Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment
Abstract
:1. Introduction
2. Galactose-Deficient IgA1 (Hit #1)
3. Autoantibodies (Hit #2)
4. Other Types of Autoantibodies Targeting Aberrantly Glycosylated Proteins
5. Circulating Immune Complexes (Hit #3)
6. Deposition of Circulating Immune Complexes and Renal Injury (Hit #4)
7. IgA Nephropathy—Disease-Specific Treatment Approaches
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- D’Amico, G. The commonest glomerulonephritis in the world: IgA nephropathy. Q. J. Med. 1987, 64, 709–727. [Google Scholar]
- Berger, J.; Hinglais, N. Intercapillary deposits of IgA-IgG. J. Urol. Nephrol. 1968, 74, 694–695. [Google Scholar]
- Conley, M.E.; Cooper, M.D.; Michael, A.F. Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J. Clin. Investig. 1980, 66, 1432–1436. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Allen, A.C.; Bailey, E.M.; Brenchley, P.E.; Buck, K.S.; Barratt, J.; Feehally, J. Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: Observations in three patients. Kidney Int. 2001, 60, 969–973. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hiki, Y.; Odani, H.; Takahashi, M.; Yasuda, Y.; Nishimoto, A.; Iwase, H.; Shinzato, T.; Kobayashi, Y.; Maeda, K. Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int. 2001, 59, 1077–1085. [Google Scholar] [CrossRef] [Green Version]
- Jennette, J.C. The immunohistology of IgA nephropathy. Am. J. Kidney Dis. 1988, 12, 348–352. [Google Scholar] [CrossRef]
- Wyatt, R.J.; Julian, B.A. IgA nephropathy. N. Engl. J. Med. 2013, 368, 2402–2414. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roberts, I.S. Pathology of IgA nephropathy. Nat. Rev. Nephrol. 2014, 10, 445–454. [Google Scholar] [CrossRef]
- D’Amico, G.; Colasanti, G.; Barbiano di Belgioioso, G.; Fellin, G.; Ragni, A.; Egidi, F.; Radaelli, L.; Fogazzi, G.; Ponticelli, C.; Minetti, L. Long-term follow-up of IgA mesangial nephropathy: Clinico-histological study in 374 patients. Semin. Nephrol. 1987, 7, 355–358. [Google Scholar]
- D’Amico, G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin. Nephrol. 2004, 24, 179–196. [Google Scholar] [CrossRef]
- Barratt, J.; Feehally, J. IgA nephropathy. J. Am. Soc. Nephrol. 2005, 16, 2088–2097. [Google Scholar] [CrossRef] [PubMed]
- Reich, H.N.; Troyanov, S.; Scholey, J.W.; Cattran, D.C.; Registry, T.G. Remission of proteinuria improves prognosis in IgA nephropathy. J. Am. Soc. Nephrol. 2007, 18, 3177–3183. [Google Scholar] [CrossRef] [PubMed]
- Hastings, M.C.; Bursac, Z.; Julian, B.A.; Villa Baca, E.; Featherston, J.; Woodford, S.Y.; Bailey, L.; Wyatt, R.J. Life expectancy for patients from the southeastern United States with IgA nephropathy. Kidney Int. Rep. 2018, 3, 99–104. [Google Scholar] [CrossRef] [Green Version]
- Woo, K.T.; Lau, Y.K.; Chan, C.M.; Wong, K.S. Angiotensin-converting enzyme inhibitor versus angiotensin 2 receptor antagonist therapy and the influence of angiotensin-converting enzyme gene polymorphism in IgA nephritis. Ann. Acad. Med. Singap. 2008, 37, 372–376. [Google Scholar]
- Yamagata, K.; Iseki, K.; Nitta, K.; Imai, H.; Iino, Y.; Matsuo, S.; Makino, H.; Hishida, A. Chronic kidney disease perspectives in Japan and the importance of urinalysis screening. Clin. Exp. Nephrol. 2008, 12, 1–8. [Google Scholar] [CrossRef]
- Wyatt, R.J.; Julian, B.A.; Baehler, R.W.; Stafford, C.C.; McMorrow, R.G.; Ferguson, T.; Jackson, E.; Woodford, S.Y.; Miller, P.M.; Kritchevsky, S. Epidemiology of IgA nephropathy in central and eastern Kentucky for the period 1975 through 1994. Central Kentucky Region of the Southeastern United States IgA Nephropathy DATABANK Project. J. Am. Soc. Nephrol. 1998, 9, 853–858. [Google Scholar] [CrossRef]
