10.3390/ijms24119210
25. Lood C, Blanco LP, Purmalek MM, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22:146-53. DOI:10.1038/nm.4027
26. Frangou E, Chrysanthopoulou A, Mitsios A, et al. REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Ann Rheum Dis. 2019;78:238-48. DOI:10.1136/annrheumdis-2018-213181
27. Bruschi M, Bonanni A, Petretto A, et al. Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis. J Rheumatol. 2020;47:377-86. DOI:10.3899/jrheum.181232
28. Moore S, Juo HH, Nielsen CT, et al. Role of Neutrophil Extracellular Traps Regarding Patients at Risk of Increased Disease Activity and Cardiovascular Comorbidity in Systemic Lupus Erythematosus. J Rheumatol. 2020;47:1652-60. DOI:10.3899/jrheum.190875
29. Hanata N, Ota M, Tsuchida Y, et al. Serum extracellular traps associate with the activation of myeloid cells in SLE patients with the low level of anti-DNA antibodies. Sci Rep. 2022;12:18397. DOI:10.1038/s41598-022-23076-1
30. Hakkim A, Fürnrohr BG, Amann K, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA. 2010;107:9813-8. DOI:10.1073/pnas.0909927107
31. Villanueva E, Yalavarthi S, Berthier CC, et al. Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus. J Immunol. 2011;187:538-52. DOI:10.4049/jimmunol.1100450
32. Pieterse E, Rother N, Garsen M, et al. Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition. Arterioscler Thromb Vasc Biol. 2017;37:1371-9. DOI:10.1161/ATVBAHA.117.309002
33. Leffler J, Gullstrand B, Jönsen A, et al. Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus. Arthritis Res Ther. 2013;15:R84. DOI:10.1186/ar4264

