Nishikori Asami, Nishimura Midori Filiz, Tomida Shuta, Chijimatsu Ryota, Ueta Himawari, Lai You Cheng, Kawahara Yuri, Takeda Yudai, Ochi Sayaka, Haratake Tomoka, Ennishi Daisuke, Nakamura Naoya, Momose Shuji, Sato Yasuharu
Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan.
J Clin Exp Hematop. 2024 Dec 25;64(4):297-306. doi: 10.3960/jslrt.24061. Epub 2024 Oct 28.
Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease unrelated to the Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8) infection. Presently, iMCD is classified into iMCD-IPL (idiopathic plasmacytic lymphadenopathy), iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis/renal insufficiency, and organomegaly), and iMCD-NOS (not otherwise specified). The most common treatment for iMCD is using IL-6 inhibitors; however, some patients resist IL-6 inhibitors, especially for iMCD-TAFRO/NOS. Nevertheless, since serum IL-6 levels are not significantly different between the iMCD-IPL and iMCD-TAFRO/NOS cases, cytokines other than IL-6 may be responsible for the differences in pathogenesis. Herein, we performed a transcriptome analysis of cytokine storm-related genes and examined the differences between iMCD-IPL and iMCD-TAFRO/NOS. The results demonstrated that counts per million of STAT2, IL1R1, IL1RAP, IL33, TAFAIP1, and VEGFA (P < 0.001); STAT3, JAK2, MAPK8, IL17RA, IL18, TAFAIP2, TAFAIP3, PDGFA, VEGFC, CXCL10, CCL4, and CXCL13 (P < 0.01); and STAT1, STAT6, JAK1, MAPK1, MAPK3, MAPK6, MAPK7, MAPK9, MAPK10, MAPK11, MAPK12, MAPK14, NFKB1, NFKBIA, NFKBIB, NFKBIZ, MTOR, IL10RB, IL12RB2, IL18BP, TAFAIP6, TNFAIP8L1, TNFAIP8L3, CSF2RBP1, PDGFB, PDGFC, and CXCL9 (P < 0.05) were significantly increased in iMCD-TAFRO/NOS. Particularly, upregulated IL33 expression was demonstrated for the first time in iMCD-TAFRO/NOS. Thus, inflammatory signaling, such as JAK-STAT and MAPK, may be enhanced in iMCD-TAFRO/NOS and may be a cytokine storm.
特发性多中心Castleman病（iMCD）是一种与卡波西肉瘤相关疱疹病毒/人类疱疹病毒8型（KSHV/HHV8）感染无关的Castleman病。目前，iMCD被分为iMCD-IPL（特发性浆细胞性淋巴结病）、iMCD-TAFRO（血小板减少、全身性水肿、发热、网状纤维增生/肾功能不全和器官肿大）和iMCD-NOS（未另行指定）。iMCD最常见的治疗方法是使用IL-6抑制剂；然而，一些患者对IL-6抑制剂耐药，尤其是iMCD-TAFRO/NOS患者。尽管如此，由于iMCD-IPL和iMCD-TAFRO/NOS病例之间的血清IL-6水平没有显著差异，因此除IL-6之外的细胞因子可能是发病机制差异的原因。在此，我们对细胞因子风暴相关基因进行了转录组分析，并研究了iMCD-IPL和iMCD-TAFRO/NOS之间的差异。结果表明，iMCD-TAFRO/NOS中每百万的STAT2、IL1R1、IL1RAP、IL33、TAFAIP1和VEGFA（P < 0.001）；STAT3、JAK2、MAPK8、IL17RA、IL18、TAFAIP2、TAFAIP3、PDGFA、VEGFC、CXCL10、CCL4和CXCL13（P < 0.01）；以及STAT1、STAT6、JAK1、MAPK1、MAPK3、MAPK6、MAPK7、MAPK9、MAPK10、MAPK11、MAPK12、MAPK14、NFKB1、NFKBIA、NFKBIB、NFKBIZ、MTOR、IL10RB、IL12RB2、IL18BP、TAFAIP6、TNFAIP8L1、TNFAIP8L3、CSF2RBP1、PDGFB、PDGFC和CXCL9（P < 0.05）计数显著增加。特别是，在iMCD-TAFRO/NOS中首次证明了IL33表达上调。因此，JAK-STAT和MAPK等炎症信号在iMCD-TAFRO/NOS中可能增强，并且可能是一种细胞因子风暴。
