Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya10962110.26442/00403660.2022.06.201563ReviewsОбзорыReview ArticleModern view on the complement system role in membranous nephropathyСовременные представления о роли системы комплемента при мембранозной нефропатииhttps://orcid.org/0000-0002-1823-0125KamyshovaElena S.КамышоваЕлена Сергеевна
Russian Federation

канд. мед. наук, доц. каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.В. Склифосовского

kamyshova_e_s@staff.sechenov.ruhttps://orcid.org/0000-0002-3271-6412SemeryukTatyana A.СемерюкТатьяна Александровна
Russian Federation

аспирант каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.В. Склифосовского

kamyshova_e_s@staff.sechenov.ruhttps://orcid.org/0000-0002-8007-5680BobkovaIrina N.БобковаИрина Николаевна
Russian Federation

д-р мед. наук, проф. каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.В. Склифосовского

kamyshova_e_s@staff.sechenov.ruSechenov First Moscow State Medical University (Sechenov University)ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)040820229467727760408202204082022Copyright ©; 2022, Consilium MedicumCopyright ©; 2022, ООО "Консилиум Медикум"2022Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/109621

Membranous nephropathy (MN), an immune-mediated glomerular disease, is the most common cause of adult nephrotic syndrome. In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens. Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage. Thus far, the main pathway of complement activation leading to the formation of MAC in MN has not been established. The review highlights current evidence of various complement pathways activation in the development of MN, as well as recently established new molecular mechanisms of complement-mediated podocyte damage.

Мембранозная нефропатия (МН) – иммунологически опосредованное гломерулярное заболевание, которое является наиболее частой причиной нефротического синдрома у взрослых. Протеинурия при МН развивается в результате повреждения подоцитов, обусловленного активацией системы комплемента в ответ на отложение в субэпителиальном пространстве иммунных комплексов, содержащих различные ауто- и экзогенные антигены. Ведущую роль в реализации комплементоопосредованного подоцитарного повреждения играет мембраноатакующий комплекс (МАК), представляющий собой конечный продукт активации системы комплемента по любому из трех путей (классическому, лектиновому или альтернативному). В настоящее время основной путь активации комплемента, приводящий к формированию МАК при МН, не установлен. В статье обсуждаются современные доказательства участия в развитии МН различных путей активации комплемента, в том числе в зависимости от природы антигена и подкласса IgG, а также недавно установленные новые молекулярные механизмы повреждения подоцитов, обусловленные активацией комплемента.

