{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:37:54Z","timestamp":1790080674343,"version":"4.0.1"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","funder":[{"DOI":"10.13039\/501100009468","name":"R\u00e9gion Nouvelle-Aquitaine","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009468","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Chaire d\u2019Immuno-pathologie des Maladies R\u00e9nales, Limoges University"},{"name":"Association Limousine pour l\u2019Utilisation du Rein Artificiel \u00e0 Domicile"},{"name":"Lebanese University and Lebanese National Council for Scientific Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>IgA nephropathy (IgAN) is characterized by IgA glomerular mesangial deposition, but its pathogenesis remains unclear. Using humanized transgenic mouse models, the authors explored whether a hypogalactosylated hinge region (found in most mesangial IgA1 in human IgAN) is required for IgA deposition, demonstrating that hinge hypoglycosylation was not mandatory for deposition. To investigate whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits, they compared mice able to produce high-affinity mature IgA antibodies with mice lacking affinity maturation. They found that the low-affinity IgA can deposit in the mesangium and activate complement, that it is especially prone to induce glomerular cell thickening, and that it can initiate nephrotoxicity. These findings offer a new perspective regarding glomerular IgA deposits involving innate-like antibody responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>IgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2018111089","type":"journal-article","created":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T14:55:13Z","timestamp":1561128913000},"page":"1238-1249","source":"Crossref","is-referenced-by-count":16,"title":["Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation"],"prefix":"10.1681","volume":"30","author":[{"given":"Batoul","family":"Wehbi","sequence":"first","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"},{"name":"Biochemistry Department, Cancer Biology and Molecular Immunology Laboratory, Lebanese University Section I, Beirut, Lebanon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Oblet","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Boyer","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Huard","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Druilhe","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Paraf","sequence":"additional","affiliation":[{"name":"Anatomy-Histopathology Department, Centre Hospitalier Universitaire Dupuytren, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Cogn\u00e9","sequence":"additional","affiliation":[{"name":"Nephrology Department, Centre Hospitalier Universitaire Dupuytren, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Moreau","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolla","family":"El Makhour","sequence":"additional","affiliation":[{"name":"Life and Earth Sciences Department, Environmental Health Research Laboratory, Lebanese University Section V, Nabatieh, Lebanon; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam","family":"Badran","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Cancer Biology and Molecular Immunology Laboratory, Lebanese University Section I, Beirut, Lebanon;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein","family":"Van Egmond","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Cogn\u00e9","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Aldigier","sequence":"additional","affiliation":[{"name":"Immunology Department, Unit\u00e9 Mixte de Recherche Centre National de la Recherche Scientifique 7276 Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale 1262, Limoges University, Limoges, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,6,21]]},"reference":[{"key":"B1-20230819","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1056\/NEJMra1206793","article-title":"IgA nephropathy.","volume":"368","author":"Wyatt","year":"2013","journal-title":"N Engl J Med"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1136\/jcp.46.7.607","article-title":"Immunoglobulin and complement deposition in glomeruli of 756 subjects who had committed suicide or met with a violent death.","volume":"46","author":"Varis","year":"1993","journal-title":"J Clin Pathol"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1046\/j.1523-1755.63.6s.2.x","article-title":"Incidence of latent mesangial IgA deposition in renal allograft donors in Japan.","volume":"63","author":"Suzuki","year":"2003","journal-title":"Kidney Int"},{"key":"B4-20230819","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1681\/ASN.2012010063","article-title":"Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria.","volume":"23","author":"Guti\u00e9rrez","year":"2012","journal-title":"J Am Soc