{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T11:53:20Z","timestamp":1792842800744,"version":"4.5.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST-108-2314-B-002 -053"],"award-info":[{"award-number":["MOST-108-2314-B-002 -053"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["107-S3759, 109-S4556"],"award-info":[{"award-number":["107-S3759, 109-S4556"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005866","name":"Far Eastern Memorial Hospital","doi-asserted-by":"publisher","award":["FEMH-2019-C-023"],"award-info":[{"award-number":["FEMH-2019-C-023"]}],"id":[{"id":"10.13039\/501100005866","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Galactose-deficient IgA<jats:sub>1<\/jats:sub> (Gd-IgA<jats:sub>1<\/jats:sub>) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA<jats:sub>1<\/jats:sub> level remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ninety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA<jats:sub>1<\/jats:sub> were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA<jats:sub>1<\/jats:sub> than control subjects. Gd-IgA<jats:sub>1<\/jats:sub> levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA<jats:sub>1<\/jats:sub> were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA<jats:sub>1<\/jats:sub> as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after\u00a0immunosuppression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicate a close relationship between alternative complement pathway activation, Gd-IgA<jats:sub>1<\/jats:sub> concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.638309","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T14:24:44Z","timestamp":1623335084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":58,"title":["Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Yen-Ling","family":"Chiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chou","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Hsiang","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wen","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan-Chi","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsiang","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Fang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chih","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuei-Liong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Ming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Shiou","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"B1","article-title":"Epidemiology of Idiopathic IgA Nephropathy","volume":"7","author":"Berger","year":"1987","journal-title":"Semin Nephrol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfq665","article-title":"The Incidence of Primary Glomerulonephritis Worldwide: A Systematic Review of the Literature","volume":"26","author":"McGrogan","year":"2011","journal-title":"Nephrol Dial Transplant"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.semnephrol.2007.10.001","article-title":"Natural History of Primary IgA Nephropathy","volume":"28","author":"Berthoux","year":"2008","journal-title":"Semin Nephrol"},{"key":"B4","article-title":"[Intercapillary Deposits of Iga-Igg]","volume":"74","author":"Berger","year":"1968","journal-title":"J Urol Nephrol (Paris)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(88)80022-2","article-title":"The Immunohistology of IgA Nephropathy","volume":"12","author":"Jennette","year":"1988","journal-title":"Am J Kidney Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1369","article-title":"Human Serum Immunoglobulin G3 Subclass Bound Preferentially to Asialo-, Agalactoimmunoglobulin A1\/Sepharose","volume":"264","author":"Iwase","year":"1999","journal-title":"Biochem Biophys Res Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/14.1.81","article-title":"Exposed Peptide Core of IgA1 Hinge Region in IgA Nephropathy","volume":"14","author":"Kokubo","year":"1999","journal-title":"Nephrol Dial Transplant"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.5114\/pjp.2017.69691","article-title":"The Utility of Glomerular C4d Immunostaining in Renal Biopsies in Patients With Immunoglobulin A Nephropathy. A Clinicopathological Study","volume":"68","author":"Wagrowska-Danilewicz","year":"2017","journal-title":"Pol J Pathol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2019.07.017","article-title":"The Role of Complement in IgA Nephropathy","volume":"114","author":"Tortajada","year":"2019","journal-title":"Mol Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2019.108331","article-title":"Predictive Value of Mesangial C3 and C4d Deposition in IgA Nephropathy","volume":"211","author":"Nam","year":"2020","journal-title":"Clin Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1987.72","article-title":"Complement Membrane Attack (MAC) in Idiopathic Iga-Glomerulonephritis","volume":"31","author":"Rauterberg","year":"1987","journal-title":"Kidney Int"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/13.8.1984","article-title":"Glomerular Deposition of Mannose-Binding Lectin (MBL) Indicates a Novel Mechanism of Complement Activation in IgA