- Schena, F.P. A retrospective analysis of the natural history of primary IgA nephropathy worldwide. Am. J. Med. 1990, 89, 209–215. [Google Scholar] [CrossRef]
- Wyatt, R.J.; Kritchevsky, S.B.; Woodford, S.Y.; Miller, P.M.; Roy, S.; Holland, N.H.; Jackson, E.; Bishof, N.A. IgA nephropathy: Long-term prognosis for pediatric patients. J. Pediatr. 1995, 127, 913–919. [Google Scholar] [CrossRef]
- Geddes, C.C.; Rauta, V.; Gronhagen-Riska, C.; Bartosik, L.P.; Jardine, A.G.; Ibels, L.S.; Pei, Y.; Cattran, D.C. A tricontinental view of IgA nephropathy. Nephrol. Dial. Transplant. 2003, 18, 1541–1548. [Google Scholar] [CrossRef]
- Shen, A.Y.; Brar, S.S.; Khan, S.S.; Kujubu, D.A. Association of race, heart failure and chronic kidney disease. Future Cardiol. 2006, 2, 441–454. [Google Scholar] [CrossRef] [PubMed]
- Varis, J.; Rantala, I.; Pasternack, A.; Oksa, H.; Jäntti, M.; Paunu, E.S.; Pirhonen, R. Immunoglobulin and complement deposition in glomeruli of 756 subjects who had committed suicide or met with a violent death. J. Clin. Pathol. 1993, 46, 607–610. [Google Scholar] [CrossRef] [Green Version]
- Sinniah, R. Occurrence of mesangial IgA and IgM deposits in a control necropsy population. J. Clin. Pathol. 1983, 36, 276–279. [Google Scholar] [CrossRef] [Green Version]
- Suzuki, K.; Honda, K.; Tanabe, K.; Toma, H.; Nihei, H.; Yamaguchi, Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003, 63, 2286–2294. [Google Scholar] [CrossRef] [Green Version]
- Nakazawa, S.; Imamura, R.; Kawamura, M.; Kato, T.; Abe, T.; Namba, T.; Iwatani, H.; Yamanaka, K.; Uemura, M.; Kishikawa, H.; et al. Difference in IgA1 O-glycosylation between IgA deposition donors and IgA nephropathy recipients. Biochem. Biophys. Res. Commun. 2019, 508, 1106–1112. [Google Scholar] [CrossRef]
- Berger, J. Recurrence of IgA nephropathy in renal allografts. Am. J. Kidney Dis. 1988, 12, 371–372. [Google Scholar] [CrossRef]
- Floege, J. Recurrent IgA nephropathy after renal transplantation. Semin. Nephrol. 2004, 24, 287–291. [Google Scholar] [CrossRef]
- Chandrakantan, A.; Ratanapanichkich, P.; Said, M.; Barker, C.V.; Julian, B.A. Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil. Nephrol. Dial. Transplant. 2005, 20, 1214–1221. [Google Scholar] [CrossRef] [Green Version]
- Silva, F.G.; Chander, P.; Pirani, C.L.; Hardy, M.A. Disappearance of glomerular mesangial IgA deposits after renal allograft transplantation. Transplantation 1982, 33, 241–246. [Google Scholar] [PubMed]
- Gharavi, A.G.; Moldoveanu, Z.; Wyatt, R.J.; Barker, C.V.; Woodford, S.Y.; Lifton, R.P.; Mestecky, J.; Novak, J.; Julian, B.A. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J. Am. Soc. Nephrol. 2008, 19, 1008–1014. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, H.; Fan, R.; Zhang, Z.; Brown, R.; Hall, S.; Julian, B.A.; Chatham, W.W.; Suzuki, Y.; Wyatt, R.J.; Moldoveanu, Z.; et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J. Clin. Investig. 2009, 119, 1668–1677. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Suzuki, H.; Kiryluk, K.; Novak, J.; Moldoveanu, Z.; Herr, A.B.; Renfrow, M.B.; Wyatt, R.J.; Scolari, F.; Mestecky, J.; Gharavi, A.G.; et al. The pathophysiology of IgA nephropathy. J. Am. Soc. Nephrol. 2011, 22, 1795–1803. [Google Scholar] [CrossRef] [Green Version]
- Berthoux, F.; Suzuki, H.; Thibaudin, L.; Yanagawa, H.; Maillard, N.; Mariat, C.; Tomino, Y.; Julian, B.A.; Novak, J. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J. Am. Soc. Nephrol. 2012, 23, 1579–1587. [Google Scholar] [CrossRef] [Green Version]
