Современные представления о патогенезе IgA нефропатии

Введение: иммуноглобулин А нефропатия является самым распространенным в мире и в России первичным хроническим гломерулонефритом и одной из наиболее значимых причин развития терминальной стадии хронической болезни почек, требующей применения заместительной почечной терапии. Заболевание дебютирует у людей преимущественно молодого и трудоспособного возраста (от 20 до 40 лет), что определяет его социальную значимость. Также известно о высокой частоте рецидивов IgA нефропатии после трансплантации донорской почки. Спектр клинических проявлений и морфологической картины заболевания чрезвычайно разнообразен, варьируя от изолированного мочевого синдрома (асимптоматическая микрогематурия/протеинурия) до нефритической активности, нефротического синдрома и даже быстропрогрессирующего гломерулонефрита. Цель настоящего обзора представить современный взгляд на патогенез IgA нефропатии. Основные сведения: в настоящее время сформировалось принципиальное понимание природы этого заболевания, а также появились отдельные данные о более тонких механизмах его развития. Стало очевидным, что IgA нефропатия является аутоиммунной болезнью, в основе которой лежит образование иммунных комплексов (ИК). В роли аутоантигена выступает галактозо-дефицитный IgA1 (Gd-IgA1), образующийся в результате ослабленного гликозилирования отдельных участков шарнирной области тяжелых цепей этого иммуноглобулина. Его продукция осуществляется клетками MALT-системы (mucosa-associated lymphoid tissue), а именно лимфоидной ткани миндалин ротоглотки NALT (nasal-associated lymphoid tissue) и дистального отдела тонкого кишечника GALT (gut-associated lymphoid tissue). Однако в последние годы значительную роль в патогенезе IgA нефропатии отводят так называемой оси «кишечник-почка». ИК, связываясь с особыми рецепторами, расположенными на мезангиоцитах почечного клубочка, запускают процесс его повреждения. В представленном научном обзоре приводится информация о структуре и продукции IgA как в норме, так и в условиях, способствующих развитию патологии. Рассматриваются триггеры недогликозилирования IgA1, в частности, роль хронических заболеваний носоглотки и кишечника, значение состояния микробиоты этих отделов желудочно-кишечного тракта и пищевых антигенов. Новые данные о патогенезе IgA нефропатии лежат в основе разрабатываемых и уже апробируемых методов лечения заболевания и поэтому могут представлять интерес для клиницистов. Например, крупное международное многоцентровое рандомизированное двойное слепое плацебо-контролируемое клиническое исследование NefigArd продемонстрировало эффективность глюкокортикостероидного препарата (будесонид/Nefecon) с таргетным высвобождением в дистальном отделе тонкого кишечника при существенно меньшей частоте нежелательных явлений, свойственных системным кортикостероидам.

IgA нефропатия, галактозо-дефицитный IgA1, иммунные комплексы, триггеры, IgA nephropathy, galactose-deficient IgA1, immune complexes, triggers

1. Schena F.P., Nistor I. Epidemiology of IgA Nephropathy: A Global Perspective. Semin Nephrol. 2018. 38:435-442. doi: 10.1016/j.semnephrol.2018.05.013

2. Zhang Z., Zhang Y., Zhang H. IgA nephropathy: a Chinese perspective. Glomerular Dis. 2021. 2(1):30-41. doi: 10.1159/000520039

3. Gharavi A.G., Yan Y., Scolari F. et al. IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet. 2000. 26(3):354-357. doi: 10.1038/81677

4. Kerr M.A. The structure and function of human IgA. Biochem. J. 1990. 271:285-296. doi: 10.1042/bj2710285

5. Kutteh W.H., Prince S.J., Mestecky J. Tissue origins of human polymeric and monomeric IgA. J Immunol. 1982. 128(2):990-995.

6. Monteiro R.C., Van De Winkel J.G. IgA Fc receptors. Annu Rev Immunol. 2003. 21:177-204. doi: 10.1146/annurev.immunol.21.120601.141011

7. Novak J., Julian B.A., Tomana M. et al. IgA glycosylation and IgA immune complexes in the of IgA nephropathy. Semin Nephrol. 2008. 28:78-87. doi: 10.1016/j.semnephrol.2007.10.009

8. Suzuki H., Kiryluk K., Novak J. et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011. 22(10):1795-1803. doi: 10.1681/ASN.2011050464

9. Papista C., Berthelot L., Monteiro R.C. Dysfunctions of the Iga system: a common link between intestinal and renal diseases. Cell Mol Immunol. 2011. 8(2):126-34. doi: 10.1038/cmi.2010.69

10. He J.W., Zhou X.J., Lv J.C. et al. Perspectives on how mucosal immune responses, infections and gut microbiome shape IgA nephropathy and future therapies. Theranostics. 2020. 10(25):11462-11478. doi: 10.7150/thno.49778

