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FRI0272 Analysis of molecular mechanism in igg4-related disease: comparison with sjögren’s syndrome
  1. H. Tsuboi1,
  2. Y. Nakai2,
  3. M. Iizuka1,
  4. H. Asashima1,
  5. Y. Kondo1,
  6. A. Tanaka3,
  7. M. Moriyama3,
  8. I. Matsumoto1,
  9. T. Yoshihara4,
  10. S. Nakamura3,
  11. K. Abe2,
  12. T. Sumida1
  1. 1Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba-city
  2. 2Functional Food Science and Nutrigenomics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo
  3. 3Faculty of Dental Science, Kyushu University, Fukuoka
  4. 4Department of Otorhinolaryngology, Tokyo Women’s Medical University, Tokyo, Japan

Abstract

Background 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].

Objectives The purpose of this study was to clarify the molecules which played pathogenic roles in IgG4-RD exhaustively.

Methods 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.

Results 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 <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<0.05).

3) Immunofluorescence assay showed that CD68 positive macrophages could produce CCL18 in lacrimal glands of IgG4-RD.

Conclusions 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.

References

  1. Umehara H, et al: A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol 2012, 22:1-14.

  2. Tsuboi H, et al: Analysis of IgG4 class switch-related molecules in IgG4-related disease. Arthritis Res Ther 2012, 23;14(4):R171.

Disclosure of Interest: None Declared

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