- Zhao, N.; Hou, P.; Lv, J.; Moldoveanu, Z.; Li, Y.; Kiryluk, K.; Gharavi, A.G.; Novak, J.; Zhang, H. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. 2012, 82, 790–796. [Google Scholar] [CrossRef] [Green Version]
- Maixnerova, D.; Ling, C.; Hall, S.; Reily, C.; Brown, R.; Neprasova, M.; Suchanek, M.; Honsova, E.; Zima, T.; Novak, J.; et al. Galactose-deficient IgA1 and the corresponding IgG autoantibodies predict IgA nephropathy progression. PLoS ONE 2019, 14, e0212254. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aucouturier, P.; Monteiro, R.C.; Noël, L.H.; Preud’homme, J.L.; Lesavre, P. Glomerular and serum immunoglobulin G subclasses in IgA nephropathy. Clin. Immunol. Immunopathol. 1989, 51, 338–347. [Google Scholar] [CrossRef]
- Placzek, W.J.; Yanagawa, H.; Makita, Y.; Renfrow, M.B.; Julian, B.A.; Rizk, D.V.; Suzuki, Y.; Novak, J.; Suzuki, H. Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy. PLoS ONE 2018, 13, e0190967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berthelot, L.; Robert, T.; Vuiblet, V.; Tabary, T.; Braconnier, A.; Dramé, M.; Toupance, O.; Rieu, P.; Monteiro, R.C.; Touré, F. Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes. Kidney Int. 2015, 88, 815–822. [Google Scholar] [CrossRef] [Green Version]
- Maixnerova, D.; Reily, C.; Bian, Q.; Neprasova, M.; Novak, J.; Tesar, V. Markers for the progression of IgA nephropathy. J. Nephrol. 2016, 29, 535–541. [Google Scholar] [CrossRef] [Green Version]
- Berthoux, F.; Suzuki, H.; Mohey, H.; Maillard, N.; Mariat, C.; Novak, J.; Julian, B.A. Prognostic value of serum biomarkers of autoimmunity for recurrence of IgA nephropathy after kidney transplantation. J. Am. Soc. Nephrol. 2017, 28, 1943–1950. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nieuwhof, C.; Kruytzer, M.; Frederiks, P.; van Breda Vriesman, P.J. Chronicity index and mesangial IgG deposition are risk factors for hypertension and renal failure in early IgA nephropathy. Am. J. Kidney Dis. 1998, 31, 962–970. [Google Scholar] [CrossRef]
- Wada, Y.; Ogata, H.; Takeshige, Y.; Takeshima, A.; Yoshida, N.; Yamamoto, M.; Ito, H.; Kinugasa, E. Clinical significance of IgG deposition in the glomerular mesangial area in patients with IgA nephropathy. Clin. Exp. Nephrol. 2013, 17, 73–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shin, D.H.; Lim, B.J.; Han, I.M.; Han, S.G.; Kwon, Y.E.; Park, K.S.; Lee, M.J.; Oh, H.J.; Park, J.T.; Han, S.H.; et al. Glomerular IgG deposition predicts renal outcome in patients with IgA nephropathy. Mod. Pathol. 2016, 29, 743–752. [Google Scholar] [CrossRef] [Green Version]
- Reily, C.; Stewart, T.J.; Renfrow, M.B.; Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol. 2019, 15, 346–366. [Google Scholar] [CrossRef] [PubMed]
- Novak, J.; Julian, B.A.; Mestecky, J.; Renfrow, M.B. Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin. Immunopathol. 2012, 34, 365–382. [Google Scholar] [CrossRef] [PubMed]
- Bellur, S.S.; Troyanov, S.; Cook, H.T.; Roberts, I.S.; Working Group of the International IgA Nephropathy Network and the Renal Pathology Society. Immunostaining findings in IgA nephropathy: Correlation with histology and clinical outcome in the Oxford classification patient cohort. Nephrol. Dial. Transplant. 2011, 26, 2533–2536. [Google Scholar] [CrossRef] [Green Version]
- Rizk, D.V.; Saha, M.K.; Hall, S.; Novak, L.; Brown, R.; Huang, Z.Q.; Fatima, H.; Julian, B.A.; Novak, J. Glomerular immunodeposits of patients with IgA nephropathy are enriched for IgG autoantibodies specific for galactose-deficient IgA1. J. Am. Soc. Nephrol. 2019, 30, 2017–2026. [Google Scholar] [CrossRef] [PubMed]
- Moldoveanu, Z.; Suzuki, H.; Reily, C.; Satake, K.; Novak, L.; Xu, N.; Huang, Z.Q.; Knoppova, B.; Khan, A.; Hall, S.; et al. Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy. J. Autoimmun. 2021, 118, 102593. [Google Scholar] [CrossRef]
