Abstract
IntroductionImmunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration, and fibrosis in various organs. The purpose of this study was to determine the mechanism of upregulation of IgG4 class switch recombination in IgG4-RD.MethodsWe extracted RNA from peripheral blood mononuclear cells (PBMCs) of patients with IgG4-RD (n = 6), Sjögren syndrome (SS) (n = 6), and healthy controls (n = 8), from CD3-positive T cells and CD20-positive B cells sorted from PBMCs of patients with IgG4-RD (n = 3), SS (n = 4), and healthy controls (n = 4), as well as from labial salivary glands (LSGs) of patients with IgG4-RD (n = 11), SS (n = 13), and healthy controls (n = 3). The mRNA expression levels of IgG4-specific class switch-related molecules, such as Th2 cytokines (IL-4 and IL-13), Treg cytokines (IL-10 and TGF-β), and transcriptional factors (GATA3 and Foxp3) were examined with quantitative polymerase chain reaction (PCR). IgG4-nonspecific class switch-related molecules, such as CD40, CD154, BAFF, APRIL, IRF4, and AID, were also examined.ResultsThe expression levels of Treg cytokines (IL-10 and TGF-β) and AID were significantly higher in LSGs of IgG4-RD than in SS and the controls (P < 0.05, each). In contrast, those of CD40 and CD154 were significantly lower in PBMCs of IgG4-RD than in SS (P < 0.05, each), whereas CD40 in CD20-positive B cells and CD154 in CD3-positive T cells were comparable in the three groups.ConclusionOverexpression of IL-10, TGF-β, and AID in LSGs might play important roles in the pathogenesis of IgG4-RD, such as IgG4-specific class-switch recombination and fibrosis. IgG4 class-switch recombination seems to be mainly upregulated in affected organs.
Highlights
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration, and fibrosis in various organs
CD40, CD154, B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), interferon regulatory factor 4 (IRF4), activation-induced cytidine deaminase (AID), and IL-21 contribute to nonspecific immunoglobulin class-switch recombination [12,13,14], as well as IL-4, IL-13, IL-10, and tumor growth factor (TGF)-b
All labial salivary gland (LSG) samples used in this study satisfied histopathologic findings of the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) proposed in 2011 by the All Japan IgG4 team [15]
Summary
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration, and fibrosis in various organs. CD40, CD154, B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), interferon regulatory factor 4 (IRF4), activation-induced cytidine deaminase (AID), and IL-21 contribute to nonspecific immunoglobulin class-switch recombination (from IgM to IgG1, IgG2, IgG3, IgG4, IgA, and IgE) [12,13,14], as well as IL-4, IL-13, IL-10, and TGF-b. The roles of these nonspecific immunoglobulin class switch-related molecules in the pathogenesis of IgG4-RD have not been reported previously
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