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We show that LN lipomatosis starts in the medullary regions of the human LN and link the initiation of lipomatosis to transdifferentiation of LN fibroblasts into adipocytes. The latter is associated with a downregulation of lymphotoxin beta expression. We also show that isolated medullary and CD34\n                    <jats:sup>+<\/jats:sup>\n                    fibroblasts, in contrast to the reticular cells of the T\u2010cell zone, display an inherently higher sensitivity for adipogenesis. Progression of lipomatosis leads to a gradual loss of the medullary lymphatic network, but at later stages, collecting\u2010like lymphatic vessels are found inside the adipose tissue. The stromal dysregulation includes a dramatic remodeling and dilation of the high endothelial venules associated with reduced density of na\u00efve T\u2010cells. Abnormal clustering of plasma cells is also observed. Thus, LN lipomatosis causes widespread stromal dysfunction with consequences for the immune contexture of the human LN. Our data warrant an increased awareness of LN lipomatosis as a factor contributing to decreased immune functions in the elderly and in disease. \u00a9 2022 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6030","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T07:02:34Z","timestamp":1668150154000},"page":"236-253","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Stromal transdifferentiation drives lipomatosis and induces extensive vascular remodeling in the aging human lymph node"],"prefix":"10.1002","volume":"259","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2868-2483","authenticated-orcid":false,"given":"Tove","family":"Bekkhus","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Olofsson","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3027-7727","authenticated-orcid":false,"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Rudbeck Laboratory Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1142-854X","authenticated-orcid":false,"given":"Peetra U","family":"Magnusson","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology, Rudbeck Laboratory Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-0978","authenticated-orcid":false,"given":"Maria H","family":"Ulvmar","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201546178"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2012.04.005"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-013-9564-5"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2010.06.010"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.33.5.454"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2010.01213.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1148\/84.3.513"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3298"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0635-3"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.04.006"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.00052"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.06.027"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17291-5"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.5.1853"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1682"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2889"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000704"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1413.007"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.06.010"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5981"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13020211"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020107192"},{"key":"e_1_2_8_24_1","doi-asserted-by":"crossref","unstructured":"Bankhead P Loughrey MB Fern\u00e1ndez JA et al. 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