- Julian, B.A.; Quiggins, P.A.; Thompson, J.S.; Woodford, S.Y.; Gleason, K.; Wyatt, R.J. Familial IgA nephropathy. Evidence of an inherited mechanism of disease. N. Engl. J. Med. 1985, 312, 202–208. [Google Scholar] [CrossRef]
- Yeo, S.C.; Goh, S.M.; Barratt, J. Is immunoglobulin A nephropathy different in different ethnic populations? Nephrology (Carlton) 2019, 24, 885–895. [Google Scholar] [CrossRef] [Green Version]
- Gharavi, A.G.; Kiryluk, K.; Choi, M.; Li, Y.; Hou, P.; **. Cancer Sci. 2006, 97, 420–429. [Google Scholar] [CrossRef] [PubMed]
- de Bono, J.S.; Rha, S.Y.; Stephenson, J.; Schultes, B.C.; Monroe, P.; Eckhardt, G.S.; Hammond, L.A.; Whiteside, T.L.; Nicodemus, C.F.; Cermak, J.M.; et al. Phase I trial of a murine antibody to MUC1 in patients with metastatic cancer: Evidence for the activation of humoral and cellular antitumor immunity. Ann. Oncol. 2004, 15, 1825–1833. [Google Scholar] [CrossRef]
- Berlyn, K.A.; Schultes, B.; Leveugle, B.; Noujaim, A.A.; Alexander, R.B.; Mann, D.L. Generation of CD4(+) and CD8(+) T lymphocyte responses by dendritic cells armed with PSA/anti-PSA (antigen/antibody) complexes. Clin. Immunol. 2001, 101, 276–283. [Google Scholar] [CrossRef] [PubMed]
- Gordon, A.N.; Schultes, B.C.; Gallion, H.; Edwards, R.; Whiteside, T.L.; Cermak, J.M.; Nicodemus, C.F. CA125- and tumor-specific T-cell responses correlate with prolonged survival in oregovomab-treated recurrent ovarian cancer patients. Gynecol. Oncol. 2004, 94, 340–351. [Google Scholar] [CrossRef]
- Iwase, H.; Yokozeki, Y.; Hiki, Y.; Tanaka, A.; Kokubo, T.; Sano, T.; Ishii-Karakasa, I.; Hisatani, K.; Kobayashi, Y.; Hotta, K. Human serum immunoglobulin G3 subclass bound preferentially to asialo-, agalactoimmunoglobulin A1/Sepharose. Biochem. Biophys. Res. Commun. 1999, 264, 424–429. [Google Scholar] [CrossRef]
- Kokubo, T.; Hiki, Y.; Iwase, H.; Tanaka, A.; Nishikido, J.; Hotta, K.; Kobayashi, Y. Exposed peptide core of IgA1 hinge region in IgA nephropathy. Nephrol. Dial. Transplant. 1999, 14, 81–85. [Google Scholar] [CrossRef] [PubMed]
- Cederholm, B.; Wieslander, J.; Bygren, P.; Heinegård, D. Circulating complexes containing IgA and fibronectin in patients with primary IgA nephropathy. Proc. Natl. Acad. Sci. USA 1988, 85, 4865–4868. [Google Scholar] [CrossRef] [Green Version]
- Jennette, J.C.; Wieslander, J.; Tuttle, R.; Falk, R.J. Serum IgA-fibronectin aggregates in patients with IgA nephropathy and Henoch-Schönlein purpura: Diagnostic value and pathogenic implications. The Glomerular Disease Collaborative Network. Am. J. Kidney Dis. 1991, 18, 466–471. [Google Scholar] [CrossRef]
- Nakamura, I.; Iwase, H.; Ohba, Y.; Hiki, Y.; Katsumata, T.; Kobayashi, Y. Quantitative analysis of IgA1 binding protein prepared from human serum by hypoglycosylated IgA1/Sepharose affinity chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2002, 776, 101–106. [Google Scholar] [CrossRef]
- Novak, J.; Tomana, M.; Matousovic, K.; Brown, R.; Hall, S.; Novak, L.; Julian, B.A.; Wyatt, R.J.; Mestecky, J. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int. 2005, 67, 504–513. [Google Scholar] [CrossRef] [Green Version]
- Novak, J.; Raskova Kafkova, L.; Suzuki, H.; Tomana, M.; Matousovic, K.; Brown, R.; Hall, S.; Sanders, J.T.; Eison, T.M.; Moldoveanu, Z.; et al. IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. Nephrol. Dial. Transplant. 2011, 26, 3451–3457. [Google Scholar] [CrossRef] [Green Version]