Nephropathy","volume":"13","author":"Endo","year":"1998","journal-title":"Nephrol Dial Transplant"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005090923","article-title":"Glomerular Activation of the Lectin Pathway of Complement in IgA Nephropathy Is Associated With More Severe Renal Disease","volume":"17","author":"Roos","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1159\/000184350","article-title":"Composition of Mesangial Deposits in IgA Nephropathy: Complement Factors","volume":"46","author":"Bene","year":"1987","journal-title":"Nephron"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/ng.787","article-title":"Genome-Wide Association Study Identifies Susceptibility Loci for IgA Nephropathy","volume":"43","author":"Gharavi","year":"2011","journal-title":"Nat Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3118","article-title":"Discovery of New Risk Loci for IgA Nephropathy Implicates Genes Involved in Immunity Against Intestinal Pathogens","volume":"46","author":"Kiryluk","year":"2014","journal-title":"Nat Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/nep.13210","article-title":"Complement Factor H Gene Polymorphism rs6677604 and the Risk, Severity and Progression of IgA Nephropathy: A Systematic Review and Meta-Analysis","volume":"23","author":"Yeo","year":"2018","journal-title":"Nephrol (Carlton)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e99645","DOI":"10.1371\/journal.pone.0099645","article-title":"Modification of Diet in Renal Disease (MDRD) Study and CKD Epidemiology Collaboration (CKD-EPI) Equations for Taiwanese Adults","volume":"9","author":"Chen","year":"2014","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2017.11.015","article-title":"Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (Masp-3) and Increased Glomerular Factor H-Related Protein-5 (Fhr5) Deposition","volume":"3","author":"Medjeral-Thomas","year":"2018","journal-title":"Kidney Int Rep"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830170304","article-title":"Activation of the Alternative Pathway of Complement by Human Serum Iga","volume":"17","author":"Hiemstra","year":"1987","journal-title":"Eur J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02166","article-title":"Complement Inhibitors in Clinical Trials for Glomerular Diseases","volume":"10","author":"Zipfel","year":"2019","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-013-0921-6","article-title":"Serum Levels of Galactose-Deficient Immunoglobulin (Ig) A1 and Related Immune Complex are Associated With Disease Activity of IgA Nephropathy","volume":"18","author":"Suzuki","year":"2014","journal-title":"Clin Exp Nephrol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1159\/000502579","article-title":"Clinical Significance of Galactose-Deficient IgA1 by KM55 in Patients With IgA Nephropathy","volume":"44","author":"Zhang","year":"2019","journal-title":"Kidney Blood Press Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.11571210","article-title":"Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy","volume":"6","author":"Camilla","year":"2011","journal-title":"Clin J Am Soc Nephrol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0206865","DOI":"10.1371\/journal.pone.0206865","article-title":"Clinical Significance of Serum and Mesangial Galactose-Deficient IgA1 in Patients With IgA Nephropathy","volume":"13","author":"Wada","year":"2018","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.512277","article-title":"Cytokines Alter IgA1 O-Glycosylation by Dysregulating C1GalT1 and ST6GalNAc-II Enzymes","volume":"289","author":"Suzuki","year":"2014","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2017.07.002","article-title":"Inhibition of STAT3 Signaling Reduces Iga1 Autoantigen Production in IgA Nephropathy","volume":"2","author":"Yamada","year":"2017","journal-title":"Kidney Int Rep"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1159\/000487903","article-title":"Glucocorticoids Reduce Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Patients","volume":"43","author":"Kosztyu","year":"2018","journal-title":"Kidney Blood Press Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1089\/mab.2018.0041","article-title":"Galactose-Deficient IgA1-Specific Antibody Recognizes Galnac-Modified Unique Epitope on Hinge Region of Iga1","volume":"37","author":"Yamasaki","year":"2018","journal-title":"Monoclon Antib Immunodiagn Immunother"},{"key":"B30","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1021\/pr200608q","article-title":"Naturally Occurring Structural Isomers in Serum IgA1 O-Glycosylation","volume":"11","author":"Takahashi","year":"2012","journal-title":"J Proteome Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.638309\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T14:24:48Z","timestamp":1623335088000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.638309\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,10]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2021.638309"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.638309","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,10]]},"article-number":"638309"}}