Современные представления о роли системы комплемента при мембранозной нефропатии
Современные представления о роли системы комплемента при мембранозной нефропатии
Камышова Е.С., Семерюк Т.А., Бобкова И.Н. Современные представления о роли системы комплемента при мембранозной нефропатии. Терапевтический архив. 2022;94(6):772–776.
DOI: 10.26442/00403660.2022.06.201563
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Kamyshova ES, Semeryuk TA, Bobkova IN. Modern view on the complement system role in membranous nephropathy. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(6):772–776. DOI: 10.26442/00403660.2022.06.201563
Современные представления о роли системы комплемента при мембранозной нефропатии
Камышова Е.С., Семерюк Т.А., Бобкова И.Н. Современные представления о роли системы комплемента при мембранозной нефропатии. Терапевтический архив. 2022;94(6):772–776.
DOI: 10.26442/00403660.2022.06.201563
________________________________________________
Kamyshova ES, Semeryuk TA, Bobkova IN. Modern view on the complement system role in membranous nephropathy. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(6):772–776. DOI: 10.26442/00403660.2022.06.201563
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 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.
1. Cybulsky 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/JCI112408
2. Perkinson DT, Baker PJ, Couser WG, et al. Membrane attack complex deposition in experimental glomerular injury. Am J Pathol. 1985;120(1):121-8.
3. 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.V5111888
4. Petermann 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.x
5. Kerjaschki 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.
6. Takano T, Elimam H, Cybulsky AV. Complement-Mediated Cellular Injury. Semin Nephrol. 2013;33(6):586-601. DOI:10.1016/j.semnephrol.2013.08.009
7. Koopman 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.2020.599974
8. Ootaka 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/91.2.144
9. Lai 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.
10. 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/17.1.57
11. Salant 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/JCI109987
12. Baker 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.
13. 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.1991.242
14. Montinaro 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.x
15. Zhang 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/s12882-019-1509-5
16. Kon 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.1995.496
17. Brenchley 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.1992.143
18. Coupes 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.a092491
19. Leenaerts 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.1995.224
20. Spicer 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.179.1.172
21. Alsharhan L, Beck LH. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021;77(3):440-53. DOI:10.1053/j.ajkd.2020.10.009
22. Beck 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/NEJMoa0810457
23. Tomas 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/NEJMoa1409354
24. Borza 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.2016.00157
25. Jennette 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/83.4.415
26. Segawa 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/s00467-009-1439-8
27. Yang 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/s12026-016-8790-1
28. Hayashi 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/gfx235
29. Haddad 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/JCI140453
30. Huang 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.2012.237
31. Zhang 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.2018.06.050
32. Wiech 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-z
33. Larsen 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.2012.207
34. Ravindran 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.2020.01.018
35. Sethi 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.2018080852
36. Debiec 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.2012060577
37. Vivarelli 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.2014.381
38. Bally 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.2015101155
39. Luo 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.2018.01433
40. Seikrit C, Ronco P, Debiec H. Factor H Autoantibodies and Membranous Nephropathy. N Engl J Med. 2018;379(25):2479-81. DOI:10.1056/NEJMc1805857
41. Valoti 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/NEJMc1905608
42. Kawata 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
________________________________________________
1. Cybulsky 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/JCI112408
2. Perkinson DT, Baker PJ, Couser WG, et al. Membrane attack complex deposition in experimental glomerular injury. Am J Pathol. 1985;120(1):121-8.
3. 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.V5111888
4. Petermann 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.x
5. Kerjaschki 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.
6. Takano T, Elimam H, Cybulsky AV. Complement-Mediated Cellular Injury. Semin Nephrol. 2013;33(6):586-601. DOI:10.1016/j.semnephrol.2013.08.009
7. Koopman 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.2020.599974
8. Ootaka 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/91.2.144
9. Lai 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.
10. 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/17.1.57
11. Salant 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/JCI109987
12. Baker 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.
13. 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.1991.242
14. Montinaro 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.x
15. Zhang 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/s12882-019-1509-5
16. Kon 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.1995.496
17. Brenchley 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.1992.143
18. Coupes 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.a092491
19. Leenaerts 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.1995.224
20. Spicer 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.179.1.172
21. Alsharhan L, Beck LH. Membranous Nephropathy: Core Curriculum 2021. Am J Kidney Dis. 2021;77(3):440-53. DOI:10.1053/j.ajkd.2020.10.009
22. Beck 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/NEJMoa0810457
23. Tomas 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/NEJMoa1409354
24. Borza 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.2016.00157
25. Jennette 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/83.4.415
26. Segawa 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/s00467-009-1439-8
27. Yang 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/s12026-016-8790-1
28. Hayashi 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/gfx235
29. Haddad 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/JCI140453
30. Huang 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.2012.237
31. Zhang 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.2018.06.050
32. Wiech 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-z
33. Larsen 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.2012.207
34. Ravindran 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.2020.01.018
35. Sethi 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.2018080852
36. Debiec 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.2012060577
37. Vivarelli 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.2014.381
38. Bally 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.2015101155
39. Luo 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.2018.01433
40. Seikrit C, Ronco P, Debiec H. Factor H Autoantibodies and Membranous Nephropathy. N Engl J Med. 2018;379(25):2479-81. DOI:10.1056/NEJMc1805857
41. Valoti 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/NEJMc1905608
42. Kawata 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
Авторы
Е.С. Камышова*, Т.А. Семерюк, И.Н. Бобкова
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*kamyshova_e_s@staff.sechenov.ru
________________________________________________
Elena S. Kamyshova*, Tatyana A. Semeryuk, Irina N. Bobkova