membranous nephropathycomplementmembrane attack complexIgG4phospholipase A2 receptorPLA2Rмембранозная нефропатиякомплементмембраноатакующий комплексIgG4рецептор фосфолипазы А2PLA2RCybulsky AV, Rennke HG, Feintzeig ID, Salant DJ. Complement-induced glomerular epithelial cell injury. Role of the membrane attack complex in rat membranous nephropathy. J Clin Invest. 1986;77(4):1096-107. DOI:10.1172/JCI112408Perkinson DT, Baker PJ, Couser WG, et al. Membrane attack complex deposition in experimental glomerular injury. Am J Pathol. 1985;120(1):121-8.Couser WG, Johnson RJ, Young BA, et al. The effects of soluble recombinant complement receptor 1 on complement-mediated experimental glomerulonephritis. J Am Soc Nephrol. 1995;5(11):1888-94. DOI:10.1681/ASN.V5111888Petermann AT, Krofft R, Blonski M, et al. Podocytes that detach in experimental membranous nephropathy are viable. Kidney Int. 2003;64(4):1222-31. DOI:10.1046/j.1523-1755.2003.00217.xKerjaschki D, Schulze M, Binder S, et al. Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. J Immunol. 1989;143(2):546-52.Takano T, Elimam H, Cybulsky AV. Complement-Mediated Cellular Injury. Semin Nephrol. 2013;33(6):586-601. DOI:10.1016/j.semnephrol.2013.08.009Koopman JJE, van Essen MF, Rennke HG, et al. Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys. Front Immunol. 2021;11:599974. DOI:10.3389/fimmu.2020.599974Ootaka T, Suzuki M, Sudo K, et al. Histologic localization of terminal complement complexes in renal diseases. An immunohistochemical study. Am J Clin Pathol. 1989;91(2):144-51. DOI:10.1093/ajcp/91.2.144Lai KN, Lo ST, Lai FM. Immunohistochemical study of the membrane attack complex of complement and S-protein in idiopathic and secondary membranous nephropathy. Am J Pathol. 1989;135(3):469-76.Papagianni AA, Alexopoulos E, Leontsini M, Papadimitriou M. C5b-9 and adhesion molecules in human idiopathic membranous nephropathy. Nephrol Dial Transplant. 2002;17(1):57-63. DOI:10.1093/ndt/17.1.57Salant DJ, Belok S, Madaio MP, Couser WG. A new role for complement in experimental membranous nephropathy in rats. J Clin Invest. 1980;66(6):1339-50. DOI:10.1172/JCI109987Baker PJ, Ochi RF, Schulze M, et al. Depletion of C6 prevents development of proteinuria in experimental membranous nephropathy in rats. Am J Pathol. 1989;135(1):185-94.Schulze M, Donadio JV Jr, Pruchno CJ, et al. Elevated urinary excretion of the C5b-9 complex in membranous nephropathy. Kidney Int. 1991;40(3):533-8. DOI:10.1038/ki.1991.242Montinaro V, Lopez A, Monno R, et al. Renal C3 synthesis in idiopathic membranous nephropathy: correlation to urinary C5b-9 excretion. Kidney Int. 2000;57(1):137-46. DOI:10.1046/j.1523-1755.2000.00812.xZhang MF, Huang J, Zhang YM, et al. Complement activation products in the circulation and urine of primary membranous nephropathy. BMC Nephrol. 2019;20(1):313. DOI:10.1186/s12882-019-1509-5Kon SP, Coupes B, Short CD, et al. Urinary C5b-9 excretion and clinical course in idiopathic human membranous nephropathy. Kidney Int. 1995;48(6):1953-8. DOI:10.1038/ki.1995.496Brenchley PE, Coupes B, Short CD, et al. Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy. Kidney Int. 1992;41(4):933-7. DOI:10.1038/ki.1992.143Coupes BM, Kon SP, Brenchley PEC, et al. The temporal relationship between urinary C5b-9 and C3dg and clinical parameters in human membranous nephropathy. Nephrol Dial Transplant. 1993;8(5):397-401. DOI:10.1093/oxfordjournals.ndt.a092491Leenaerts PL, Hall BM, Van Damme BJ, et al. Active Heymann nephritis in complement component C6 deficient rats. Kidney Int. 1995;47(6):1604-14. DOI:10.1038/ki.1995.224Spicer ST, Tran GT, Killingsworth MC, et al. Induction of passive Heymann nephritis in complement component 6-deficient PVG rats. J Immunol. 2007;179(1):172-8. DOI:10.4049/jimmunol.179.1.172Alsharhan L, Beck LH. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021;77(3):440-53. DOI:10.1053/j.ajkd.2020.10.009Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21. DOI:10.1056/NEJMoa0810457Tomas NM, Beck LH Jr, Meyer-Schwesinger C, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277-87. DOI:10.1056/NEJMoa1409354Borza DB. Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy. Front Immunol. 2016;7:157. DOI:10.3389/fimmu.2016.00157Jennette JC, Hipp CG. Immunohistopathologic evaluation of C1q in 800 renal biopsy specimens. Am J Clin Pathol. 1985;83(4):415-20. DOI:10.1093/ajcp/83.4.415Segawa Y, Hisano S, Matsushita M, et al. IgG subclasses and complement pathway in segmental and global membranous nephropathy. Pediatr Nephrol. 2010;25(6):1091-9. DOI:10.1007/s00467-009-1439-8Yang Y, Wang C, Jin L, et al. IgG4 anti-phospholipase A2 receptor might activate lectin and alternative complement pathway meanwhile in idiopathic membranous nephropathy: an inspiration from a cross-sectional study. Immunol Res. 2016;64(4):919-30. DOI:10.1007/s12026-016-8790-1Hayashi N, Okada K, Matsui Y, et al. G-32lomerular mannose-binding lectin deposition in intrinsic antigen-related membranous nephropathy. Nephrol Dial Transplant. 2018;33(5):832-40. DOI:10.1093/ndt/gfx235Haddad G, Lorenzen JM, Ma H, et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1-associated membranous nephropathy. J Clin Invest. 2021;131(5):e140453. DOI:10.1172/JCI140453Huang CC, Lehman A, Albawardi A, et al. IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression. Mod Pathol. 2013;26(6):799-805. DOI:10.1038/modpathol.2012.237Zhang MF, Cui Z, Zhang YM, et al. Clinical and prognostic significance of glomerular C1q deposits in primary MN. Clin Chim Acta. 2018;485:152-7. DOI:10.1016/j.cca.2018.06.050Wiech T, Stahl RAK, Hoxha E. Diagnostic role of renal biopsy in PLA2R1-antibody-positive patients with nephrotic syndrome. Mod Pathol. 2019;32(9):1320-8. DOI:10.1038/s41379-019-0267-zLarsen CP, Messias NC, Silva FG, et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol. 2013;26(5):709-15. DOI:10.1038/modpathol.2012.207Ravindran A, Madden B, Charlesworth MC, et al. Proteomic Analysis of Complement Proteins in Membranous Nephropathy. Kidney Int Rep. 2020;5(5):618-26. DOI:10.1016/j.ekir.2020.01.018Sethi S, Madden BJ, Debiec H, et al. Exostosin 1/Exostosin 2-Associated Membranous Nephropathy. J Am Soc Nephrol. 2019;30(6):1123-36. DOI:10.1681/ASN.2018080852Debiec H, Hanoy M, Francois A, et al. Recurrent membranous nephropathy in an allograft caused by IgG3κ targeting the PLA2 receptor. J Am Soc Nephrol. 2012;23(12):1949-54. DOI:10.1681/ASN.2012060577Vivarelli M, Emma F, Pellé T, et al. Genetic homogeneity but IgG subclass-dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies. Kidney Int. 2015;87(3):602-9. DOI:10.1038/ki.2014.381Bally S, Debiec H, Ponard D, et al. Phospholipase A2 Receptor-Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency. J Am Soc Nephrol. 2016;27(12):3539-44. DOI:10.1681/ASN.2015101155Luo W, Olaru F, Miner JH, et al. Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy. Front Immunol. 2018;9:1433. DOI:10.3389/fimmu.2018.01433Seikrit C, Ronco P, Debiec H. Factor H Autoantibodies and Membranous Nephropathy. N Engl J Med. 2018;379(25):2479-81. DOI:10.1056/NEJMc1805857Valoti E, Noris M, Remuzzi G. More about Factor H Autoantibodies in Membranous Nephropathy. N Engl J Med. 2019;381(16):1590-2. DOI:10.1056/NEJMc1905608Kawata N, Kang D, Aiuchi T, et al. Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography-tandem mass spectrometry. Nephrology (Carlton). 2020;25(4):351-9. DOI:10.1111/nep.13676