Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

• Published in: Clinical immunology (Orlando, Fla.) Vol. 156; no. 1; pp. 9 - 18
• Main Authors: Furukawa, Sachiko, Moriyama, Masafumi, Tanaka, Akihiko, Maehara, Takashi, Tsuboi, Hiroto, Iizuka, Mana, Hayashida, Jun-Nosuke, Ohta, Miho, Saeki, Takako, Notohara, Kenji, Sumida, Takayuki, Nakamura, Seiji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2015
• Subjects: Adult; Aged; Allergy and Immunology; CCL18; Chemokines, CC - genetics; Chemokines, CC - metabolism; Dacryocystitis - physiopathology; Female; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Humans; IgG4-related dacryoadenitis and sialoadenitis; IL-10; Immunoglobulin G - metabolism; Immunohistochemistry; Interleukin-10 - genetics; Interleukin-10 - metabolism; M2 macrophage; Macrophages - metabolism; Male; Middle Aged; Mikulicz' Disease - physiopathology; Polymerase Chain Reaction; Severity of Illness Index; Sialadenitis - physiopathology; Sjogren's Syndrome - physiopathology; Submandibular Gland - physiopathology; SS; eGC; OSCC; MT; Treg; SMG; IgG4-related dacryoadenitis and sialoadenitis; IL-10; CS; M2 macrophage; MD; Fibrosis; LG; IgG4-DS; CCL18; IgG4-RD; Th2; ectopic germinal center; lacrimal gland; helper T type 2; Mikulicz's disease; Submandibular gland; oral squamous cell carcinoma; regulatory T cell; IgG4-related disease; Sjögren's syndrome; chronic sialoadenitis; Masson's trichrome
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2014.10.008

IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by bilateral swelling of glandular tissues with extensive fibrosis, and is immunologically considered a Th2-predominant disease. Recent studies reported that alternatively activated (M2) macrophages enhanced Th2 immune responses and fibrosis by production of pro-fibrotic factors (IL-10, IL-13 and CCL18). Therefore, we examined the association between M2 macrophages and fibrosis in submandibular glands from 7 patients with IgG4-DS, 10 patients with chronic sialoadenitis, 10 patients with Sjögren's syndrome, and 10 healthy subjects. The number of M2 macrophages in SMGs from patients with IgG4-DS was also significantly higher than in the other groups. Double immunofluorescence staining showed that IL-10 and CCL18 expression co-localized with M2 macrophage-marker (CD163). Furthermore, the SMG fibrosis score was positively correlated with the frequency of M2 macrophages in only IgG4-DS. These results indicate that IL-10 and CCL18 secreted by preferential M2 macrophages possibly play a key role in the development of severe fibrosis in IgG4-DS. •IgG4-DS showed strong infiltration of M2 macrophages in SMGs, whereas it was rarely detected in controls, CS, and SS.•The pro-fibrotic factors such as CCL18 and IL-10 were almost consistent with M2 macrophages in IgG4-DS.•The fibrosis scores were positively correlated with the frequency of M2 macrophages only in IgG4-DS patients.•IL-10 and CCL18 secreted by preferential M2 macrophages play a key role in the development of severe fibrosis in IgG4-DS.