- Yanagihara, T.; Brown, R.; Hall, S.; Moldoveanu, Z.; Goepfert, A.; Tomana, M.; Julian, B.A.; Mestecky, J.; Novak, J. In vitro-generated immune complexes containing galactose-deficient IgA1 stimulate proliferation of mesangial cells. Results Immunol. 2012, 2, 166–172. [Google Scholar] [CrossRef] [Green Version]
- Czerkinsky, C.; Koopman, W.J.; Jackson, S.; Collins, J.E.; Crago, S.S.; Schrohenloher, R.E.; Julian, B.A.; Galla, J.H.; Mestecky, J. Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies. J. Clin. Investig. 1986, 77, 1931–1938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maillard, N.; Boerma, L.; Hall, S.; Huang, Z.Q.; Mrug, M.; Moldoveanu, Z.; Julian, B.A.; Renfrow, M.B.; Novak, J. Proteomic analysis of engineered IgA1-IgG immune complexes reveals association with activated complement C3. J. Am. Soc. Nephrol. 2013, 24, 490A. [Google Scholar]
- Wyatt, R.J.; Kanayama, Y.; Julian, B.A.; Negoro, N.; Sugimoto, S.; Hudson, E.C.; Curd, J.G. Complement activation in IgA nephropathy. Kidney Int. 1987, 31, 1019–1023. [Google Scholar] [CrossRef] [Green Version]
- Rizk, D.V.; Maillard, N.; Julian, B.A.; Knoppova, B.; Green, T.J.; Novak, J.; Wyatt, R.J. The emerging role of complement proteins as a target for therapy of IgA nephropathy. Front. Immunol. 2019, 10, 504. [Google Scholar] [CrossRef] [PubMed]
- Medjeral-Thomas, N.R.; Cook, H.T.; Pickering, M.C. Complement activation in IgA nephropathy. Semin. Immunopathol. 2021, 31, 1019–1023. [Google Scholar] [CrossRef]
- Xu, B.; Zhu, L.; Wang, Q.; Zhao, Y.; Jia, M.; Shi, S.; Liu, L.; Lv, J.; Lai, W.; Ji, J.; et al. Mass spectrometry-based screening identifies circulating immunoglobulinA-α1-microglobulin complex as potential biomarker in immunoglobulin A nephropathy. Nephrol. Dial. Transplant. 2021, 36, 782–792. [Google Scholar] [CrossRef] [PubMed]
- Coppo, R.; Basolo, B.; Martina, G.; Rollino, C.; De Marchi, M.; Giacchino, F.; Mazzucco, G.; Messina, M.; Piccoli, G. Circulating immune complexes containing IgA, IgG and IgM in patients with primary IgA nephropathy and with Henoch-Schoenlein nephritis. Correlation with clinical and histologic signs of activity. Clin. Nephrol. 1982, 18, 230–239. [Google Scholar]
- Schena, F.P.; Pastore, A.; Ludovico, N.; Sinico, R.A.; Benuzzi, S.; Montinaro, V. Increased serum levels of IgA1-IgG immune complexes and anti-F(ab’)2 antibodies in patients with primary IgA nephropathy. Clin. Exp. Immunol. 1989, 77, 15–20. [Google Scholar]
- Kemper, C.; Pangburn, M.K.; Fishelson, Z. Complement nomenclature 2014. Mol. Immunol. 2014, 61, 56–58. [Google Scholar] [CrossRef]
- Floege, J.; Daha, M.R. IgA nephropathy: New insights into the role of complement. Kidney Int. 2018, 94, 16–18. [Google Scholar] [CrossRef]
- Novak, J.; Rizk, D.; Takahashi, K.; Zhang, X.; Bian, Q.; Ueda, H.; Ueda, Y.; Reily, C.; Lai, L.Y.; Hao, C.; et al. New Insights into the Pathogenesis of IgA Nephropathy. Kidney Dis. 2015, 1, 8–18. [Google Scholar] [CrossRef]
- Knoppova, B.; Reily, C.; Maillard, N.; Rizk, D.V.; Moldoveanu, Z.; Mestecky, J.; Raska, M.; Renfrow, M.B.; Julian, B.A.; Novak, J. The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front. Immunol. 2016, 7, 117. [Google Scholar] [CrossRef] [Green Version]
- Chen, A.; Chen, W.P.; Sheu, L.F.; Lin, C.Y. Pathogenesis of IgA nephropathy: In vitro activation of human mesangial cells by IgA immune complex leads to cytokine secretion. J. Pathol. 1994, 173, 119–126. [Google Scholar] [CrossRef]
- Coppo, R.; Amore, A.; Cirina, P.; Messina, M.; Basolo, B.; Segoloni, G.; Berthoux, F.; Boulahrouz, R.; Egido, J.; Alcazar, R. Characteristics of IgA and macromolecular IgA in sera from IgA nephropathy transplanted patients with and without IgAN recurrence. Contrib. Nephrol. 1995, 111, 85–92. [Google Scholar] [CrossRef] [PubMed]
