FRI0272 Analysis of molecular mechanism in igg4-related disease: comparison with sjögren’s syndrome
Authors: H. Tsuboi, Y. Nakai, M. Iizuka, H. Asashima, Y. Kondo, A. Tanaka, M. Moriyama, I. Matsumoto, T. Yoshihara, S. Nakamura, K. Abe, T. Sumida
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> IgG4-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, infiltration of IgG4-positive plasmacytes and fibrosis in various organs such as the pancreas, salivary and lacrimal glands. Although the clinical features have been clarified recently, the pathogenesis of this disease remains unclear [1]. We previously showed that significantly higher expressions of IL-10, TGFb, and AID in labial salivary glands (LSG) of IgG4-RD than Sjögren's syndrome (SS) and controls. In LSG of IgG4-RD, increased IL-10 and TGFb might play pathogenic roles in IgG4-specific class switch recombination and fibrosis. AID also might contribute to up-regulation of IgG4-specific class switch recombination along with IL-10 in LSG [2]. <h3>Objectives</h3> The purpose of this study was to clarify the molecules which played pathogenic roles in IgG4-RD exhaustively. <h3>Methods</h3> 1) Gene expression was analyzed by DNA microarray using GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix) in LSG of IgG4-RD (N=3) and SS (N=3). Differentially expressed genes (DEGs) in IgG4-RD and SS were identified, and gene-annotation enrichment analysis of these DEGs was performed using Gene Ontology (GO) annotation. 2) Validation of the result was performed by quantitative PCR using LSG from IgG4-RD (N=8), SS (N=11), and controls (N=3) other than the patients analyzed by DNA microarray. 3) We also examined the expression of molecules in protein level by immunofluorescence assay using lacrimal glands from patients with IgG4-RD. <h3>Results</h3> 1) Gene expression patterns in IgG4-RD and SS were quite different in hierarchical clustering. In IgG4-RD, 580 up-regulated and 280 down-regulated genes were identified as DEGs (false discovery rate &lt;0.05). GO analysis indicated the up-regulated set of DEGs in IgG4-RD encoded proteins that function in T cell activation, T cell differentiation, chemotaxis, mitosis, immune responses, and inflammatory response. 2) PCR validated significantly higher expression of CCL18 which related to chemotaxis and fibrosis, in LSG of IgG4-RD than in SS and controls (P&lt;0.05). 3) Immunofluorescence assay showed that CD68 positive macrophages could produce CCL18 in lacrimal glands of IgG4-RD. <h3>Conclusions</h3> DNA microarray analysis in this study showed that the gene expression pattern in LSG of IgG4-RD was different from that of SS, suggesting different pathogenic mechanisms of IgG4-RD and SS. CCL18 produced by macrophages might relate to the pathogenesis of IgG4-RD via the chemotaxis of T cells and B cells, and the induction of collagen production from fibroblasts. <h3>References</h3> Umehara H, et al: A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 2012, 22:1-14. Tsuboi H, et al: Analysis of IgG4 class switch-related molecules in IgG4-related disease. Arthritis Res Ther 2012, 23;14(4):R171. <b>Disclosure of Interest</b>: None Declared