Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

• Published in: Annals of the rheumatic diseases Vol. 71; no. 12; pp. 2011 - 2019
• Main Authors: Maehara, Takashi, Moriyama, Masafumi, Nakashima, Hitoshi, Miyake, Katsuhisa, Hayashida, Jun-Nosuke, Tanaka, Akihiko, Shinozaki, Shouichi, Kubo, Yoshiaki, Nakamura, Seiji
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.12.2012; BMJ Publishing Group; Elsevier Limited
• Subjects: Adult; Aged; Asthma; Biological and medical sciences; Biopsy; Cytokines; Dacryocystitis - immunology; Dacryocystitis - pathology; Disease; Diseases of the osteoarticular system; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Female; Germinal Center - immunology; Germinal Center - metabolism; Germinal Center - pathology; Hepatitis; Humans; Immunoglobulin G - immunology; Immunoglobulins; Immunohistochemistry; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukin-21; Interleukin-4 - genetics; Interleukin-4 - immunology; Interleukins - genetics; Interleukins - immunology; Interleukins - metabolism; Lymphocytes; Male; Medical sciences; Middle Aged; Mikulicz' Disease - immunology; Mikulicz' Disease - pathology; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Pathogenesis; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-maf - genetics; Proto-Oncogene Proteins c-maf - immunology; Proto-Oncogene Proteins c-maf - metabolism; Receptors, CCR4 - genetics; Receptors, CCR4 - immunology; Receptors, CCR4 - metabolism; Receptors, CXCR5 - genetics; Receptors, CXCR5 - immunology; RNA, Messenger - metabolism; Salivary Glands - immunology; Salivary Glands - metabolism; Salivary Glands - pathology; Sialadenitis - immunology; Sialadenitis - pathology; Studies; Th2 Cells - immunology; Th2 Cells - pathology; Eye disease; Immunoglobulins; Dacryoadenitis; Production; Rheumatology; Interleukin 21; IgG4; Lacrimal apparatus disease
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2012-201477

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.