Pathogenesis of IgG4-related disease. Comparison with Sjögren's syndrome.

IgG4-related disease (IgG4-RD) is characterized by lympho-plasmacytic infiltration and fibrosis in multiple organs, accompanied by high serum IgG4 levels. Although both IgG4-RD and Sjögren's syndrome (SS) frequently affect salivary and lacrimal glands, the clinical and pathological features of these two conditions are different. In an attempt to delineate the pathomechanisms of IgG4-RD, we compared the gene expression patterns of various molecules in labial salivary glands (LSGs) between IgG4-RD and SS. First, using quantitative PCR, we demonstrated significantly higher mRNA expression levels of activation-induced cytidine deaminase (AID), IL-10, and TGFβ in LSGs of IgG4-RD than SS and healthy controls (HCs). We propose that the combination of AID and IL-10 contributes to IgG4-specific immunoglobulin class switch recombination, and that TGFβ induces LSGs fibrosis in IgG4-RD. Second, DNA microarray identified 2641 differentially expressed genes (DEGs) in LSGs; with 1321 up-regulated and 1320 down-regulated genes in IgG4-RD, relative to SS. Among the up-regulated DEGs in IgG4-RD, quantitative PCR confirmed significantly higher expression levels of chemokine (C-C motif) ligand 18 (CCL18) and lactotransferrin in LSGs of IgG4-RD than SS and HCs. The former has chemotactic activity on various types of lymphocytes and enhances collagen production from fibroblasts, while lactotransferrin is an iron-binding protein abundantly present in milk and has a wide range of functions, including fibroblast proliferation and maturation of dendritic cells (DCs). Third, immunofluorescence staining confirmed specific upregulation of CCL18 in macrophages, CD11c + and B cells, and plasmacytes of LSGs-IgG4-RD. These pathological findings could help in the identification of disease-specific biomarkers as well as development of novel therapeutic strategies.