{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:03:45Z","timestamp":1789625025727,"version":"build-2803163510"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous cytokine storm disorder involving systemic inflammation, multicentric lymphadenopathy with characteristic histopathology, and life-threatening multiple organ dysfunction. Patients can present with symptoms ranging from thrombocytopenia, anasarca, fever\/elevated C-reactive protein (CRP), reticulin myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO) to thrombocytosis, hypergammaglobulinemia, and plasmacytosis (iMCD-IPL), with patients not falling into either group (iMCD-NOS). The molecular mechanisms across the clinical subtypes have not been elucidated and new effective treatments are needed. Here, we performed bulk RNA sequencing and targeted gene expression quantification in lymph node tissue from multiple iMCD clinical subtypes, pathologically related disorders, and controls. We identified 249 upregulated and 42 downregulated genes in iMCD-TAFRO lymph node tissue, which were enriched in the following pathways: angiogenesis, cell proliferation, and various aspects of the humoral and innate immune response. The targeted gene expression analysis revealed shared differentially expressed genes (DEGs) across all three iMCD clinical subtypes, including\n                    <jats:italic>SPP1<\/jats:italic>\n                    ,\n                    <jats:italic>XBP1<\/jats:italic>\n                    ,\n                    <jats:italic>PRDM1<\/jats:italic>\n                    , and\n                    <jats:italic>CLU<\/jats:italic>\n                    . We identified unique DEGs in each iMCD clinical subtype, including\n                    <jats:italic>PLA2G2A, MSR1, IL8<\/jats:italic>\n                    (iMCD-TAFRO),\n                    <jats:italic>IL9, KIR3DL1, IL18RAP<\/jats:italic>\n                    (iMCD-IPL), and\n                    <jats:italic>IL7, TLR8, and CX3CR1<\/jats:italic>\n                    (iMCD-NOS). Since Clusterin (\n                    <jats:italic>CLU<\/jats:italic>\n                    ) was significantly upregulated in iMCD but not in related conditions, we performed immunohistochemistry and observed that Clusterin is elevated in the germinal center and mantle zone regions of iMCD patient lymph nodes. A composite model incorporating CLU expression in these lymph node compartments with germinal center features demonstrated strong performance in differentiating iMCD from selected lymphadenopathies. Together, this work identified pathways dysregulated in iMCD lymph nodes and suggests that Clusterin, particularly when integrated with germinal center features, could be a novel biomarker.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1872505","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:32:20Z","timestamp":1789623140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clusterin expression and germinal center morphometry help distinguish idiopathic multicentric castleman disease from select lymphadenopathies"],"prefix":"10.3389","volume":"17","author":[{"given":"Michael V.","family":"Gonzalez","sequence":"first","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Zinski","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie D.","family":"Mumau","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Forsyth","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abiola H.","family":"Irvine","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Brandstadter","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania","place":["Philadelphia, Pennsylvania, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy G.","family":"Guzman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Biophysics, and Chemical Biology, University of Pennsylvania Perelman School of Medicine","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila K.","family":"Pierson","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget","family":"Austin","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Fajgenbaum","sequence":"additional","affiliation":[{"name":"Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2014.953145","article-title":"Use of a claims database to characterize and estimate the incidence rate for Castleman disease","volume":"56","author":"Munshi","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"B2","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1002\/ajh.23291","article-title":"The clinical spectrum of Castleman\u2019s disease","volume":"87","author":"Dispenzieri","year":"2012","journal-title":"Am J 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histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease","volume":"95","author":"Fajgenbaum","year":"2020","journal-title":"Am J Hematol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(14)70319-5","article-title":"Siltuximab for multicentric Castleman\u2019s disease: a randomised, double-blind, placebo-controlled trial","volume":"15","author":"van Rhee","year":"2014","journal-title":"Lancet Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3599","DOI":"10.1182\/blood-2019-128284","article-title":"Quantitative changes in serum proteins including CXCL13 are early indicators of response to anti-IL6 therapy in idiopathic multicentric Castleman disease","volume":"134","author":"Pierson","year":"2019","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","first-page":"7236","DOI":"10.1038\/s41467-022-34873-7","article-title":"CXCL13 is a predictive biomarker in idiopathic multicentric Castleman 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enhances B cell antigen binding and activation","volume":"38","author":"Heesters","year":"2013","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","first-page":"102332","DOI":"10.1016\/j.coi.2023.102332","article-title":"Persistent germinal center responses: slow-growing trees bear the best fruits","volume":"83","author":"Matz","year":"2023","journal-title":"Curr Opin Immunol"}],"container-title":["Frontiers in 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