{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T15:42:09Z","timestamp":1766504529468,"version":"3.37.3"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2018,2,2]],"date-time":"2018-02-02T00:00:00Z","timestamp":1517529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Erasmus MC, University Medical Center","award":["343564"],"award-info":[{"award-number":["343564"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,4,18]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>We hypothesize that T cells such as interleukin (IL)-21+B cell lymphoma 6 (BCL6)+ T follicular helper cells can regulate B cell-mediated immunity within the allograft during acute T cell-mediated rejection; this process may feed chronic allograft rejection in the long term. To investigate this mechanism, we determined the presence and activation status of organized T and B cells in so-called ectopic lymphoid structures (ELSs) in different types of acute renal allograft rejection. Biopsies showing the following primary diagnosis were included: acute\/active antibody-mediated rejection, C4d+ (a\/aABMR), acute T cell-mediated rejection grade I (aTCMRI) and acute T cell-mediated rejection grade II (aTCMRII). Paraffin sections were stained for T cells (CD3 and CD4), B cells (CD20), follicular dendritic cells (FDCs, CD23), activated B cells (CD79A), immunoglobulin (Ig)D, cell proliferation (Ki67) and double immunofluorescent stainings for IL-21 and BCL6 were performed. Infiltrates of T cells were detected in all biopsies. In aTCMRI, B cells formed aggregates surrounded by T cells. In these aggregates, FDCs, IgD and Ki67 were detected, suggesting the presence of ELSs. In contrast, a\/aABMR and aTCMRII showed diffuse infiltrates of T and B cells but no FDCs and IgD. IL-21 was present in all biopsies. However, co-localization with BCL6 was observed mainly in aTCMRI biopsies. In conclusion, ELSs with an activated phenotype are found predominantly in aTCMRI where T cells co-localize with B cells. These findings suggest a direct pathway of B cell alloactivation at the graft site during T cell mediated rejection.<\/jats:p>","DOI":"10.1111\/cei.13099","type":"journal-article","created":{"date-parts":[[2018,1,10]],"date-time":"2018-01-10T17:13:10Z","timestamp":1515604390000},"page":"224-232","source":"Crossref","is-referenced-by-count":40,"title":["Characterization of ectopic lymphoid structures in different types of acute renal allograft rejection"],"prefix":"10.1093","volume":"192","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-9033","authenticated-orcid":false,"given":"K","family":"de Leur","sequence":"first","affiliation":[{"name":"Section Transplantation and Nephrology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands"},{"name":"Division of HPB and Transplant Surgery, Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M C","family":"Clahsen-van Groningen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T P P","family":"van den Bosch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G N","family":"de Graav","sequence":"additional","affiliation":[{"name":"Section Transplantation and Nephrology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D A","family":"Hesselink","sequence":"additional","affiliation":[{"name":"Section Transplantation and Nephrology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J N","family":"Samsom","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C C","family":"Baan","sequence":"additional","affiliation":[{"name":"Section Transplantation and Nephrology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K","family":"Boer","sequence":"additional","affiliation":[{"name":"Section Transplantation and Nephrology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,2,2]]},"reference":[{"key":"2021120808312530600_cei13099-bib-0001","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1097\/TP.0b013e3181e065de","article-title":"Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure","volume":"90","author":"Gaston","year":"2010","journal-title":"Transplantation"},{"key":"2021120808312530600_cei13099-bib-0002","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1600-6143.2008.02519.x","article-title":"Identifying specific causes of kidney allograft loss","volume":"9","author":"El-Zoghby","year":"2009","journal-title":"Am J Transplant"},{"key":"2021120808312530600_cei13099-bib-0003","doi-asserted-by":"crossref","first-page":"646","DOI":"10.3389\/fimmu.2016.00646","article-title":"Lymphoid neogenesis and tertiary lymphoid organs in transplanted organs","volume":"7","author":"Koenig","year":"2016","journal-title":"Front Immunol"},{"key":"2021120808312530600_cei13099-bib-0004","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1681\/ASN.2014040399","article-title":"Subclinical rejection phenotypes at 1 year post-transplant and outcome of kidney allografts","volume":"26","author":"Loupy","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"2021120808312530600_cei13099-bib-0005","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1681\/ASN.2014060588","article-title":"Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients","volume":"26","author":"Halloran","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"2021120808312530600_cei13099-bib-0006","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1097\/TP.0000000000001217","article-title":"T