11. Wehbi B., Oblet C., Boyer F. et al. Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation. J Am Soc Nephrol. 2019. 30(7):1238-1249. doi: 10.1681/ASN.2018111089

12. Tomana M., Kulhavy R., Mestecky J. Receptor-mediated binding and uptake of immunoglobulin A by human liver. Gastroenterology. 1988. 94(3):762-770. doi: 10.1016/0016-5085(88)90252-1

13. Stockert R.J., Kressner M.S., Collins J.C. et al. IgA interaction with the asialoglycoprotein receptor. Proc Natl Acad Sci U S A. 1982. 79(20):6229-6231. doi: 10.1073/pnas.79.20.6229

14. Griffiss J.M., Goroff D.K. IgA blocks IgM and IgG-initiated immune lysis by separate molecular mechanisms. J Immunol. 1983. 130(6):2882-2885.

15. Wilton J.M. Suppression by IgA of IgG-mediated phagocytosis by human polymorphonuclear leucocytes. Clin Exp Immunol. 1978. 34(3):423-428.

16. Van Epps D.E., Williams R.C. Jr. Suppression of leukocyte chemotaxis by human IgA myeloma components. J Exp Med. 1976. 144(5):1227-1242. doi: 10.1084/jem.144.5.1227

17. Russell M.W., Sibley D.A., Nikolova E.B. et al. IgA antibody as a non-inflammatory regulator of immunity. Biochem. Soc. Trans. 1997. 25:466-470.

18. Pasquier B., Launay P., Kanamaru Y. et al. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity. 2005. 22(1):31-42. doi: 10.1016/j.immuni.2004.11.017

19. Rossato E., Ben Mkaddem S., Kanamaru Y. et al. Reversal of Arthritis by Human Monomeric IgA Through the Receptor-Mediated SH2 Domain-Containing Phosphatase 1 Inhibitory Pathway. Arthritis Rheumatol. 2015. 67(7):1766-1777. doi: 10.1002/art.39142

20. Jacob C.M., Pastorino A.C., Fahl K. et al. Autoimmunity in IgA deficiency: revisiting the role of IgA as a silent housekeeper. J Clin Immunol. 2008. 28 Suppl 1:56-61. doi: 10.1007/s10875-007-9163-2

21. Ammann A.J., Hong R. Selective IgA deficiency: presentation of 30 cases and a review of the literature. Medicine (Baltimore). 1971. 50(3):223-236.

22. Monteiro R.C. Role of IgA and IgA fc receptors in inflammation. J Clin Immunol. 2010. 30(1):1-9. doi: 10.1007/s10875-009-9338-0

23. Monteiro R.C., Rafeh D., Gleeson P.J. Is There a Role for Gut Microbiome Dysbiosis in IgA Nephropathy? Microorganisms. 2022. 10(4):683. doi: 10.3390/microorganisms10040683

24. Gesualdo L., Di Leo V., Coppo R. The mucosal immune system and IgA nephropathy. Semin Immunopathol. 2021. 43(5):657-668. doi: 10.1007/s00281-021-00871-y

25. Мерфи К., Уивер К. Иммунобиология по Джанвэю; пер. с англ. Под ред. Г.А. Игнатьевой, О.А. Свитич, И.Н. Дьякова. М.: Логосфера, 2020. 613-663 с.

26. Cerutti A. The regulation of IgA class switching. Nat Rev Immunol. 2008. 8(6):421-434. doi: 10.1038/nri2322

27. Chen K., Magri G., Grasset E.K. et al. Rethinking mucosal antibody responses: IgM, IgG and IgD join IgA. Nat Rev Immunol. 2020. 20(7):427-441. doi: 10.1038/s41577-019-0261-1

28. Du Y., Cheng T., Liu C. et al. IgA Nephropathy: Current Understanding and Perspectives on Pathogenesis and Targeted Treatment. Diagnostics (Basel). 2023. 13(2):303. doi: 10.3390/diagnostics13020303

29. Saha M.K., Julian B.A., Novak J. et al. Secondary IgA nephropathy. Kidney Int. 2018. 94:674-681. doi: 10.1016/j.kint.2018.02.030

30. Kaetzel C.S., Mestecky J., Johansen F.E. Two Cells, One Antibody: The Discovery of the Cellular Origins and Transport of Secretory IgA. J. Immunol. 2017. 198:1765-1767. doi: 10.4049/jimmunol.1700025

31. Tuma P., Hubbard A.L. Transcytosis: crossing cellular barriers. Physiol Rev. 2003. 83:871-932. doi: 10.1152/physrev.00001.2003

32. Kiyono H., Fukuyama S. NALT- versus Peyer's-patch-mediated mucosal immunity. Nat Rev Immunol. 2004. 4(9):699-710. doi: 10.1038/nri1439

33. Fagarasan S., Kawamoto S., Kanagawa O. et al. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol. 2010. 28:243-273. doi: 10.1146/annurev-immunol-030409-101314

34. Grasset E.K., Chorny A., Casas-Recasens S. et al. Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells. Sci Immunol. 2020. 5(49):eaat7117. doi: 10.1126/sciimmunol.aat7117

35. Berger J., Hinglais N. Les ddpôts intercapillaires d'IgA-IgG [Intercapillary deposits of IgA-IgG]. J Urol Nephrol (Paris). 1968. 74(9):694-695.