- Amore, A.; Cirina, P.; Conti, G.; Brusa, P.; Peruzzi, L.; Coppo, R. Glycosylation of circulating IgA in patients with IgA nephropathy modulates proliferation and apoptosis of mesangial cells. J. Am. Soc. Nephrol. 2001, 12, 1862–1871. [Google Scholar] [CrossRef]
- Leung, J.C.; Tsang, A.W.; Chan, L.Y.; Tang, S.C.; Lam, M.F.; Lai, K.N. Size-dependent binding of IgA to HepG2, U937, and human mesangial cells. J. Lab. Clin. Med. 2002, 140, 398–406. [Google Scholar] [CrossRef] [PubMed]
- Novak, J.; Vu, H.L.; Novak, L.; Julian, B.A.; Mestecky, J.; Tomana, M. Interactions of human mesangial cells with IgA and IgA-containing immune complexes. Kidney Int. 2002, 62, 465–475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leung, J.C.; Tang, S.C.; Chan, L.Y.; Tsang, A.W.; Lan, H.Y.; Lai, K.N. Polymeric IgA increases the synthesis of macrophage migration inhibitory factor by human mesangial cells in IgA nephropathy. Nephrol. Dial. Transplant. 2003, 18, 36–45. [Google Scholar] [CrossRef] [Green Version]
- Moura, I.C.; Arcos-Fajardo, M.; Sadaka, C.; Leroy, V.; Benhamou, M.; Novak, J.; Vrtovsnik, F.; Haddad, E.; Chintalacharuvu, K.R.; Monteiro, R.C. Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J. Am. Soc. Nephrol. 2004, 15, 622–634. [Google Scholar] [CrossRef] [Green Version]
- Leung, J.C.; Tang, S.C.; Chan, L.Y.; Chan, W.L.; Lai, K.N. Synthesis of TNF-alpha by mesangial cells cultured with polymeric anionic IgA--role of MAPK and NF-kappaB. Nephrol. Dial. Transplant. 2008, 23, 72–81. [Google Scholar] [CrossRef] [Green Version]
- Lai, K.N.; Leung, J.C.; Chan, L.Y.; Saleem, M.A.; Mathieson, P.W.; Tam, K.Y.; **ao, J.; Lai, F.M.; Tang, S.C. Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy. Nephrol. Dial. Transplant. 2009, 24, 62–72. [Google Scholar] [CrossRef] [Green Version]
- Tam, K.Y.; Leung, J.C.K.; Chan, L.Y.Y.; Lam, M.F.; Tang, S.C.W.; Lai, K.N. Macromolecular IgA1 taken from patients with familial IgA nephropathy or their asymptomatic relatives have higher reactivity to mesangial cells in vitro. Kidney Int. 2009, 75, 1330–1339. [Google Scholar] [CrossRef] [Green Version]
- Coppo, R.; Fonsato, V.; Balegno, S.; Ricotti, E.; Loiacono, E.; Camilla, R.; Peruzzi, L.; Amore, A.; Bussolati, B.; Camussi, G. Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes. Kidney Int. 2010, 77, 417–427. [Google Scholar] [CrossRef] [Green Version]
- Tamouza, H.; Chemouny, J.M.; Raskova Kafkova, L.; Berthelot, L.; Flamant, M.; Demion, M.; Mesnard, L.; Paubelle, E.; Walker, F.; Julian, B.A.; et al. The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy. Kidney Int. 2012, 82, 1284–1296. [Google Scholar] [CrossRef] [Green Version]
- Novak, J.; Moldoveanu, Z.; Julian, B.A.; Raska, M.; Wyatt, R.J.; Suzuki, Y.; Tomino, Y.; Gharavi, A.G.; Mestecky, J.; Suzuki, H. Aberrant glycosylation of IgA1 and anti-glycan antibodies in IgA nephropathy: Role of mucosal immune system. Adv. Otorhinolaryngol. 2011, 72, 60–63. [Google Scholar] [CrossRef]
- Novak, J.; Barratt, J.; Julian, B.A.; Renfrow, M.B. Aberrant glycosylation of the IgA1 molecule in IgA nephropathy. Semin. Nephrol. 2018, 38, 461–476. [Google Scholar] [CrossRef]
- Moura, I.C.; Arcos-Fajardo, M.; Gdoura, A.; Leroy, V.; Sadaka, C.; Mahlaoui, N.; Lepelletier, Y.; Vrtovsnik, F.; Haddad, E.; Benhamou, M.; 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, 2667–2676. [Google Scholar] [CrossRef]
- Moura, I.C.; Centelles, M.N.; Arcos-Fajardo, M.; Malheiros, D.M.; Collawn, J.F.; Cooper, M.D.; Monteiro, R.C. 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, 417–425. [Google Scholar] [CrossRef]
