Skip to main content

Advertisement

SpringerLink
Log in

A Non-invasive Diagnosis of Histiocytic Necrotizing Lymphadenitis by Means of Gene Expression Profile Analysis of Peripheral Blood Mononuclear Cells

  • Original Research
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Histiocytic necrotizing lymphadenitis (HNL), also called Kikuchi-Fujimoto disease, is a benign, self-limiting inflammatory disease with fever and painful cervical lymphadenopathy of unknown etiology. A lymph node biopsy is required for the definitive diagnosis because of no specific symptoms or laboratory findings for HNL. To establish the rapid non-invasive diagnostic method for this disease, we investigated genes specifically expressed in the patients by analyzing whole transcriptome using microarray analysis of peripheral blood mononuclear cells (PBMC). The top five up-regulated genes (IFI44L, CXCL10, GBP1, EPSTI1 and IFI27) in HNL were interferon-induced genes (ISGs). The expression levels of the up-regulated genes by microarray were verified by quantitative PCR. High levels of serum CXCL10 concentration were confirmed at the symptomatic phase of HNL patients. The expression levels of these 5 genes positively correlated with each other (r2 = 0.28–0.60). The genes were also highly expressed in HNL lymph nodes. The discriminant analysis using the expression levels of these five genes distinguished HNL with 84 % accuracy. The combination of up-regulated ISGs in HNL seemed to be a specific response induced by viral infections or autoantigens. An analysis of the gene expression profile of PBMC may provide a rapid non-invasive diagnosis of HNL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ACTB:

Beta actin

ADV:

Adenovirus

AUC:

Area under the curve

cDNA:

Complementary DNA

CT :

Threshold cycle

CXCL10:

Chemokine (C-X-C motif) ligand 10

EPSTI1:

Epithelial stromal interaction 1 (breast)

FluA:

Influenza type A virus

GBP1:

Guanylate binding protein 1 interferon-inducible

HNL:

Histiocytic necrotizing lymphadenitis

IFN:

Interferon

IFI27:

Interferon alpha-inducible protein 27

IFI44L:

Interferon-induced protein 44-like

IL:

Interleukin

IM:

Infectious mononucleosis

ISG:

Interferon-stimulated gene

KD:

Kawasaki disease

LNitis:

Purulent lymphadenitis

PBMC:

Peripheral blood mononuclear cells

PCR:

Polymerase chain reaction

SLE:

Systemic lupus erythematosus

SoJIA:

Systemic onset juvenile idiopathic arthritis

References

  1. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic Kikuchi-Fujimoto disease: a comprehensive review. Am J Clin Pathol. 2004;122:141–52.

    Article  PubMed  Google Scholar 

  2. Hutchinson CB, Wang E. Kikuchi-Fujimoto disease. Arch Pathol Lab Med. 2010;134:289–93.

    PubMed  Google Scholar 

  3. Yoshioka K, Miyashita T, Nakamura T, et al. Treatment of histiocytic necrotizing lymphadenitis (Kikuchi’s disease) with prolonged fever by a single course of methylprednisolone pulse therapy without maintenance therapy: experience with 13 cases. Intern Med. 2010;49:2267–70.

    Article  PubMed  Google Scholar 

  4. Pileri SA, Facchetti F, Ascani S, et al. Myeloperoxidase expression by histiocytes in Kikuchi’s and Kikuchi-like lymphadenopathy. Am J Pathol. 2001;159:915–24.

    Article  PubMed  CAS  Google Scholar 

  5. Pilichowska ME, Pinkus JL, Pinkus GS. Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease): lesional cells exhibit an immature dendritic cell phenotype. Am J Clin Pathol. 2009;131:174–82.

    Article  PubMed  Google Scholar 

  6. Ohshima K, Shimazaki K, Kume T, et al. Perforin and Fas pathways of cytotoxic T-cells in histiocytic necrotizing lymphadenitis. Histopathology. 1998;33:471–8.

    Article  PubMed  CAS  Google Scholar 

  7. Ohshima K, Shimazaki K, Suzumiya J, et al. Apoptosis of cytotoxic T-cells in histiocytic necrotizing lymphadenitis. Virchows Arch. 1998;433:131–4.

    Article  PubMed  CAS  Google Scholar 

  8. Ohshima K, Karube K, Hamasaki M, et al. Apoptosis- and cell cycle-associated gene expression profiling of histiocytic necrotising lymphadenitis. Eur J Haematol. 2004;72:322–9.

    Article  PubMed  CAS  Google Scholar 

  9. Hu S, Kuo TT, Hong HS. Lupus lymphadenitis simulating Kikuchi’s lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature. Pathol Int. 2003;53:221–6.