36. Coppo R. The intestine-renal connection in IgA nephropathy. Nephrol Dial Transplant. 2015. 30(3):360-366. doi: 10.1093/ndt/gfu343

37. Maillard N., Wyatt R.J., Julian B.A. et al. Current Understanding of the Role of Complement in IgA Nephropathy. J Am Soc Nephrol. 2015. 26(7):1503-1512. doi: 10.1681/ASN.2014101000

38. Sinniah R. Occurrence of mesangial IgA and IgM deposits in a control necropsy population. J Clin Pathol. 1983. 36(3):276-279. doi: 10.1136/jcp.36.3.276

39. Waldherr R., Rambausek M., Duncker W.D. et al. Frequency of mesangial IgA deposits in a non-selected autopsy series. Nephrol Dial Transplant. 1989. 4(11):943-946. doi: 10.1093/ndt/4.11.943

40. Cuevas X., Lloveras J., Mir M. et al. Disappearance of mesangial IgA deposits from the kidneys of two donors after transplantation. Transplant Proc. 1987. 19(1 Pt 3):2208-2209.

41. Silva F.G., Chander P., Pirani C.L. et al. Disappearance of glomerular mesangial IgA deposits after renal allograft transplantation. Transplantation. 1982. 33(2):241-246.

42. Novak J., Tomana M., Matousovic K. et al. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int. 2005. 67(2):504-513. doi: 10.1111/j.1523-1755.2005.67107.x

43. Novak J., Raskova Kafkova L., Suzuki H. et al. IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. Nephrol Dial Transplant. 2011. 26(11):3451-3457. doi: 10.1093/ndt/gfr448

44. Rifai A., Small P.A. Jr., Teague P.O. et al. Experimental IgA nephropathy. J Exp Med. 1979. 150(5):1161-1173. doi: 10.1084/jem.150.5.1161

45. Isaacs K.L., Miller F. Role of antigen size and charge in immune complex glomerulonephritis. Lab. Investig. 1982. 47:198-205.

46. Tomino Y., Sakai H., Miura M. et al. Detection of polymeric IgA in glomeruli from patients with IgA nephropathy. Clin. Exp. Immunol. 1982. 49:419-425.

47. Monteiro R.C., Halbwachs-Mecarelli L., Roque-Barreira M.C. et al. Charge and size of mesangial IgA in IgA nephropathy. Kidney Int. 1985. 28(4):666-671. doi: 10.1038/ki.1985.181

48. Mestecky J., Tomana M., Crowley-Nowick P.A. et al. Defective galactosylation and clearance of IgA1 molecules as a possible etiopathogenic factor in IgA nephropathy. Contrib Nephrol. 1993. 104:172-182. doi: 10.1159/000422410

49. Tomana M., Matousovic K., Julian B.A. et al. Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int. 1997. 52(2):509-516. doi: 10.1038/ki.1997.361

50. Allen A.C., Bailey E.M., Brenchley P.E. et al. Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. Kidney Int. 2001. 60(3):969-973. doi: 10.1046/j.1523-1755.2001.060003969.x

51. Gharavi A.G., Moldoveanu Z., Wyatt R.J. et al. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol. 2008. 19(5):1008.

52. Wang Y.N., Zhou X.J., Chen P. et al. Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy. J Am Soc Nephrol. 2021. 32(3):545-552. doi: 10.1681/ASN.2020060823

53. Serino G., Sallustio F., Cox S.N. et al. Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy. J Am Soc Nephrol. 2012. 23(5):814-824. doi: 10.1681/ASN.2011060567

54. Qin W., Zhong X., Fan J.M. et al. External suppression causes the low expression of the Cosmc gene in IgA nephropathy. Nephrol Dial Transplant. 2008. 23(5):1608-1614. doi: 10.1093/ndt/gfm781

55. Suzuki H., Moldoveanu Z., Hall S. et al. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest. 2008. 118(2):629-639. doi: 10.1172/JCI33189

56. Bene M.C., Faure G., Duheille J. IgA nephropathy: characterization of the polymeric nature of mesangial deposits by in vitro binding of free secretory component. Clin Exp Immunol. 1982. 47(3):527-534.

