{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:00:34Z","timestamp":1786132834043,"version":"build-2736575974"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1147388"],"award-info":[{"award-number":["APP1147388"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Myeloperoxidase ANCA-associated vasculitis (MPO-AAV) is an important cause of renal failure. Although rituximab has been shown to effectively attenuate MPO-AAV, its underlying mechanism of action beyond depletion of CD20\n                      <jats:sup>+<\/jats:sup>\n                      B cells producing ANCA is unknown. Administration of mouse anti-CD20 mAb to a murine anti-MPO GN mouse model reduced not only serum MPO-ANCA but also, T cell responses. Interestingly, anti-CD20 mAb treatment increased the frequency and functional potency of Tregs. Administration of anti-CD20 mAb rendered B cells apoptotic and resulted in the attenuation of anti-MPO autoimmunity and GN. This highlights a novel pathway by which anti-CD20 mAb therapy may attenuate T cell\u2013mediated autoimmunity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>MPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Anti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell\u2013mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      \u2013induced apoptotic splenocytes to unmanipulated mice attenuated autoimmunity and GN, whereas deletion of splenic marginal zone macrophages prevented anti-CD20 mAb-induced immunomodulation and treatment efficacy. Six days after administering anti-CD20 mAb to mice with murine anti-MPO GN, cell-mediated anti-MPO responses and GN were attenuated, and Tregs were enhanced, but ANCA levels were unchanged, suggesting humoral autoimmunity was redundant at this time point.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20\u2013induced apoptotic B cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2020060834","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T16:06:23Z","timestamp":1617206783000},"page":"1071-1083","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":20,"title":["Anti-CD20 mAb-Induced B Cell Apoptosis Generates T Cell Regulation of Experimental Myeloperoxidase ANCA-Associated Vasculitis"],"prefix":"10.1681","volume":"32","author":[{"given":"Poh-Yi","family":"Gan","sequence":"first","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"},{"name":"Department of Immunology, Monash Medical Center, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Dick","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-7948","authenticated-orcid":false,"given":"Kim M.","family":"O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Oudin","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Cao Le","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Koo Yuk Cheong","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Shim","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maliha","family":"Alikhan","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2713-2391","authenticated-orcid":false,"given":"A. Richard","family":"Kitching","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"},{"name":"Department of Nephrology, Monash Medical Center, Clayton, Victoria, Australia"},{"name":"Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Ooi","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Holdsworth","sequence":"additional","affiliation":[{"name":"Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia"},{"name":"Department of Immunology, Monash Medical Center, Clayton, Victoria, Australia"},{"name":"Department of Nephrology, Monash Medical Center, Clayton, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"B1-20240826","first-page":"139","article-title":"Kidney disease: Improving global outcomes (KGIDO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis","volume":"2","author":"Cattran","year":"2012","journal-title":"Kidney Int Suppl"},{"key":"B2-20240826","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1056\/NEJMoa0909905","article-title":"Rituximab versus cyclophosphamide for ANCA-associated vasculitis","volume":"363","author":"Stone","year":"2010","journal-title":"N Engl J Med"},{"key":"B3-20240826","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1136\/annrheumdis-2016-209133","article-title":"EULAR\/ERA-EDTA recommendations for the management of ANCA-associated vasculitis","volume":"75","author":"Yates","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"B4-20240826","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1681\/ASN.2015121356","article-title":"CD8+ T cells effect glomerular injury in experimental anti-myeloperoxidase GN","volume":"28","author":"Chang","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B5-20240826","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.kint.2017.09.018","article-title":"C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis","volume":"93","author":"Dick","year":"2018","journal-title":"Kidney Int"},{"key":"B6-20240826","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.kint.2019.05.012","article-title":"Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis","volume":"96","author":"Gan","year":"2019","journal-title":"Kidney Int"},{"key":"B7-20240826","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.4049\/jimmunol.1602025","article-title":"Pathogenic role for \u03b3\u03b4 T cells in autoimmune anti-myeloperoxidase glomerulonephritis","volume":"199","author":"Gan","year":"2017","journal-title":"J Immunol"},{"key":"B8-20240826","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1681\/ASN.2018090955","article-title":"Apoptotic cell-induced, antigen-specific immunoregulation to treat experimental antimyeloperoxidase GN","volume":"30","author":"Gan","year":"2019","journal-title":"J Am Soc Nephrol"},{"key":"B9-20240826","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1681\/ASN.2014090906","article-title":"Mast cell stabilization ameliorates autoimmune anti-myeloperoxidase glomerulonephritis","volume":"27","author":"Gan","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B10-20240826","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1681\/ASN.2009070763","article-title":"Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis","volume":"21","author":"Gan","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"B11-20240826","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1681\/ASN.2012060572","article-title":"Mast cells contribute to peripheral tolerance and attenuate autoimmune vasculitis","volume":"23","author":"Gan","year":"2012","journal-title":"J Am Soc Nephrol"},{"key":"B12-20240826","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1681\/ASN.2015010089","article-title":"Myeloperoxidase peptide-based nasal tolerance in experimental ANCA-associated GN","volume":"27","author":"Gan","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B13-20240826","doi-asserted-by":"crossref","first-page":"E2615","DOI":"10.1073\/pnas.1210147109","article-title":"The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis","volume":"109","author":"Ooi","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B14-20240826","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/ki.2014.189","article-title":"Fc\u03b3RIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis","volume":"86","author":"Ooi","year":"2014","journal-title":"Kidney Int"},{"key":"B15-20240826","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1038\/s41467-019-11255-0","article-title":"A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity","volume":"10","author":"Ooi","year":"2019","journal-title":"Nat Commun"},{"key":"B17-20240826","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jim.2005.10.011","article-title":"The isolation and purification of biologically active recombinant and native autoantigens for the study of autoimmune disease","volume":"308","author":"Apostolopoulos","year":"2006","journal-title":"J Immunol Methods"},{"key":"B18-20240826","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1172\/JCI65292","article-title":"Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis","volume":"123","author":"Roth","year":"2013","journal-title":"J Clin Invest"},{"key":"B19-20240826","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1172\/JCI0215918","article-title":"Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice","volume":"110","author":"Xiao","year":"2002","journal-title":"J Clin Invest"},{"key":"B20-20240826","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1681\/ASN.2006020108","article-title":"Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis","volume":"17","author":"Ruth","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"B21-20240826","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/ki.2015.202","article-title":"Renal participation of myeloperoxidase in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis","volume":"88","author":"O\u2019Sullivan","year":"2015","journal-title":"Kidney Int"},{"key":"B22-20240826","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.4049\/jimmunol.1004175","article-title":"Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells","volume":"187","author":"Getts","year":"2011","journal-title":"J Immunol"},{"key":"B23-20240826","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.4049\/jimmunol.1302070","article-title":"Exploiting apoptosis for therapeutic tolerance induction","volume":"191","author":"Getts","year":"2013","journal-title":"J Immunol"},{"key":"B24-20240826","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1093\/ckj\/sfx014","article-title":"Immunoglobulin levels and infection risk with rituximab induction for anti-neutrophil cytoplasmic antibody-associated vasculitis","volume":"10","author":"Shah","year":"2017","journal-title":"Clin Kidney J"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2020060834","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:24:47Z","timestamp":1786130687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1681\/ASN.2020060834"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":23,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2020060834","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]},"assertion":[{"value":"2020-06-16","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-31","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}