    Article  PubMed  Google Scholar 

  10. Sumiyoshi Y, Kikuchi M, Takeshita M, et al. Alpha-interferon in Kikuchi’s disease. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;61:201–7.

    Article  PubMed  CAS  Google Scholar 

  11. Kubota M, Tsukamoto R, Kurokawa K, et al. Elevated serum interferon gamma and interleukin-6 in patients with necrotizing lymphadenitis (Kikuchi’s disease). Br J Haematol. 1996;95:613–5.

    Article  PubMed  CAS  Google Scholar 

  12. Ikeda K, Yamaguchi K, Tanaka T, et al. Unique activation status of peripheral blood mononuclear cells at acute phase of Kawasaki disease. Clin Exp Immunol. 2010;160:246–55.

    Article  PubMed  CAS  Google Scholar 

  13. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–8.

    Article  PubMed  CAS  Google Scholar 

  14. Schoggins JW, Wilson SJ, Panis M, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472:481–5.

    Article  PubMed  CAS  Google Scholar 

  15. Ohshima K, Haraoka S, Takahata Y, et al. Interferon-gamma, interleukin-18, monokine induced by interferon-gamma and interferon-gamma-inducible protein-10 in histiocytic necrotizing lymphadenitis. Leuk Lymphoma. 2002;43:1115–20.

    PubMed  CAS  Google Scholar 

  16. Ishii T, Onda H, Tanigawa A, et al. Isolation and expression profiling of genes upregulated in the peripheral blood cells of systemic lupus erythematosus patients. DNA Res. 2005;12:429–39.

    Article  PubMed  CAS  Google Scholar 

  17. Ansell SM, Maurer MJ, Ziesmer SC, et al. Elevated pretreatment serum levels of interferon-inducible protein-10 (CXCL10) predict disease relapse and prognosis in diffuse large B-cell lymphoma patients. Am J Hematol. 2012;87:865–9.

    Article  PubMed  CAS  Google Scholar 

  18. Lee Y, Chittezhath M, Andre V, et al. Protumoral role of monocytes in human B-cell precursor acute lymphoblastic leukemia: involvement of the chemokine CXCL10. Blood. 2012;119:227–37.

    Article  PubMed  CAS  Google Scholar 

  19. Nzeusseu Toukap A, Galant C, Theate I, et al. Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis Rheum. 2007;56:1579–88.

    Article  PubMed  CAS  Google Scholar 

  20. Naschberger E, Wenzel J, Kretz CC, et al. Increased expression of guanylate binding protein-1 in lesional skin of patients with cutaneous lupus erythematosus. Exp Dermatol. 2011;20:102–6.

    Article  PubMed  CAS  Google Scholar 

  21. Kimoto O, Sawada J, Shimoyama K, et al. Activation of the interferon pathway in peripheral blood of patients with Sjogren’s syndrome. J Rheumatol. 2011;38:310–6.

    Article  PubMed  CAS  Google Scholar 

  22. Szturz P, Adam Z, Chovancová J, et al. Cytokine analysis in a patient with relapsing Kikuchi-Fujimoto disease. Leuk Lymphoma. 2012;53:743–5.

    Article  PubMed  Google Scholar 

  23. Itsui Y, Sakamoto N, Kakinuma S, et al. Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein. Hepatology. 2009;50:1727–37.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Department of Pathology, Faculty of Medicine, Fukuoka University, Japan, for the material support. The statistical analyses were advised by Junji Kishimoto at Kyushu University Hospital, Japan. This work was supported by a Grant-in-Aid for research on intractable diseases for Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masataka Ishimura, Hiroyuki Yamamoto, Hidetoshi Takada, Motohiro Goto, Takehiko Doi, Takayuki Hoshina, Shouichi Ohga & Toshiro Hara

  2. Fukuoka Children’s Hospital and Medical Center for Infectious Diseases, Fukuoka, Japan

    Yumi Mizuno

  3. Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shouichi Ohga

  4. Department of Pathology, School of Medicine, Kurume University, Kurume, Japan

    Koichi Ohshima

Authors
  1. Masataka Ishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroyuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yumi Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hidetoshi Takada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Motohiro Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takehiko Doi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takayuki Hoshina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shouichi Ohga
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Koichi Ohshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toshiro Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masataka Ishimura.

Additional information

Masataka Ishimura and Hiroyuki Yamamoto contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishimura, M., Yamamoto, H., Mizuno, Y. et al. A Non-invasive Diagnosis of Histiocytic Necrotizing Lymphadenitis by Means of Gene Expression Profile Analysis of Peripheral Blood Mononuclear Cells. J Clin Immunol 33, 1018–1026 (2013). https://doi.org/10.1007/s10875-013-9897-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-013-9897-y

Keywords

Search

Navigation