57. Knoppova B., Reily C., Maillard N. et al. The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy. Front Immunol. 2016. 7:117. doi: 10.3389/fimmu.2016.00117

58. Coppo R. Treatment of IgA nephropathy: Recent advances and prospects. Nephrol Ther. 2018. 14 Suppl 1:13-21. doi: 10.1016/j.nephro.2018.02.010

59. Tomana M., Novak J., Julian B.A. et al. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest. 1999. 104(1):73-81. doi: 10.1172/JCI5535

60. Rizk D.V., Saha M.K., Hall S. et al. Glomerular Immunodeposits of Patients with IgA Nephropathy Are Enriched for IgG Autoantibodies Specific for Galactose-Deficient IgA1. J Am Soc Nephrol. 2019. 30(10):2017-2026. doi: 10.1681/ASN.2018111156

61. Mestecky J., Hashim O.H., Tomana M. Alterations in the IgA carbohydrate chains influence the cellular distribution of IgA1. Contrib Nephrol. 1995. 111:66-71. doi: 10.1159/000423879

62. Novak J., Vu H.L., Novak L. et al. Interactions of human mesangial cells with IgA and IgA-containing immune complexes. Kidney Int. 2002. 62(2):465-475. doi: 10.1046/j.1523-1755.2002.00477.x

63. Phillips J.O., Komiyama K., Epps J.M. et al. Role of hepatocytes in the uptake of IgA and IgA-containing immune complexes in mice. Mol Immunol. 1988. 25(9):873-879. doi: 10.1016/0161-5890(88)90124-1

64. Launay P., Grossetête B., Arcos-Fajardo M. et al. Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger's disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice. J Exp Med. 2000. 191(11):1999-2009. doi: 10.1084/jem.191.11.1999

65. Van der Boog P.J., De Fijter J.W., Van Kooten C. et al. Complexes of IgA with FcalphaRI/CD89 are not specific for primary IgA nephropathy. Kidney Int. 2003. 63(2):514-521. doi: 10.1046/j.1523-1755.2003.00756.x

66. Vuong M.T., Hahn-Zoric M., Lundberg S. et al. Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy. Kidney Int. 2010. 78(12):1281-1287. doi: 10.1038/ki.2010.314

67. Berthelot L., Robert T., Vuiblet V. et al. Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes. Kidney Int. 2015. 88(4):815-822. doi: 10.1038/ki.2015.158

68. Cambier A., Gleeson P.J., Abbad L. et al. Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy. Kidney Int. 2022. 101(2):274-287. doi: 10.1016/j.kint.2021.09.023

69. Boyd J.K., Barratt J. Immune complex formation in IgA nephropathy: CD89 a 'saint' or a 'sinner'? Kidney Int. 2010. 78(12):1211-1213. doi: 10.1038/ki.2010.365

70. Xie X., Gao L., Liu P. et al. Propensity of IgA to self-aggregate via tailpiece cysteine-471 and treatment of IgA nephropathy using cysteamine. JCI Insight. 2021. 6(19):e150551. doi: 10.1172/jci.insight.150551

71. Nihei Y., Suzuki H., Suzuki Y. Current understanding of IgA antibodies in the pathogenesis of IgA nephropathy. Front Immunol. 2023. 14:1165394. doi: 10.3389/fimmu.2023.1165394

72. Гуляев С.В., Стрижаков Л.А., Чеботарева Н.В., и соавт. Роль MALT-системы кишечника в патогенезе IgA-нефропатии. Терапевтический архив. 2021. 93(6):724-728. doi: 10.26442/00403660.2021.06.200868

73. Luvizotto M.J., Menezes-Silva L., Woronik V. et al. Gut-kidney axis in IgA nephropathy: Role on mesangial cell metabolism and inflammation. Frontiers in Cell and Developmental Biology. 2022. 10:993716. doi: 10.3389/fcell.2022.993716

74. Moura I.C., Centelles M.N., Arcos-Fajardo M. et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J Exp Med. 2001. 194(4):417-425. doi: 10.1084/jem.194.4.417

75. Moura I.C., Arcos-Fajardo M., Sadaka C. et al. Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol. 2004. 15(3):622-634. doi: 10.1097/01.asn.0000115401.07980.0c

76. Moura I.C., Arcos-Fajardo M., Gdoura A. et al. Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy. J Am Soc Nephrol. 2005. 16(9):2667-2676. doi: 10.1681/ASN.2004111006

77. Jhee J.H., Nam B.Y., Park J.T. et al. CD71 mesangial IgA1 receptor and the progression of IgA nephropathy. Transl Res. 2021. 230:34-43. doi: 10.1016/j.trsl.2020.10.007

78. Gómez-Guerrero C., Duque N., Egido J. Stimulation of Fc(alpha) receptors induces tyrosine phosphorylation of phospholipase C-gamma(1), phosphatidylinositol phosphate hydrolysis, and Ca2+ mobilization in rat and human mesangial cells. J Immunol. 1996. 156(11):4369-76.

79. Gómez-Guerrero C., López-Armada M.J., González E. et al. Soluble IgA and IgG aggregates are catabolized by cultured rat mesangial cells and induce production of TNF-alpha and IL-6, and proliferation. J Immunol. 1994. 153(11):5247-55.