- Tamouza, H.; Vende, F.; Tiwari, M.; Arcos-Fajardo, M.; Vrtovsnik, F.; Benhamou, M.; Monteiro, R.C.; Moura, I.C. Transferrin receptor engagement by polymeric IgA1 induces receptor expression and mesangial cell proliferation: Role in IgA nephropathy. Contrib. Nephrol. 2007, 157, 144–147. [Google Scholar] [CrossRef] [PubMed]
- Kaneko, Y.; Otsuka, T.; Tsuchida, Y.; Gejyo, F.; Narita, I. Integrin α1/β1 and α2/β1 as a receptor for IgA1 in human glomerular mesangial cells in IgA nephropathy. Int. Immunol. 2012, 24, 219–232. [Google Scholar] [CrossRef] [Green Version]
- Molyneux, K.; Wimbury, D.; Pawluczyk, I.; Muto, M.; Bhachu, J.; Mertens, P.R.; Feehally, J.; Barratt, J. β1,4-galactosyltransferase 1 is a novel receptor for IgA in human mesangial cells. Kidney Int. 2017, 92, 1458–1468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Launay, P.; Grossetête, B.; Arcos-Fajardo, M.; Gaudin, E.; Torres, S.P.; Beaudoin, L.; Patey-Mariaud de Serre, N.; Lehuen, A.; Monteiro, R.C. 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, 1999–2009. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hansen, I.S.; Baeten, D.L.P.; den Dunnen, J. The inflammatory function of human IgA. Cell Mol. Life Sci. 2019, 76, 1041–1055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heineke, M.H.; van Egmond, M. Immunoglobulin A: Magic bullet or Trojan horse? Eur. J. Clin. Investig. 2017, 47, 184–192. [Google Scholar] [CrossRef] [Green Version]
- Breedveld, A.; van Egmond, M. IgA and FcαRI: Pathological roles and therapeutic opportunities. Front. Immunol. 2019, 10, 553. [Google Scholar] [CrossRef]
- Cheung, C.K.; Rajasekaran, A.; Barratt, J.; Rizk, D.V. An update on the current state of management and clinical trials for IgA nephropathy. J. Clin. Med. 2021, 10, 2493. [Google Scholar] [CrossRef]
- Harris, L.J.; Larson, S.B.; Hasel, K.W.; McPherson, A. Refined structure of an intact IgG2a monoclonal antibody. Biochemistry 1997, 36, 1581–1597. [Google Scholar] [CrossRef]
- Harris, L.J.; Skaletsky, E.; McPherson, A. Crystallographic structure of an intact IgG1 monoclonal antibody. J. Mol. Biol. 1998, 275, 861–872. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saphire, E.O.; Parren, P.W.; Pantophlet, R.; Zwick, M.B.; Morris, G.M.; Rudd, P.M.; Dwek, R.A.; Stanfield, R.L.; Burton, D.R.; Wilson, I.A. Crystal structure of a neutralizing human IgG against HIV-1: A template for vaccine design. Science 2001, 293, 1155–1159. [Google Scholar] [CrossRef] [PubMed]
- Boehm, M.K.; Woof, J.M.; Kerr, M.A.; Perkins, S.J. The Fab and Fc fragments of IgA1 exhibit a different arrangement from that in IgG: A study by X-ray and neutron solution scattering and homology modelling. J. Mol. Biol. 1999, 286, 1421–1447. [Google Scholar] [CrossRef] [PubMed]
- Almogren, A.; Furtado, P.B.; Sun, Z.; Perkins, S.J.; Kerr, M.A. Purification, properties and extended solution structure of the complex formed between human immunoglobulin A1 and human serum albumin by scattering and ultracentrifugation. J. Mol. Biol. 2006, 356, 413–431. [Google Scholar] [CrossRef] [PubMed]
- Bonner, A.; Furtado, P.B.; Almogren, A.; Kerr, M.A.; Perkins, S.J. Implications of the near-planar solution structure of human myeloma dimeric IgA1 for mucosal immunity and IgA nephropathy. J. Immunol. 2008, 180, 1008–1018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bonner, A.; Almogren, A.; Furtado, P.B.; Kerr, M.A.; Perkins, S.J. Location of secretory component on the Fc edge of dimeric IgA1 reveals insight into the role of secretory IgA1 in mucosal immunity. Mucosal Immunol. 2009, 2, 74–84. [Google Scholar] [CrossRef]
- Woods Group. GLYCAM Web. Complex. Carbohydrate Research Center, University of Georgia, Athens, Georgia, 2005–2021. Available online: http://glycam.org (accessed on 8 August 2021).