________________________________________________

1. Nasonov EL, Reshetnyak TM, Solovyev SK, et al. Systemic lupus erythematosus and antiphospholipid syndrome: Past, present, future. Terapevticheskii Arkhiv (Ter. Arkh.).
2023;95:365-74 (in Russian). DOI:10.26442/00403660.2023.05.202246
2. Alforaih N, Whittall-Garcia L, Touma Z. A Review of Lupus Nephritis. J Applied Lab Med. 2022;7(6):1450-67. DOI:10.1093/jalm/jfac036
3. Hanly JG, O'Keeffe AG, Su L, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford). 2016;55(2):252-62. DOI:10.1093/rheumatology/kev311
4. Juha M, Molnár A, Jakus Z, et al. NETosis: an emerging therapeutic target in renal diseases. Front Immunol. 2023;14:1253667. DOI:10.3389/fimmu.2023.1253667
5. Vorobjeva NV, Chernyak BV. NETosis: Molecular Mechanisms, Role in Physiology and Pathology. Biochemistry. 2020;85:1178-90. DOI:10.1134/S0006297920100065
6. Schultz BM, Acevedo OA, Kalergis AM, et al. Role of Extracellular Trap Release during Bacterial and Viral Infection. Front. Microbiol. 2022;13:798853. DOI:10.3389/fmicb.2022.798853
7. Nasonov EL, Avdeeva AS, Reshetnyak TM, et al. The role of NETosis in the pathogenesis of immunoinflammatory rheumatic diseases. Rheumatology Science and Practice. 2023;61(5):513-53 (in Russian). DOI:10.47360/1995-4484-2023-513-530
8. Wang M, Ishikawa T, Lai Y, et al. Diverse Roles of NETosis in the Pathogenesis of Lupus. Front Immunol. 2022;13:895216. DOI:10.3389/fimmu.2022.895216
9. Chen SY, Wang CT, Chen CY, et al. Galectin-3 Mediates NETosis and Acts as an Autoantigen in Systemic Lupus Erythematosus-Associated Diffuse Alveolar Haemorrhage. Int J Mol Sci. 2023;24:9493. DOI:10.3390/ijms24119493
10. Gestermann N, Di Domizio J, Lande R, et al. Netting Neutrophils Activate Autoreactive B Cells in Lupus. J Immunol. 2018;200:3364-71. DOI:10.4049/jimmunol.1700778
11. Leffler J, Martin M, Gullstrand B, et al. Neutrophil Extracellular Traps That Are Not Degraded in Systemic Lupus Erythematosus Activate Complement Exacerbating the Disease. J Immunol. 2012;188:3522-31. DOI:10.4049/jimmunol.1102404
12. Lande R, Ganguly D, Facchinetti V, et al. Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA-Peptide Complexes in Systemic Lupus Erythematosus. Sci Transl Med. 2011;3:73ra19. DOI:10.1126/scitranslmed.3001180
13. Garcia-Romo GS, Caielli S, Vega B, et al. Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus. Sci Transl Med. 2011;3:73ra20. DOI:10.1126/scitranslmed.3001201
14. Reshetnyak T, Nurbaeva K. The Role of Neutrophil Extracellular Traps (NETs) in the Pathogenesis of Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Int J Mol Sci. 2023;24(17):13581. DOI:10.3390/ijms241713581
15. Masuda S, Nakazawa D, Shida H, et al. NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta. 2016;459:89-93. DOI:10.1016/j.cca.2016.05.029
16. Kessenbrock K, Krumbholz M, Schönermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623-5. DOI:10.1038/nm.1959
17. Wang W, Peng W, Ning X. Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis. Int J Rheum Dis. 2018;21(2):415-21. DOI:10.1111/1756-185X.13226
18. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. DOI:10.1002/art.1780400928
19. Gladman DD, Ibanez D, Urowitz MB. Systemic Lupus Erythematosus Disease Activity Index 2000. J Rheumatol. 2002;29(2):288-91.
20. Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39(3):363-9. DOI:10.1002/art.1780390303
21. Dooley MA, Aranow C, Ginzler EM. Review of ACR renal criteria in systemic lupus erythematosus. Lupus. 2004;13(11):857-60. DOI:10.1191/0961203304lu2023oa
22. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65(2):521-30.
DOI:10.1111/j.1523-1755.2004.00443.x
23. Mina R, Abulaban K, Klein-Gitelman MS, et al. Validation of the Lupus Nephritis Clinical Indices in Childhood-Onset Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 2016;68(2):195-202. DOI:10.1002/acr.22651
24. Reshetnyak T, Nurbaeva K, Ptashnik I, et al. Markers of NETosis in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Int J Mol Sci. 2023;24(11):9210. DOI:10.3390/ijms24119210
25. Lood C, Blanco LP, Purmalek MM, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22:146-53. DOI:10.1038/nm.4027
26. Frangou E, Chrysanthopoulou A, Mitsios A, et al. REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Ann Rheum Dis. 2019;78:238-48. DOI:10.1136/annrheumdis-2018-213181
27. Bruschi M, Bonanni A, Petretto A, et al. Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis. J Rheumatol. 2020;47:377-86. DOI:10.3899/jrheum.181232
28. Moore S, Juo HH, Nielsen CT, et al. Role of Neutrophil Extracellular Traps Regarding Patients at Risk of Increased Disease Activity and Cardiovascular Comorbidity in Systemic Lupus Erythematosus. J Rheumatol. 2020;47:1652-60. DOI:10.3899/jrheum.190875
29. Hanata N, Ota M, Tsuchida Y, et al. Serum extracellular traps associate with the activation of myeloid cells in SLE patients with the low level of anti-DNA antibodies. Sci Rep. 2022;12:18397. DOI:10.1038/s41598-022-23076-1
30. Hakkim A, Fürnrohr BG, Amann K, et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA. 2010;107:9813-8. DOI:10.1073/pnas.0909927107
31. Villanueva E, Yalavarthi S, Berthier CC, et al. Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus Erythematosus. J Immunol. 2011;187:538-52. DOI:10.4049/jimmunol.1100450
32. Pieterse E, Rother N, Garsen M, et al. Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition. Arterioscler Thromb Vasc Biol. 2017;37:1371-9. DOI:10.1161/ATVBAHA.117.309002
33. Leffler J, Gullstrand B, Jönsen A, et al. Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus. Arthritis Res Ther. 2013;15:R84. DOI:10.1186/ar4264

Авторы

Т.М. Решетняк*^1,2, К.С. Нурбаева^1,2, И.В. Пташник³, А.А. Кудряева³, А.А. Белогуров^3,4, А.М. Лила^1,2, Е.Л. Насонов^1,5

¹ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой», Москва, Россия;
²ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
³ФГБУН «Институт биоорганической химии им. акад. М.М. Шемякина и Ю.А. Овчинникова» РАН, Москва, Россия;
⁴ФГБОУ ВО «"Российский университет медицины» Минздрава России, Москва, Россия;
⁵ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*reshetnyak.tatjana@yandex.ru

________________________________________________

Tatiana M. Reshetnyak*^1,2, Kamila S. Nurbaeva^1,2, Ivan V. Ptashnik³, Anna A. Kudriaeva³, Alexey A. Belogurov^3,4, Aleksander M. Lila^1,2, Evgeny L. Nasonov^1,5

¹Nasonova Research Institute of Rheumatology, Moscow, Russia;
²Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
³Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia;
⁴Russian University of Medicine, Moscow, Russia;
⁵Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
*reshetnyak.tatjana@yandex.ru

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