Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Yale School of Medicine, Yale University, New Haven, CT, USA.
Mod Pathol. 2022 Apr;35(4):462-469. doi: 10.1038/s41379-021-00992-7. Epub 2021 Dec 24.
Kikuchi-Fujimoto disease (KFD) is a reactive lymphadenitis of unclear etiology. To understand the pathogenesis of KFD, we performed targeted RNA sequencing of a well-characterized cohort of 15 KFD specimens with 9 non-KFD lymphadenitis controls. Two thousand and three autoimmunity-related genes were evaluated from archived formalin-fixed paraffin-embedded lymph node tissue and analyzed by a bioinformatics approach. Differential expression analysis of KFD cases compared to controls revealed 44 significantly upregulated genes in KFD. Sixty-eight percent of these genes were associated with the type I interferon (IFN) response pathway. Key component of the pathway including nucleic acid sensors, IFN regulatory factors, IFN-induced antiviral proteins, IFN transcription factors, IFN-stimulated genes, and IFN-induced cytokines were significantly upregulated. Unbiased gene expression pathway analysis revealed enrichment of IFN signaling and antiviral pathways in KFD. Protein-protein interaction analysis and a molecular complex detection algorithm identified a densely interacting 15-gene module of type I IFN pathway genes. Apoptosis regulator IFI6 was identified as a key seed gene. Transcription factor target analysis identified enrichment of IFN-response elements and IFN-response factors. T-cell-associated genes were upregulated while myeloid and B-cell-associated genes were downregulated in KFD. CD123+ plasmacytoid dendritic cells (PDCs) and activated T cells were noted in KFD. In conclusion, KFD is mediated by an aberrant type I interferon response that is likely driven by PDCs and T cells.
菊池古氏病（KFD）是一种病因不明的反应性淋巴结炎。为了了解 KFD 的发病机制，我们对 15 例特征明确的 KFD 标本和 9 例非 KFD 淋巴结炎对照进行了靶向 RNA 测序。从存档的福尔马林固定石蜡包埋淋巴结组织中评估了 2030 个自身免疫相关基因，并通过生物信息学方法进行了分析。与对照组相比，KFD 病例的差异表达分析显示 KFD 中有 44 个基因显著上调。这些基因中有 68%与 I 型干扰素（IFN）反应途径相关。该途径的关键组成部分，包括核酸传感器、IFN 调节因子、IFN 诱导的抗病毒蛋白、IFN 转录因子、IFN 刺激基因和 IFN 诱导的细胞因子，均显著上调。无偏见的基因表达途径分析显示 KFD 中 IFN 信号和抗病毒途径富集。蛋白质-蛋白质相互作用分析和分子复合物检测算法鉴定出 I 型 IFN 途径基因的密集相互作用 15 基因模块。凋亡调节因子 IFI6 被鉴定为关键种子基因。转录因子靶分析鉴定出 IFN 反应元件和 IFN 反应因子的富集。KFD 中 T 细胞相关基因上调，而髓样和 B 细胞相关基因下调。KFD 中可见 CD123+浆细胞样树突状细胞（PDC）和活化 T 细胞。总之，KFD 是由异常的 I 型干扰素反应介导的，这种反应可能是由 PDC 和 T 细胞驱动的。