80. Boyd J.K., Cheung C.K., Molyneux K. et al. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int. 2012. 81(9):833-843. doi: 10.1038/ki.2011.501

81. Monteiro R.C. Recent advances in the physiopathology of IgA nephropathy. Nephrol Ther. 2018. 14 Suppl 1:1-8. doi: 10.1016/j.nephro.2018.02.004

82. Berthelot L., Papista C., Maciel T.T. et al. Transglutaminase is essential for IgA nephropathy development acting through IgA receptors. J Exp Med. 2012. 209:793-806. doi: 10.1084/jem.20112005

83. Ikee R., Kobayashi S., Hemmi N. et al. Involvement of transglutaminase-2 in pathological changes in renal disease. Nephron Clin Pract. 2007. 105:139-146. doi: 10.1159/000098646

84. Berger J. IgA glomerular deposits in renal disease. Transplant Proc. 1969. 1(4):939-944.

85. Béné M.C., Faure G.C. Mucosal immunity and IgA nephropathies. Semin Nephrol. 1987. 7(4):297-300.

86. Wyatt R.J., Kanayama Y., Julian B.A. et al. Complement activation in IgA nephropathy. Kidney Int. 1987. 31(4):1019-1023. doi: 10.1038/ki.1987.101

87. Bene M.C., Faure G.C. Composition of mesangial deposits in IgA nephropathy: complement factors. Nephron. 1987. 46(2):219. doi: 10.1159/000184350

88. Evans D.J., Williams D.G., Peters D.K. et al. Glomerular deposition of properdin in Henoch-Schönlein syndrome and idiopathic focal nephritis. Br Med J. 1973. 3(5875):326-328. doi: 10.1136/bmj.3.5875.326

89. Zhang J.J., Jiang L., Liu G. et al. Levels of urinary complement factor H in patients with IgA nephropathy are closely associated with disease activity. Scand J Immunol. 2009. 69(5):457-464. doi: 10.1111/j.1365-3083.2009.02234.x

90. Murphy B., Georgiou T., Machet D. et al. Factor H-related protein-5: a novel component of human glomerular immune deposits. Am J Kidney Dis. 2002. 39(1):24-27. doi: 10.1053/ajkd.2002.29873

91. Roos A., Bouwman L.H., van Gijlswijk-Janssen D.J. et al. Human IgA activates the complement system via the mannan-binding lectin pathway. J Immunol. 2001. 167(5):2861-2868. doi: 10.4049/jimmunol.167.5.2861

92. Endo M., Ohi H., Ohsawa I. et al. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant. 1998. 13(8):1984-1990. doi: 10.1093/ndt/13.8.1984

93. Matsuda M., Shikata K., Wada J. et al. Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy. Nephron. 1998. 80(4):408-413. doi: 10.1159/000045212

94. Roos A., Rastaldi M.P., Calvaresi N. et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006. 17(6):1724-1734. doi: 10.1681/ASN.2005090923

95. Miyazaki R., Kuroda M., Akiyama T. et al. Glomerular deposition and serum levels of complement control proteins in patients with IgA nephropathy. Clin Nephrol. 1984. 21(6):335-340.

96. Wan J.X., Fukuda N., Endo M. et al. Complement 3 is involved in changing the phenotype of human glomerular mesangial cells. J Cell Physiol. 2007. 213(2):495-501. doi: 10.1002/jcp.21129

97. Nakamura T., Ebihara I., Shirato I. et al. Endothelin-1 mRNA expression by peripheral blood monocytes in IgA nephropathy. Lancet. 1993. 342(8880):1147-1148. doi: 10.1016/0140-6736(93)92126-e

98. Barton M., Yanagisawa M. Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol. 2008. 86(8):485-498. doi: 10.1139/Y08-059

99. Kohan D.E, Barton M. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. 2014. 86(5):896-904. doi: 10.1038/ki.2014.143

100. Trimarchi H., Barratt J., Cattran D.C. et al. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017. 91(5):1014-1021. doi: 10.1016/j.kint.2017.02.003

101. Trimarchi H., Haas M., Coppo R. Crescents and IgA Nephropathy: A Delicate Marriage. J Clin Med. 2022. 11(13):3569. doi: 10.3390/jcm11133569

102. Tomino Y., Yagame M., Omata F. et al. A case of IgA nephropathy associated with adeno- and herpes simplex viruses. Nephron. 1987. 47(4):258-261. doi: 10.1159/000184520

103. Iwama H., Horikoshi S., Shirato I. et al. Epstein-Barr virus detection in kidney biopsy specimens correlates with glomerular mesangial injury. Am J Kidney Dis. 1998. 32(5):785-93. doi: 10.1016/s0272-6386(98)70134-9

104. Park J.S., Song J.H., Yang W.S. et al. Cytomegalovirus is not specifically associated with immunoglobulin A nephropathy. J Am Soc Nephrol. 1994. 4:1623-1626. doi: 10.1681/ASN.V481623

105. Sharmin S., Shimizu Y., Hagiwara M. et al. Staphylococcus aureus antigens induce IgA-type glomerulonephritis in Balb/c mice. J Nephrol. 2004. 17(4):504-511.