follicular helper cells in transplantation","volume":"100","author":"Walters","year":"2016","journal-title":"Transplantation"},{"key":"2021120808312530600_cei13099-bib-0007","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1097\/TP.0000000000001588","article-title":"Crosstalk between T and B cells in the germinal center after transplantation","volume":"101","author":"Kwun","year":"2017","journal-title":"Transplantation"},{"key":"2021120808312530600_cei13099-bib-0008","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of T follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science"},{"key":"2021120808312530600_cei13099-bib-0009","doi-asserted-by":"crossref","first-page":"e150","DOI":"10.1371\/journal.pbio.0030150","article-title":"Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells","volume":"3","author":"Okada","year":"2005","journal-title":"PLOS Biol"},{"key":"2021120808312530600_cei13099-bib-0010","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.immuni.2014.10.004","article-title":"T follicular helper cell differentiation, function, and roles in disease","volume":"41","author":"Crotty","year":"2014","journal-title":"Immunity"},{"key":"2021120808312530600_cei13099-bib-0011","doi-asserted-by":"crossref","first-page":"828","DOI":"10.4049\/jimmunol.1004233","article-title":"A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures","volume":"187","author":"Muniz","year":"2011","journal-title":"J Immunol"},{"key":"2021120808312530600_cei13099-bib-0012","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nri3700","article-title":"Ectopic lymphoid-like structures in infection, cancer and autoimmunity","volume":"14","author":"Pitzalis","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"2021120808312530600_cei13099-bib-0013","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1056\/NEJMoa035588","article-title":"Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling","volume":"349","author":"Sarwal","year":"2003","journal-title":"N Engl J Med"},{"key":"2021120808312530600_cei13099-bib-0014","doi-asserted-by":"crossref","first-page":"14723","DOI":"10.1073\/pnas.0507223102","article-title":"Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response","volume":"102","author":"Thaunat","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021120808312530600_cei13099-bib-0015","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/cei.12576","article-title":"Follicular T helper cells and humoral reactivity in kidney transplant patients","volume":"180","author":"de Graav","year":"2015","journal-title":"Clin Exp Immunol"},{"key":"2021120808312530600_cei13099-bib-0016","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.4049\/jimmunol.1001836","article-title":"Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets","volume":"185","author":"Astorri","year":"2010","journal-title":"J Immunol"},{"key":"2021120808312530600_cei13099-bib-0017","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/ajt.14107","article-title":"The Banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology","volume":"17","author":"Loupy","year":"2017","journal-title":"Am J Transplant"},{"key":"2021120808312530600_cei13099-bib-0018","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1038\/nri1733","article-title":"Monocyte and macrophage heterogeneity","volume":"5","author":"Gordon","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"2021120808312530600_cei13099-bib-0019","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12967-017-1141-8","article-title":"Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity","volume":"15","author":"Navegantes","year":"2017","journal-title":"J Transl Med"},{"key":"2021120808312530600_cei13099-bib-0020","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/ki.2008.249","article-title":"Characterization of intra-graft B cells during renal allograft rejection","volume":"74","author":"Zarkhin","year":"2008","journal-title":"Kidney Int"},{"key":"2021120808312530600_cei13099-bib-0021","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.it.2015.12.001","article-title":"TLS in tumors: what lies within","volume":"37","author":"Sautes-Fridman","year":"2016","journal-title":"Trends Immunol"},{"key":"2021120808312530600_cei13099-bib-0022","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1111\/j.1600-6143.2005.01009.x","article-title":"Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts","volume":"5","author":"Hippen","year":"2005","journal-title":"Am J Transplant"},{"key":"2021120808312530600_cei13099-bib-0023","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1097\/01.tp.0000250572.46679.45","article-title":"CD20+ lymphocytes in renal allografts are associated with poor graft survival in pediatric patients","volume":"82","author":"Tsai","year":"2006","journal-title":"Transplantation"},{"key":"2021120808312530600_cei13099-bib-0024","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1111\/j.1600-6143.2007.01885.x","article-title":"CD20-positive infiltrates in renal allograft biopsies with acute cellular rejection are not associated with worse graft survival","volume":"7","author":"Bagnasco","year":"2007","journal-title":"Am J Transplant"},{"key":"2021120808312530600_cei13099-bib-0025","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1016\/j.transproceed.2006.10.173","article-title":"The