- Krieger, E.; Joo, K.; Lee, J.; Lee, J.; Raman, S.; Thompson, J.; Tyka, M.; Baker, D.; Karplus, K. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins 2009, 77 (Suppl. 9), 114–122. Available online: http://www.yasara.org (accessed on 20 August 2021). [CrossRef] [Green Version]
- DeLano, W.L. The PyMOL Molecular Graphics System; Version 1.7.1.1; Schrödinger, LLC.: New York, NY, USA, 2002; Available online: http://www.pymol.org (accessed on 17 November 2019).
- Wilson, I.A.; Stanfield, R.L. 50 Years of structural immunology. J. Biol. Chem. 2021, 296, 100745. [Google Scholar] [CrossRef]
- Sarma, V.R.; Silverton, E.W.; Davies, D.R.; Terry, W.D. The three-dimensional structure at 6 A resolution of a human gamma Gl immunoglobulin molecule. J. Biol. Chem. 1971, 246, 3753–3759. [Google Scholar] [CrossRef]
- Poljak, R.J.; Amzel, L.M.; Avey, H.P.; Becka, L.N. Structure of Fab’ New at 6 A resolution. Nat. New Biol. 1972, 235, 137–140. [Google Scholar] [CrossRef] [PubMed]
- Amzel, L.M.; Poljak, R.J.; Saul, F.; Varga, J.M.; Richards, F.F. The three dimensional structure of a combining region-ligand complex of immunoglobulin NEW at 3.5-A resolution. Proc. Natl. Acad. Sci. USA 1974, 71, 1427–1430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Deisenhofer, J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochemistry 1981, 20, 2361–2370. [Google Scholar] [CrossRef] [PubMed]
- Silverton, E.W.; Navia, M.A.; Davies, D.R. Three-dimensional structure of an intact human immunoglobulin. Proc. Natl. Acad. Sci. USA 1977, 74, 5140–5144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235–242. [Google Scholar] [CrossRef] [Green Version]
- Dunbar, J.; Krawczyk, K.; Leem, J.; Baker, T.; Fuchs, A.; Georges, G.; Shi, J.; Deane, C.M. SAbDab: The structural antibody database. Nucleic Acids Res. 2014, 42, D1140–D1146. [Google Scholar] [CrossRef]
- Kuhlbrandt, W. Biochemistry. The resolution revolution. Science 2014, 343, 1443–1444. [Google Scholar] [CrossRef]
- Callaway, E. The revolution will not be crystallized: A new method sweeps through structural biology. Nature 2015, 525, 172–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumar, N.; Arthur, C.P.; Ciferri, C.; Matsumoto, M.L. Structure of the secretory immunoglobulin A core. Science 2020, 367, 1008–1014. [Google Scholar] [CrossRef] [PubMed]
- Kumar Bharathkar, S.; Parker, B.W.; Malyutin, A.G.; Haloi, N.; Huey-Tubman, K.E.; Tajkhorshid, E.; Stadtmueller, B.M. The structures of secretory and dimeric immunoglobulin A. eLife 2020, 9, e56098. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Wang, G.; Li, Y.; Zhu, Q.; Shen, H.; Gao, N.; **ao, J. Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin. Cell Res. 2020, 30, 602–609. [Google Scholar] [CrossRef]
- Wang, Z.; Rahkola, J.; Redzic, J.S.; Chi, Y.C.; Tran, N.; Holyoak, T.; Zheng, H.; Janoff, E.; Eisenmesser, E. Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease. Nat. Commun. 2020, 11, 6063. [Google Scholar] [CrossRef] [PubMed]
- Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455–461. [Google Scholar] [CrossRef] [Green Version]
- Shin, W.H.; Christoffer, C.W.; Wang, J.; Kihara, D. PL-PatchSurfer2: Improved local surface matching-based virtual screening method that is tolerant to target and ligand structure variation. J. Chem. Inf. Model. 2016, 56, 1676–1691. [Google Scholar] [CrossRef] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Knoppova, B.; Reily, C.; King, R.G.; Julian, B.A.; Novak, J.; Green, T.J. Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment. J. Clin. Med. 2021, 10, 4501. https://doi.org/10.3390/jcm10194501
Knoppova B, Reily C, King RG, Julian BA, Novak J, Green TJ. Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment. Journal of Clinical Medicine. 2021; 10(19):4501. https://doi.org/10.3390/jcm10194501
Chicago/Turabian StyleKnoppova, Barbora, Colin Reily, R. Glenn King, Bruce A. Julian, Jan Novak, and Todd J. Green. 2021. "Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment" Journal of Clinical Medicine 10, no. 19: 4501. https://doi.org/10.3390/jcm10194501