106. Suzuki S., Nakatomi Y., Sato H. et al. Haemophilus parainfluenzae antigen and antibody in renal biopsy samples and serum of patients with IgA nephropathy. Lancet. 1994. 343(8888):12-16. doi: 10.1016/s0140-6736(94)90875-3

107. Suzuki S., Kimura H., Gejyo F. [Haemophilus parainfluenzae antigens in IgA nephropathy]. Rinsho Byori. 1998. 46(1):17-25.

108. Ogura Y., Suzuki S., Shirakawa T. et al. Haemophilus parainfluenzae antigen and antibody in children with IgA nephropathy and Henoch-Schönlein nephritis. Am J Kidney Dis. 2000. 36(1):47-52. doi: 10.1053/ajkd.2000.8264

109. Koyama A., Sharmin S., Sakurai H. et al. Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy. Kidney Int. 2004. 66(1):121-132. doi: 10.1111/j.1523-1755.2004.00714.x

110. Takayasu M., Hirayama K., Shimohata H. et al. Staphylococcus aureus Infection-Related Glomerulonephritis with Dominant IgA Deposition. Int J Mol Sci. 2022. 23(13):7482. doi: 10.3390/ijms23137482

111. Sethi S., De Vriese A.S., Fervenza F.C. Acute glomerulonephritis. Lancet. 2022. 399(10335):1646-1663. doi: 10.1016/S0140-6736(22)00461-5

112. Suwarti S., Yamazaki T., Svetlana C. et al. Recognition of CpG oligodeoxynucleotides by human Toll-like receptor 9 and subsequent cytokine induction. Biochem Biophys Res Commun. 2013. 430(4):1234-1239. doi: 10.1016/j.bbrc.2012.12.068

113. Goto T., Bandoh N., Yoshizaki T. et al. Increase in B-cell-activation factor (BAFF) and IFN-gamma productions by tonsillar mononuclear cells stimulated with deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) in patients with IgA nephropathy. Clin Immunol. 2008. 126(3):260-269. doi: 10.1016/j.clim.2007.11.003

114. Takahara M., Kumai T., Komabayashi Y. et al. Aberrant expression of APRIL (a proliferation-inducing ligand) in tonsils from IgA nephropathy patients. J Immunol Allergo Otolaryngol. 2013. 31(2):57-58.

115. Harabuchi Y., Takahara M. Recent advances in the immunological understanding of association between tonsil and immunoglobulin A nephropathy as a tonsil-induced autoimmune/inflammatory syndrome. Immun Inflamm Dis. 2019. 7(2):86-93. doi: 10.1002/iid3.248

116. Zhai Y.L., Zhu L., Shi S.F. et al. Increased APRIL Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy. Medicine (Baltimore). 2016. 95(11):e3099. doi: 10.1097/MD.0000000000003099

117. Suzuki H., Suzuki Y., Narita I. et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol. 2008. 19(12):2384-2395. doi: 10.1681/ASN.2007121311

118. Nozawa H., Takahara M., Yoshizaki T. et al. Selective expansion of T cell receptor (TCR) V beta 6 in tonsillar and peripheral blood T cells and its induction by in vitro stimulation with Haemophilus parainfluenzae in patients with IgA nephropathy. Clin Exp Immunol. 2008. 151(1):25-33. doi: 10.1111/j.1365-2249.2007.03523.x

119. Segerer S., Banas B., Wörnle M. et al. CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Am J Pathol. 2004. 164(2):635-49. doi: 10.1016/S0002-9440(10)63152-5

120. Takahara M., Komabayashi Y., Nagato T. et al. Expression of APRIL and CXCR3 in tonsils from IgA nephropathy patients. J Immunol Allergo Otolaryngol. 2012. 30(2):109-110.

121. Imai T., Hieshima K., Haskell C. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell. 1997. 91(4):521-530. doi: 10.1016/s0092-8674(00)80438-9

122. Otaka R., Takahara M., Ueda S. et al. Up-regulation of CX3CR1 on tonsillar CD8-positive cells in patients with IgA nephropathy. Hum Immunol. 2017. 78(4):375-383. doi: 10.1016/j.humimm.2017.02.004

123. Rehnberg J., Symreng A., Ludvigsson J.F. et al. Inflammatory Bowel Disease Is More Common in Patients with IgA Nephropathy and Predicts Progression of ESKD: A Swedish Population-Based Cohort Study. J Am Soc Nephrol. 2021. 32(2):411-423. doi: 10.1681/ASN.2020060848

124. Barratt J., Lafayette R., Kristensen J. et al. NefIgArd Trial Investigators. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int. 2023. 103(2):391-402. doi: 10.1016/j.kint.2022.09.017

