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

• Published in: Modern pathology 2022-04, Vol.35 (4), p.462-469
• Main Authors: Li, Elizabeth Y., Xu, Jason, Nelson, Nya D., Teachey, David T., Tan, Kai, Romberg, Neil, Behrens, Ed, Pillai, Vinodh
• Format: Article
• Language: English
• Subjects: 13/51; 38/39; 38/91; 631/208/199; 692/699/1541; Antiviral Agents; Apoptosis; Autoimmunity; Bioinformatics; CD123 antigen; Dendritic cells; Etiology; Gene expression; Histiocytic Necrotizing Lymphadenitis - diagnosis; Histiocytic Necrotizing Lymphadenitis - genetics; Histiocytic Necrotizing Lymphadenitis - pathology; Humans; Interferon; Interferon Type I - genetics; Laboratory Medicine; Lymph nodes; Lymph Nodes - pathology; Lymphadenitis; Lymphadenitis - pathology; Lymphatic diseases; Lymphocytes B; Lymphocytes T; Medicine; Medicine & Public Health; Paraffin; Pathology; Regulatory sequences; Transcription factors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-021-00992-7

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.