IgG4-related disease: why high IgG4 and fibrosis?

The hallmarks of IgG4-related disease (IgG4-RD) are lymphoplasmacytic tissue infiltration with a predominance of IgG4-positive plasma cells, accompanied by fibrosis, obliterative phlebitis, dacryoadenitis, and elevated levels of IgG4. In a recent issue of Arthritis Research & Therapy, Tsuboi and colleagues demonstrated that regulatory T (Treg) cell-and T helper 2 (Th2) cell-derived cytokines contribute to the pathogenesis of Mikulicz's disease, an activation pathway that appears to be common for IgG4-RD. Additional organ-specific factors may account for the different organ involvement of IgG4-RD.

IgG4-related disease (IgG4-RD) is a newly categorized disease entity initially recognized in Japan but increasingly also in other parts of the world [1,2]. Most often the diagnosis is made in patients with autoimmune pan creatitis. Additional presentations include patients with lacrimal and salivary gland involvement, formerly Mikulicz's disease (MD), which was once thought to be a subset of Sjögren's syndrome (SS).
Th e hallmarks of IgG4-RD are lymphoplasmacytic tissue infi ltration with a dominance of IgG4-positive plasma cells, accompanied by fi brosis, obliterative phlebitis, dacryo adenitis, and elevated levels of IgG4. Th e pathogenesis of IgG4-RD is poorly understood; fi ndings consistent with both an autoimmune disorder and an allergic disorder are present [1,2].
IgG4 production is controlled primarily by T helper 2 (Th 2) cells [3,4]. Th 2 cytokines interleukin-4 (IL-4) and IL-13 enhance the production of IgG4 and IgE. In contrast, IL-10, IL-12, and IL-21 shift the balance between IgG4 and IgE, favoring IgG4. In the Th 2 cytokine-driven immune reaction, IgG4 production is induced preferentially by the activation of IL-10 produced by regulatory T (Treg) cells [3]. Th us, selective IgG4 induction is referred to as the combined eff ect of Th 2 and Treg cells.
In a recent issue of Arthritis Research & Th erapy, Tsuboi and colleagues [5] analyzed the expression of IgG4-specifi c class switch molecules such as Th 2 cytokines (IL-4 and IL-13) and Treg cytokines (IL-10 and TGF-β), IgG4-nonspecifi c B cell regulatory molecules (CD40, CD154, BAFF, APRIL, and IRF4), and activationinduced cytidine deaminase (AID) in the labial salivary glands (LSGs) and peripheral blood mononuclear cells (PBMCs) from patients with IgG4-RD (MD) and SS. Th e authors provided evidence that IL-10, TGF-β, and AID were overexpressed in LSGs from IgG4-RD (MD) compared with those in patients with SS, suggesting that Treg cytokines (IL-10 and TGF-β) contribute to IgG4-specifc class switch recombination and fi brosis in patients with IgG4-RD (MD) in combination with the IgG4-unrelated molecule, AID (Figure 1).
Very recently, Tanaka and colleagues [6] examined the Th 1, Th 2, and Treg cytokine expression in LSGs from patients with IgG4-RD and SS. Th e authors showed that the levels of mRNA for both Th 2 and Treg cytokines were signifi cantly higher in LSGs from patients with IgG4-RD (MD) but that the expressions of Th 1 and Th 2 cytokines were higher in LSGs from patients with SS. Th e upregulation of Treg cytokines is identical to the fi ndings reported by Tsuboi and colleagues [5], indicating that Treg cells play an important role in the pathogenesis of IgG4-RD (MD). In contrast, Tsuboi and colleagues showed that Th 2 cytokines such as IL-4 and IL-13 were not signifi cantly overexpressed in LSGs from patients with IgG4-RD (MD) but were increased if compared with those in healthy subjects. Th is fi nding supports the notion that Th 2 cytokines such as IL-4 and IL-13 play a common B cell-activating role in both IgG4-RD (MD) and SS. Contrary to Th 2 and Treg cytokines, Th 1 cytokines were upregulated only in LSGs from patients with SS [6], suggesting that Th 1 cells function as key players in the pathogenesis of SS.
Consistent with the fi ndings in MD, analyses of the expression of cytokines in infl ammatory lesions from patients with IgG4-related sclerosing pancreatitis and cholangitis [7] or tubulointerstitial nephritis [8] showed that tissue mRNA expression of Th 2 (IL-4) and Treg