125. Davin J.C., Forget P., Mahieu P.R. Increased intestinal permeability to (51 Cr) EDTA is correlated with IgA immune complex-plasma levels in children with IgA-associated nephropathies. Acta Paediatr Scand. 1988. 77(1):118-124. doi: 10.1111/j.1651-2227.1988.tb10609.x

126. Kovács T., Kun L., Schmelczer M. et al. Do intestinal hyperpermeability and the related food antigens play a role in the progression of IgA nephropathy? I. Study of intestinal permeability. Am J Nephrol. 1996. 16(6):500-505. doi: 10.1159/000169050

127. Rollino C., Vischini G., Coppo R. IgA nephropathy and infections. J Nephrol. 2016. 29(4):463-468. doi: 10.1007/s40620-016-0265-x

128. Kiryluk K., Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Invest. 2014. 124(6):2325-2332. doi: 10.1172/JCI74475

129. Stecher B., Maier L., Hardt W.D. 'Blooming' in the gut: how dysbiosis might contribute to pathogen evolution. Nat Rev Microbiol. 2013. 11(4):277-284. doi: 10.1038/nrmicro2989

130. Currie E.G., Coburn B., Porfilio E.A. et al. Immunoglobulin A nephropathy is characterized by anticommensal humoral immune responses. JCI Insight. 2022. 7(5):e141289. doi: 10.1172/jci.insight.141289

131. He J.W., Zhou X.J., Hou P. et al. Potential Roles of Oral Microbiota in the Pathogenesis of Immunoglobin A Nephropathy. Front Cell Infect Microbiol. 2021. 11:652837. doi: 10.3389/fcimb.2021.652837

132. Cao Y., Qiao M., Tian Z. et al. Comparative Analyses of Subgingival Microbiome in Chronic Periodontitis Patients with and Without IgA Nephropathy by High Throughput 16S rRNA Sequencing. Cell Physiol Biochem. 2018. 47(2):774-783. doi: 10.1159/000490029

133. Park J.I., Kim T.Y., Oh B. et al. Comparative analysis of the tonsillar microbiota in IgA nephropathy and other glomerular diseases. Sci Rep. 2020. 10(1):16206. doi: 10.1038/s41598-020-73035-x

134. Chemouny J.M., Gleeson P.J., Abbad L. et al. Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice. Nephrol Dial Transplant. 2019. 34(7):1135-1144. doi: 10.1093/ndt/gfy323

135. Nakawesi J., This S., Hütter J. et al. αvβ8 integrin-expression by BATF3-dependent dendritic cells facilitates early IgA responses to Rotavirus. Mucosal Immunol. 2021. 14(1):53-67. doi: 10.1038/s41385-020-0276-8

136. McCarthy D.D., Kujawa J., Wilson C. et al. Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. J Clin Invest. 2011. 121(10):3991-4002. doi: 10.1172/JCI45563

137. Yang C., Mogno I., Contijoch E.J. et al. Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation. Cell Host Microbe. 2020. 27(3):467-475.e6. doi: 10.1016/j.chom.2020.01.016

138. De Angelis M., Montemurno E., Piccolo M. et al. Microbiota and metabolome associated with immunoglobulin A nephropathy (IgAN). PLoS One. 2014. 9(6):e99006. doi: 10.1371/journal.pone.0099006

139. Sallustio F., Curci C., Chaoul N. et al. High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients. Nephrol Dial Transplant. 2021. 36(3):452-464. doi: 10.1093/ndt/gfaa264

140. Nyangale E.P., Mottram D.S., Gibson G.R. Gut microbial activity, implications for health and disease: the potential role of metabolite analysis. J Proteome Res. 2012. 11(12):5573-5585. doi: 10.1021/pr300637d

141. Coppo R., Amore A., Roccatello D. et al. IgA antibodies to dietary antigens and lectin-binding IgA in sera from Italian, Australian, and Japanese IgA nephropathy patients. Am J Kidney Dis. 1991. 17(4):480-487. doi: 10.1016/s0272-6386(12)80644-5

142. Yap H.K., Sakai R.S., Woo K.T. et al. Detection of bovine serum albumin in the circulating IgA immune complexes of patients with IgA nephropathy. Clin Immunol Immunopathol. 1987. 43(3):395-402. doi: 10.1016/0090-1229(87)90149-8

143. Sato M., Takayama K., Wakasa M. et al. Estimation of circulating immune complexes following oral challenge with cow's milk in patients with IgA nephropathy. Nephron. 1987. 47(1):43-48. doi: 10.1159/000184455

144. Serena G., D’Avino P., Fasano A. Celiac Disease and Non-celiac Wheat Sensitivity: State of Art of Non-dietary Therapies. Front Nutr. 2020. 7:152. doi: 10.3389/fnut.2020.00152

145. Yin J., Yu F.S. Rho kinases regulate corneal epithelial wound healing. Am J Physiol Cell Physiol. 2008. 295:378-387. doi: 10.1152/ajpcell.90624.2007