presence of B-cell nodules does not necessarily portend a less favorable outcome to therapy in patients with acute cellular rejection of a renal allograft","volume":"38","author":"Doria","year":"2006","journal-title":"Transplant Proc"},{"key":"2021120808312530600_cei13099-bib-0026","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1097\/TXD.0000000000000659","article-title":"Absence of intragraft B cells in rejection biopsies after rituximab induction therapy: consequences for clinical outcome","volume":"3","author":"van den Hoogen","year":"2017","journal-title":"Transplant Direct"},{"key":"2021120808312530600_cei13099-bib-0027","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1111\/j.1600-6143.2010.03223.x","article-title":"B cells help alloreactive T cells differentiate into memory T cells","volume":"10","author":"Ng","year":"2010","journal-title":"Am J Transplant"},{"key":"2021120808312530600_cei13099-bib-0028","doi-asserted-by":"crossref","first-page":"7715","DOI":"10.4049\/jimmunol.177.11.7715","article-title":"B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection","volume":"177","author":"Noorchashm","year":"2006","journal-title":"J Immunol"},{"key":"2021120808312530600_cei13099-bib-0029","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nri2729","article-title":"Effector and regulatory B cells: modulators of CD4+ T cell immunity","volume":"10","author":"Lund","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"2021120808312530600_cei13099-bib-0030","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/eji.201040759","article-title":"Tertiary lymphoid organs in renal allografts can be associated with donor-specific tolerance rather than rejection","volume":"41","author":"Brown","year":"2011","journal-title":"Eur J Immunol"},{"key":"2021120808312530600_cei13099-bib-0031","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.ajpath.2010.12.024","article-title":"Early acceptance of renal allografts in mice is dependent on foxp3(+) cells","volume":"178","author":"Miyajima","year":"2011","journal-title":"Am J Pathol"},{"key":"2021120808312530600_cei13099-bib-0032","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1681\/ASN.2014040404","article-title":"Tolerant kidney transplant patients produce B cells with regulatory properties","volume":"26","author":"Chesneau","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"2021120808312530600_cei13099-bib-0033","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1097\/TP.0000000000000465","article-title":"B cell markers of operational tolerance can discriminate acute kidney allograft rejection from stable graft function","volume":"99","author":"Heidt","year":"2014","journal-title":"Transplantation"},{"key":"2021120808312530600_cei13099-bib-0034","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1111\/ajt.13122","article-title":"Transitional B lymphocytes are associated with protection from kidney allograft rejection: a prospective study","volume":"15","author":"Shabir","year":"2015","journal-title":"Am J Transplant"},{"key":"2021120808312530600_cei13099-bib-0035","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nature11501","article-title":"Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions","volume":"491","author":"Yoshizaki","year":"2012","journal-title":"Nature"},{"key":"2021120808312530600_cei13099-bib-0036","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S1074-7613(02)00295-9","article-title":"IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity","volume":"16","author":"Kasaian","year":"2002","journal-title":"Immunity"},{"key":"2021120808312530600_cei13099-bib-0037","doi-asserted-by":"crossref","first-page":"5344","DOI":"10.4049\/jimmunol.0902999","article-title":"Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection","volume":"184","author":"Deteix","year":"2010","journal-title":"J Immunol"},{"key":"2021120808312530600_cei13099-bib-0038","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/ni.2053","article-title":"The development of inducible bronchus-associated lymphoid tissue depends on IL-17","volume":"12","author":"Rangel-Moreno","year":"2011","journal-title":"Nat Immunol"},{"key":"2021120808312530600_cei13099-bib-0039","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3109\/08820139.2015.1085394","article-title":"Characterisation of tertiary lymphoid organs in explanted rejected donor kidneys","volume":"45","author":"Xu","year":"2016","journal-title":"Immunol Invest"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.13099","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/192\/2\/224\/41644786\/cei13099.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/192\/2\/224\/41644786\/cei13099.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T16:25:49Z","timestamp":1641054349000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/192\/2\/224\/6412273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,2]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2,2]]},"published-print":{"date-parts":[[2018,4,18]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13099","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"type":"print","value":"0009-9104"},{"type":"electronic","value":"1365-2249"}],"subject":[],"published-other":{"date-parts":[[2018,5]]},"published":{"date-parts":[[2018,2,2]]}}}