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Background <p>Idiopathic Multicentric Castleman Disease, Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Organomegaly (iMCD-TAFRO) is a rare cytokine storm syndrome with high mortality. Pathogenesis of Castleman disease (CD) remain largely unknown. We aim to unravel the role of Mediterranean fever gene MEFV variants, the key gene variants implicated in familial Mediterranean fever, in CD.</p> Methods <p>Clinical data from a retrospective cohort of 37 patients with CD were collected. Blood and/or lymph node biopsy specimens were obtained for whole-exome sequencing. In vitro lipopolysaccharide stimulation experiment and single-cell RNA-sequencing (scRNA-seq) were performed to characterize the immune signature using peripheral blood mononuclear cells from an adolescent TAFRO patient, his asymptomatic parents, and a healthy control. The relative gene expression were examined by quantitative PCR. Cytokine levels were assessed using Luminex. Statistics were performed by SPSS and GraphPad Prism.</p> Results <p>Here we show an adolescent TAFRO patient with familial MEFV mutations demonstrates responsiveness to anti-IL-6 containing therapy. Through comprehensive analysis of a cohort of 37 CD patients, we observe a high prevalence of MEFV mutations (76%, 28/37). Notably, the MEFV E148Q-P369S-R408Q variant is present in 19% (7/37) of all patients and 50% (2/4) of the TAFRO subtype, with variant carriers exhibiting more severe disease course. Inflammation responses experiments and scRNA landscape reveal that MEFV expression is dominant in CD16<sup>+</sup> monocytes and correlated with IL-6 pathway activation likely via the interaction with naïve B/memory B cells in the TAFRO.</p> Conclusions <p>This study presents one of the largest cohorts demonstrating the high prevalence of MEFV variants in CD, providing important insights for understanding and treating CD, particularly TAFRO.</p>

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The clinical significance of the Mediterranean fever gene MEFV variants in Castleman disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Yumo Du,
  • Shuangfeng Xie,
  • Zhen Dai,
  • Wenqi Jia,
  • Wenjuan Li,
  • Long Zhang,
  • Guangzhou Du,
  • Haijiao Zhang,
  • Qiao Lin,
  • Meiping Wu,
  • Yiqing Li,
  • Wenjuan Yang,
  • Jie Xiao,
  • Yongxun Zhuansun,
  • Jianguo Li,
  • Wenying Zhang,
  • Shanping Jiang,
  • Danian Nie,
  • Kezhi Huang

摘要

Background

Idiopathic Multicentric Castleman Disease, Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Organomegaly (iMCD-TAFRO) is a rare cytokine storm syndrome with high mortality. Pathogenesis of Castleman disease (CD) remain largely unknown. We aim to unravel the role of Mediterranean fever gene MEFV variants, the key gene variants implicated in familial Mediterranean fever, in CD.

Methods

Clinical data from a retrospective cohort of 37 patients with CD were collected. Blood and/or lymph node biopsy specimens were obtained for whole-exome sequencing. In vitro lipopolysaccharide stimulation experiment and single-cell RNA-sequencing (scRNA-seq) were performed to characterize the immune signature using peripheral blood mononuclear cells from an adolescent TAFRO patient, his asymptomatic parents, and a healthy control. The relative gene expression were examined by quantitative PCR. Cytokine levels were assessed using Luminex. Statistics were performed by SPSS and GraphPad Prism.

Results

Here we show an adolescent TAFRO patient with familial MEFV mutations demonstrates responsiveness to anti-IL-6 containing therapy. Through comprehensive analysis of a cohort of 37 CD patients, we observe a high prevalence of MEFV mutations (76%, 28/37). Notably, the MEFV E148Q-P369S-R408Q variant is present in 19% (7/37) of all patients and 50% (2/4) of the TAFRO subtype, with variant carriers exhibiting more severe disease course. Inflammation responses experiments and scRNA landscape reveal that MEFV expression is dominant in CD16+ monocytes and correlated with IL-6 pathway activation likely via the interaction with naïve B/memory B cells in the TAFRO.

Conclusions

This study presents one of the largest cohorts demonstrating the high prevalence of MEFV variants in CD, providing important insights for understanding and treating CD, particularly TAFRO.