Nephrol"},{"key":"B5-20230819","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1172\/JCI5535","article-title":"Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies.","volume":"104","author":"Tomana","year":"1999","journal-title":"J Clin Invest"},{"key":"B6-20230819","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00281-013-0411-7","article-title":"New insights into the pathogenesis of IgA nephropathy.","volume":"36","author":"Floege","year":"2014","journal-title":"Semin Immunopathol"},{"key":"B7-20230819","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1038\/mi.2013.113","article-title":"Follicular dendritic cell secreted protein FDC-SP controls IgA production.","volume":"7","author":"Hou","year":"2014","journal-title":"Mucosal Immunol"},{"key":"B8-20230819","doi-asserted-by":"crossref","first-page":"12698","DOI":"10.1038\/ncomms12698","article-title":"Limited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization.","volume":"7","author":"Bemark","year":"2016","journal-title":"Nat Commun"},{"key":"B9-20230819","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1073\/pnas.0912393107","article-title":"Premature replacement of mu with alpha immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturation.","volume":"107","author":"Duchez","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B10-20230819","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1681\/ASN.2015080911","article-title":"IgA structure variations associate with immune stimulations and IgA mesangial deposition.","volume":"27","author":"Oruc","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B11-20230819","doi-asserted-by":"crossref","first-page":"7613","DOI":"10.1038\/ncomms8613","article-title":"Efficient AID targeting of switch regions is not sufficient for optimal class switch recombination.","volume":"6","author":"Bonaud","year":"2015","journal-title":"Nat Commun"},{"key":"B12-20230819","doi-asserted-by":"crossref","first-page":"4387","DOI":"10.1182\/blood.V93.12.4387","article-title":"Human immunoglobulin A receptor (FcalphaRI, CD89) function in transgenic mice requires both FcR gamma chain and CR3 (CD11b\/CD18).","volume":"93","author":"van Egmond","year":"1999","journal-title":"Blood"},{"key":"B13-20230819","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","article-title":"Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.","volume":"102","author":"Muramatsu","year":"2000","journal-title":"Cell"},{"key":"B14-20230819","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.20112005","article-title":"Transglutaminase is essential for IgA nephropathy development acting through IgA receptors.","volume":"209","author":"Berthelot","year":"2012","journal-title":"J Exp Med"},{"key":"B16-20230819","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3389\/fimmu.2016.00117","article-title":"The origin and activities of IgA1-containing immune complexes in IgA nephropathy.","volume":"7","author":"Knoppova","year":"2016","journal-title":"Front Immunol"},{"key":"B17-20230819","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/ki.1985.181","article-title":"Charge and size of mesangial IgA in IgA nephropathy.","volume":"28","author":"Monteiro","year":"1985","journal-title":"Kidney Int"},{"key":"B19-20230819","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s10719-012-9465-3","article-title":"Diverse IgG serum response to novel glycopeptide epitopes detected within immunodominant stretches of Epstein-Barr virus glycoprotein 350\/220: Diagnostic potential of O-glycopeptide microarrays.","volume":"30","author":"D\u2019Arrigo","year":"2013","journal-title":"Glycoconj J"},{"key":"B20-20230819","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s10157-007-0002-9","article-title":"Protective role of anti-synthetic hinge peptide antibody for glomerular deposition of hypoglycosylated IgA1.","volume":"12","author":"Hiki","year":"2008","journal-title":"Clin Exp Nephrol"},{"key":"B21-20230819","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/sj.ki.5002748","article-title":"B-cell O-galactosyltransferase activity, and expression of O-glycosylation genes in bone marrow in IgA nephropathy.","volume":"73","author":"Buck","year":"2008","journal-title":"Kidney Int"},{"key":"B22-20230819","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/ki.2011.501","article-title":"An update on the pathogenesis and treatment of IgA nephropathy.","volume":"81","author":"Boyd","year":"2012","journal-title":"Kidney Int"},{"key":"B23-20230819","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1084\/jem.191.11.1999","article-title":"Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger\u2019s disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice.","volume":"191","author":"Launay","year":"2000","journal-title":"J Exp Med"},{"key":"B24-20230819","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0165-2478(99)00034-6","article-title":"The