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      Pathogenic role of glycan-specific IgG antibodies in IgA nephropathy

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          Abstract

          Background

          Accumulating evidences proved the important roles of circulating IgA1-containing immune complexes (cIgA1) in IgA nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG antibody have been identified as major components in cIgA1. Before, Gd-IgA1 was reported as a vital factor in IgAN, partly via of its pathogenic role to induce mesangial cells activation. However, we still lack direct evidences to clarify the biological effect of glycan-specific IgG antibody in IgAN.

          Methods

          In the present study, we enrolled 35 IgAN patients and 17 age- and sex-matched healthy controls. Using uniform aberrant glycosylated IgA1 molecules, and IgG from different individuals, we in vitro prepared IgG-ddIgA1 complexes, and compared the biological differences among these immune complexes regarding their proliferative and inflammatory effects on mesangial cells.

          Results

          IgG-ddIgA1 complexes from both patients with IgA nephropathy (IgAN-IgG-dd-IgA1) and healthy controls (HC-IgG-dd-IgA1) could induce the proliferation of mesangial cells and up-regulate expression of MCP-1, IL-6 and CXCL1. The levels of mesangial cells proliferation induced by IgAN-IgG-dd-IgA1 were significantly higher than those induced by HC-IgG-dd-IgA1 (1.10 ± 0.05 vs. 1.03 ± 0.03; p < 0.001). However, the levels of secreted MCP-1, IL-6 and CXCL1 from mesangial cells challenged by IgAN-IgG-dd-IgA1 and HC-IgG-dd-IgA1 were comparable.

          Conclusions

          We found that glycan-specific IgG antibodies derived from patients with IgAN had the biological effect to induce mesangial cells proliferation. Moreover, in the present study we also established a method for in vitro preparation of pathogenic IgG-ddIgA1 complexes, which could be applied in future studies exploring IgAN pathogenesis.

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          Most cited references 23

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          IgA nephropathy.

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            The commonest glomerulonephritis in the world: IgA nephropathy.

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              Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity.

              IgA nephropathy (IgAN) is characterized by circulating immune complexes composed of galactose-deficient IgA1 and a glycan-specific IgG antibody. These immune complexes deposit in the glomerular mesangium and induce the mesangioproliferative glomerulonephritis characteristic of IgAN. To define the precise specificities and molecular properties of the IgG antibodies, we generated EBV-immortalized IgG-secreting lymphocytes from patients with IgAN and found that the secreted IgG formed complexes with galactose-deficient IgA1 in a glycan-dependent manner. We cloned and sequenced the heavy- and light-chain antigen-binding domains of IgG specific for galactose-deficient IgA1 and identified an A to S substitution in the complementarity-determining region 3 of the variable region of the gene encoding the IgG heavy chain in IgAN patients. Furthermore, site-directed mutagenesis that reverted the residue to alanine reduced the binding of recombinant IgG to galactose-deficient IgA1. Finally, we developed a dot-blot assay for the glycan-specific IgG antibody that differentiated patients with IgAN from healthy and disease controls with 88% specificity and 95% sensitivity and found that elevated levels of this antibody in the sera of patients with IgAN correlated with proteinuria. Collectively, these findings indicate that glycan-specific antibodies are associated with the development of IgAN and may represent a disease-specific marker and potential therapeutic target.
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                Author and article information

                Contributors
                dreamriver_247@163.com
                +86-10-83572388 , funnyzhuli@bjmu.edu.cn
                lijun.liu@medmail.com.cn
                shisufang0510@163.com
                chenglv@263.net
                hongzh@bjmu.edu.cn
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                29 September 2017
                29 September 2017
                2017
                : 18
                Affiliations
                [1 ]ISNI 0000 0004 1764 1621, GRID grid.411472.5, Renal Division, Department of Medicine, , Peking University First Hospital, ; Beijing, China
                [2 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, Peking University Institute of Nephrology, ; Beijing, China
                [3 ]ISNI 0000 0004 1769 3691, GRID grid.453135.5, Key Laboratory of Renal Disease, Ministry of Health of China, ; Beijing, China
                [4 ]ISNI 0000 0004 0369 313X, GRID grid.419897.a, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, ; Beijing, China
                [5 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, Renal Division, Department of Medicine, Peking University First Hospital, , Peking University Institute of Nephrology, ; No 8, Xishiku Street, Xicheng District, Beijing, 100034 China
                Article
                722
                10.1186/s12882-017-0722-3
                5623975
                28969604
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: National Science Foundation of China
                Award ID: 81470945;81670638
                Award Recipient :
                Funded by: the Training Program of the Major Research Plan of the National Natural Science Foundation of China
                Award ID: 91642120
                Award Recipient :
                Funded by: Capital of Clinical Characteristics and the Applied Research Fund
                Award ID: Z141107002514037
                Award ID: Z161100000516005
                Award Recipient :
                Funded by: Beijing New-star Plan of Science and Technology
                Award ID: Z161100004916167
                Award Recipient :
                Funded by: the National Key Research and Development Program of China
                Award ID: 2016YFC0904102
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Nephrology

                iga nephropathy, glycan-specific igg antibody, galactose-deficient iga1

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