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Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease
  1. Takashi Maehara1,
  2. Masafumi Moriyama1,
  3. Hitoshi Nakashima2,
  4. Katsuhisa Miyake2,
  5. Jun-Nosuke Hayashida1,
  6. Akihiko Tanaka1,
  7. Shouichi Shinozaki1,
  8. Yoshiaki Kubo1,
  9. Seiji Nakamura1
  1. 1Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
  2. 2Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
  1. Correspondence to Dr Masafumi Moriyama, Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; moriyama{at}dent.kyushu-u.ac.jp

Abstract

Objectives Interleukin (IL)-21 is mainly produced by CD4 T helper (Th) cells including Th2, Th17 and follicular helper T (Tfh) cells. Recent studies have reported that IL-21 is involved in the formation of germinal centres (GCs) and class switching of IgG4. It has been suggested that IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease (MD), is distinct from Sjögren's syndrome (SS) and shows a high frequency of GC formation in salivary glands. In this study the expression of IL-21 in IgG4-DS and SS patients was examined.

Methods Twelve patients with IgG4-DS, 15 with SS and 15 healthy subjects were screened for (1) ectopic GC formation in formalin-fixed labial salivary gland (LSG) biopsy samples; (2) expression of IL-21, Th2-, Th17- and Tfh-related molecules (cytokines, chemokine receptors and transcription factors) in LSGs; (3) relationship between IgG4/IgG ratio and mRNA expression of IL-21 in LSGs.

Results mRNA expression of IL-21 and Bcl-6 in LSGs from patients with IgG4-DS was significantly higher than in patients with SS and controls. IL-21 and CXCR5 were detected by immunohistochemistry in or around GC in patients with SS and those with IgG4-DS. IL-21 was detected in infiltrating lymphocytes outside GC only in patients with IgG4-DS. Expression of IL-21 was consistent with that of Th2-related molecules while IL-17 was rarely seen in IgG4-DS. Furthermore, the expression of IL-21 in LSGs was correlated with the number of GC formations and the IgG4/IgG ratio in patients with IgG4-DS.

Conclusions These results suggest that overexpression of IL-21 by Th2 cells might play a key role in GC formation and IgG4 production in IgG4-DS.

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Footnotes

  • Funding This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (22791990) and by Intractable Diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour, and Welfare of Japan (H23-005, H24-043).

  • Competing interest None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was obtained from the ethics committee of Kyushu University, Japan.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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