Kikuchi-Fujimoto disease is mediated by an aberrant type I interferon response

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents
  • Histiocytic Necrotizing Lymphadenitis* / diagnosis
  • Histiocytic Necrotizing Lymphadenitis* / genetics
  • Histiocytic Necrotizing Lymphadenitis* / pathology
  • Humans
  • Interferon Type I* / genetics
  • Lymph Nodes / pathology
  • Lymphadenitis* / pathology


  • Antiviral Agents
  • Interferon Type I