human Fc receptor for IgA (Fc \u03b1 RI, CD89) on transgenic peritoneal macrophages triggers phagocytosis and tumor cell lysis.","volume":"68","author":"van Egmond","year":"1999","journal-title":"Immunol Lett"},{"key":"B25-20230819","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.immuni.2016.09.001","article-title":"Germinal center B cell dynamics.","volume":"45","author":"Mesin","year":"2016","journal-title":"Immunity"},{"key":"B26-20230819","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1126\/science.1077336","article-title":"Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora.","volume":"298","author":"Fagarasan","year":"2002","journal-title":"Science"},{"key":"B27-20230819","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1172\/JCI45563","article-title":"Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy.","volume":"121","author":"McCarthy","year":"2011","journal-title":"J Clin Invest"},{"key":"B28-20230819","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1365-2249.1994.tb06011.x","article-title":"Low antibody affinity restricted to the IgA isotype in IgA nephropathy.","volume":"95","author":"Layward","year":"1994","journal-title":"Clin Exp Immunol"},{"key":"B29-20230819","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.immuni.2015.10.002","article-title":"Activation-induced cytidine deaminase expression in human B cell precursors is essential for central B cell tolerance.","volume":"43","author":"Cantaert","year":"2015","journal-title":"Immunity"},{"key":"B30-20230819","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1126\/science.aao3859","article-title":"Germinal center antibody mutation trajectories are determined by rapid self\/foreign discrimination.","volume":"360","author":"Burnett","year":"2018","journal-title":"Science"},{"key":"B31-20230819","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3389\/fimmu.2016.00324","article-title":"B-1 cell heterogeneity and the regulation of natural and antigen-induced IgM production.","volume":"7","author":"Baumgarth","year":"2016","journal-title":"Front Immunol"},{"key":"B32-20230819","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1126\/science.1216557","article-title":"Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis.","volume":"335","author":"Yuan","year":"2012","journal-title":"Science"},{"key":"B33-20230819","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.1002\/art.25015","article-title":"A novel subpopulation of B-1 cells is enriched with autoreactivity in normal and lupus-prone mice.","volume":"60","author":"Zhong","year":"2009","journal-title":"Arthritis Rheum"},{"key":"B34-20230819","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1365-2249.2012.04656.x","article-title":"Immunophenotyping of putative human B1 B cells in healthy controls and common variable immunodeficiency (CVID) patients.","volume":"170","author":"Suchanek","year":"2012","journal-title":"Clin Exp Immunol"},{"key":"B36-20230819","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.4049\/jimmunol.170.9.4564","article-title":"B1 cells contribute to serum IgM, but not to intestinal IgA, production in gnotobiotic Ig allotype chimeric mice.","volume":"170","author":"Thurnheer","year":"2003","journal-title":"J Immunol"},{"key":"B37-20230819","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/nyas.12801","article-title":"B-1 cells as a source of IgA.","volume":"1362","author":"Meyer-Bahlburg","year":"2015","journal-title":"Ann N Y Acad Sci"},{"key":"B38-20230819","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1681\/ASN.2014101000","article-title":"Current understanding of the role of complement in IgA nephropathy.","volume":"26","author":"Maillard","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B39-20230819","doi-asserted-by":"crossref","first-page":"321","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":"B40-20230819","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.4049\/jimmunol.167.5.2861","article-title":"Human IgA activates the complement system via the mannan-binding lectin pathway.","volume":"167","author":"Roos","year":"2001","journal-title":"J Immunol"},{"key":"B41-20230819","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.kint.2017.05.002","article-title":"\u03b21,4-galactosyltransferase 1 is a novel receptor for IgA in human mesangial cells.","volume":"92","author":"Molyneux","year":"2017","journal-title":"Kidney Int"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/00001751-201907000-00013","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:34:16Z","timestamp":1786131256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/00001751-201907000-00013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,21]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2018111089","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,21]]}}}