Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Song, J. Y. et al. Clinical outcome and predictive factors of recurrence among patients with Kikuchi’s disease. Int. J. Infect. Dis. 13, 322–326 (2009).

    Article  Google Scholar 

  2. Zhang, J. et al. Kikuchi-Fujimoto disease associated with Sjogren’s syndrome: a case report and review of the literature. Int. J. Clin. Exp. Med. 8, 17061–17066 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. Kunz, M. & Ibrahim, S. M. Cytokines and cytokine profiles in human autoimmune diseases and animal models of autoimmunity. Mediators Inflamm. 2009, 979258 (2009).

    Article  Google Scholar 

  4. Psarras, A., Emery, P. & Vital, E. M. Type I interferon-mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy. Rheumatology 56, 1662–1675 (2017).

    CAS  PubMed  Google Scholar 

  5. Bengtsson, A. A. et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 9, 664–671 (2000).

    CAS  Article  Google Scholar 

  6. Baechler, E. C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. USA 100, 2610–2615 (2003).

    CAS  Article  Google Scholar 

  7. Han, G. M. et al. Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray. Genes Immun. 4, 177–186 (2003).

    CAS  Article  Google Scholar 

  8. Nelson, N. D. et al. Characterization of plasmacytoid dendritic cells, microbial sequences, and identification of a candidate public T-cell clone in Kikuchi-Fujimoto disease. Pediatr. Dev. Pathol. 24, 193–205 (2021).

    Article  Google Scholar 

  9. Wing, A. et al. Transcriptome and unique cytokine microenvironment of Castleman disease. Mod. Pathol. https://doi.org/10.1038/s41379-021-00950-3 (2021).

  10. Qi, Z. et al. Reliable gene expression profiling from small and hematoxylin and eosin-stained clinical formalin-fixed, paraffin-embedded specimens using the HTG EdgeSeq platform. J. Mol. Diagn. 21, 796–807 (2019).

    CAS  Article  Google Scholar 

  11. Godoy, P. M. et al. Comparison of reproducibility, accuracy, sensitivity, and specificity of miRNA quantification platforms. Cell Rep. 29, 4212–4222.e4215 (2019).

    CAS  Article  Google Scholar 

  12. Zhang, L. et al. Cross-platform comparison of immune-related gene expression to assess intratumor immune responses following cancer immunotherapy. J. Immunol. Methods. 494, 113041 (2021).

    CAS  Article  Google Scholar 

  13. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

    Article  Google Scholar 

  14. Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).

    Article  Google Scholar 

  15. Szklarczyk, D. et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447–D452 (2015).

    CAS  Article  Google Scholar 

  16. Cline, M. S. et al. Integration of biological networks and gene expression data using Cytoscape. Nat. Protoc. 2, 2366–2382 (2007).

    CAS  Article  Google Scholar 

  17. Bader, G. D. & Hogue, C. W. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 4, 2 (2003).

    Article  Google Scholar 

  18. Scardoni, G., Petterlini, M. & Laudanna, C. Analyzing biological network parameters with CentiScaPe. Bioinformatics 25, 2857–2859 (2009).

    CAS  Article  Google Scholar 

  19. Yu, J., Liang, C. & Liu, S. L. Interferon-inducible LY6E protein promotes HIV-1 infection. J. Biol. Chem. 292, 4674–4685 (2017).

    CAS  Article  Google Scholar 

  20. Tabata, T. et al. Characteristic distribution pattern of CD30-positive cytotoxic T cells aids diagnosis of Kikuchi-Fujimoto disease. Appl. Immunohistochem. Mol. Morphol. 26, 274–282 (2018).

    CAS  Article  Google Scholar 

  21. Chamulak, G. A., Brynes, R. K. & Nathwani, B. N. Kikuchi-Fujimoto disease mimicking malignant lymphoma. Am. J. Surg. Pathol. 14, 514–523 (1990).

    CAS  Article  Google Scholar 

  22. Pilichowska, M. E., Pinkus, J. L. & Pinkus, G. S. Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease): lesional cells exhibit an immature dendritic cell phenotype. Am. J. Clin. Pathol. 131, 174–182 (2009).

    Article  Google Scholar 

  23. Wahadat, M. J. et al. Type I IFN signature in childhood-onset systemic lupus erythematosus: a conspiracy of DNA- and RNA-sensing receptors? Arthritis Res. Ther. 20, 4 (2018).

    Article  Google Scholar 

  24. Mahajan, A., Herrmann, M. & Munoz, L. E. Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front. Immunol. 7, 35 (2016).

    Article  Google Scholar 

  25. Braunstein, I., Klein, R., Okawa, J. & Werth, V. P. The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. Br. J. Dermatol. 166, 971–975 (2012).

    CAS  Article  Google Scholar 

  26. Niewold, T. B., Hua, J., Lehman, T. J., Harley, J. B. & Crow, M. K. High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Genes. Immun. 8, 492–502 (2007).

    CAS  Article  Google Scholar 

  27. Dorfman, R. F. & Berry, G. J. Kikuchi’s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis. Semin. Diagn. Pathol. 5, 329–345 (1988).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Vinodh Pillai.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/s41379-021-00992-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41379-021-00992-7

Search

Quick links