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

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. 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. 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. 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. Castleman disease (CD) is a rare disease about which our understanding is still limited. In this study, we comprehensively analyzed an adolescent patient with the most severe subtype of CD, known as TAFRO, alongside further investigation of samples from 37 CD patients collected over 11 years. We found that many of the CD patients carried changes in their DNA, specifically in a gene called Mediterranean Fever (MEFV), which could play a large role in this rare disease. Targeting MEFV-related inflammation might be an effective intervention for treating CD. Our study thus provides important insights for understanding the cause of Castleman disease and ways in which it might be treated. Du, Xie, Dai, Jia, et al. assess the role of MEFV variants in Castleman Disease using both in vitro experiments and patient samples. The inflammatory response, scRNA landscape, and high prevalence of MEFV variants propose a critical role for MEFV in Castleman disease.