Abstract
Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (non-specific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD.
Highlights
Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder characterized by the formation of benign masses and tumefactive lesions in various organs[1]
Various numbers of AIDexpressing cells were observed in sialolithiasis specimens (Fig. 1c); none were noted in normal tissues (Fig. 1d)
The Activation-induced cytidine deaminase (AID) staining intensity index was significantly higher in IgG4-related sialadenitis samples [9 (64%), 3 (21%), 2 (14%), and 0 (0%) cases were categorized as 3+, 2+, 1+, and 0, respectively] than in sialolithiasis [3 (23%), 3 (23%), 3 (23%), and 4 (31%) cases, respectively] (P = 0.02) or normal control [all 13 (100%) cases were categorized as 0] (P < 0.01) (Fig. 2)
Summary
Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder characterized by the formation of benign masses and tumefactive lesions in various organs[1]. Histological observations of affected tissues exhibit dense fibrosis and infiltration of large numbers of lymphocytes, plasma cells, and eosinophils[2] In patients with these types of diseases, many plasma cells express IgG4 and its serum levels are highly elevated[2]. AID plays a crucial role in B-cell maturation and is normally expressed in activated B-cells in germinal centres[8]. This enzyme induces somatic hypermutations in the Ig www.nature.com/scientificreports/. In addition to B-cells, AID expression can be induced in various epithelial tissues due to chronic inflammation and infection[11]. Up-regulation of AID during inflammatory conditions is believed to cause uncontrolled somatic mutations of various genes, resulting in chronic inflammation-associated cancers[12]. In this study, we investigated the expression of AID in IgG4-related sialadenitis
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