146. Tripathi A., Lammers K.M., Goldblum S. et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci U S A. 2009. 106:16799-16804. doi: 10.1073/pnas.0906773106

147. Rubio-Tapia A., Murray J.A. Celiac disease. Curr Opin Gastroenterol. 2010. 26:116-122. doi: 10.1097/MOG.0b013e3283365263

148. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011. 91:151-175. doi: 10.1152/physrev.00003.2008

149. Kim S.M., Mayassi T., Jabri B. Innate immunity: actuating the gears of celiac disease pathogenesis. Best Pract Res Clin Gastroenterol. 2015. 29:425-443. doi: 10.1016/j.bpg.2015.05.001

150. Dieterich W., Ehnis T., Bauer M. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997. 3:797-801. doi: 10.1038/nm0797-797

151. Korponay-Szabó I.R., Halttunen T. et al. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut. 2004. 53:641-648. doi: 10.1136/gut.2003.024836

152. Pasternack A., Collin P., Mustonen J. et al. Glomerular IgA deposits in patients with celiac disease. Clin Nephrol. 1990. 34(2):56-60.

153. Woodrow G., Innes A., Boyd S.M. et al. A case of IgA nephropathy with coeliac disease responding to a gluten-free diet. Nephrol Dial Transplant. 1993. 8:1382-1383.

154. Papista C., Lechner S., Ben Mkaddem S. et al. Gluten exacerbates IgA nephropathy in humanized mice through gliadin-CD89 interaction. Kidney Int. 2015. 88:276-285. doi: 10.1038/ki.2015.94

155. Costa S., Currò G., Pellegrino S. et al. Case report on pathogenetic link between gluten and IgA nephropathy. BMC Gastroenterol. 2018. 18(1):64. doi: 10.1186/s12876-018-0792-0

156. Welаnder A., Sundelin B., Fored M. et al. Increased risk of IgA Nephropathy among individuals with celiac disease. J Clin Gastroenterol. 2013. 47:678-683. doi: 10.1097/MCG.0b013e318284792e

157. Nurmi R., Pasternack C., Salmi T. et al. J Intern Med. The risk of renal comorbidities in celiac disease patients depends of the phenotype of celiac disease. 2022. 292:279-287. doi: 10.1111/joim.13532

158. Collin P., Syrjänen J., Partanen J. et al. Celiac disease and HLA DQ in patients with IgA nephropathy. Am J Gastroenterol. 2002. 97:2572-2576. doi: 10.1111/j.1572-0241.2002.06025.x

159. Slavin S.F. IgA Nephropathy as the Initial Presentation of Celiac Disease in an Adolescent. Pediatrics. 2021. 148(4):e2021051332. doi: 10.1542/peds.2021-051332

160. Habura I., Fiedorowicz K., Wozniak A. et al. IgA nephropathy associated with coeliac disease. Centr Eur J Immunol. 2019. 44 (1):106-108. doi: 10.5114/ceji.2019.84021

161. Welender A., Prutz K.G., Fored M. et al. Increased risk of end-stage renal disease in individuals with celiac disease. Gut. 2012. 61:64-68. doi: 10.1136/gutjnl-2011-300134

162. Coppo R., Amore A., Roccatello D. Dietary antigens and primary immunoglobulin A nephropathy. J Am Soc Nephrol. 1992. 2:173-180. doi: 10.1681/ASN.V210s173

163. Koivuviita N., Tertti R., Heiro M. et al. A case report: a patient with IgA nephropathy and coeliac disease. Complete clinical remission following gluten-free diet. Nephrol Dial Transplant. 2009. 2:161-163. doi: 10.1093/ndtplus/sfn205

164. Salmi T.T., Collin P., Korponay-Szabó I.R. et al. Endomysial antibody-negative coeliac disease: Clinical characteristics and intestinal autoantibody deposits. Gut. 2006. 55:1746-1753. doi: 10.1136/gut.2005.071514

165. Hadjivassiliou M., Mäki M., Sanders D.S. et al. Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology. 2006. 66:373-377. doi: 10.1212/01.wnl.0000196480.55601.3a

166. Koskinen O., Collin P., Korponay-Szabo I. et al. Gluten dependent small bowel mucosal transglutaminase 2-specific IgA deposits in overt and mild enteropathy coeliac disease. J Pediatr Gastroenterol Nutr. 2008. 47:436-442. doi: 10.1097/MPG.0b013e31817b6dec

167. Kaukinen K., Peräaho M., Collin P. et al. Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: A prospective and randomized clinical study. Scand J Gastroenterol. 2005. 40:564-572. doi: 10.1080/00365520510023422

168. Nurmi R., Korponay-Szabó I., Laurila К. et al. Celiac Disease-Type Tissue Transglutaminase Autoantibody Deposits in Kidney Biopsies of Patients with IgA Nephropathy. Nutrients. 2021. 13(5):1594. doi: 10.3390/nu13051594