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


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.

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Fig. 1: Characteristic histologic and immunophenotypic features of KFD.
Fig. 2: Gene expression signature of KFD compared to controls.
Fig. 3: IFN-associated genes are strongly upregulated in KFD.
Fig. 4: Type I IFN pathways are enriched in KFD.
Fig. 5: Overview of the IFN-response pathway.

Data availability

Data generated or analyzed during this study are included in this published article (and its supplementary information files). Any other data will be provided on reasonable request to the corresponding author.


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We would like to thank Ms. Rachel Olson, Mr. Brian Lockhart, and the Division of Hematopathology for their support. We would like to thank Drs. Eline Luning Prak, Adam Bagg, Bob Doms, and Dale Frank for comments on the manuscript and scientific discussions. Copy editing of the manuscript was performed by the Durnam Consulting Group. The study was funded in part by an autoimmune disease grant from HTG Molecular Diagnostics, Inc.

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Authors and Affiliations



V.P. performed study concept and design; V.P., E.Y.L., J.X., D.T.T., E.B., and N.R. performed writing, review, and revision of the paper; V.P., J.X., N.D.N., E.Y.L., D.T.T., and K.T. provided acquisition, analysis and interpretation of data, and statistical analysis; All authors read and approved the final paper.

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Correspondence to Vinodh Pillai.

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The authors declare no competing interests.

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The study was approved by the CHOP Institutional Review Board (IRB 16-013199) and performed in accordance with the Declaration of Helsinki.

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Li, E.Y., Xu, J., Nelson, N.D. et al. Kikuchi-Fujimoto disease is mediated by an aberrant type I interferon response. Mod Pathol 35, 462–469 (2022).

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