Journal Article

THU0014 Composition of Dendritic Cell and NK Cell-Related Network with Abnormally Expressed Glycosylation-Related Molecules in the Bone Marrow Cells from Patients with Rheumatoid Arthritis

Nishimoto, N., Ito, M.N., Ochi, T., Murakami, M., Ochi, K., Shimaoka, Y.

2015

Overview

BackgroundGlycosylation is an important post-translational modification of proteins. Modification of glycan structure has been reported in some disease conditions such as rheumatoid arthritis (RA). RA is a chronic, systemic autoimmune disease where many inflammatory cytokines play pathological roles. In patients with RA, a significant defect in the galactosyltransferase enzyme activity results in a change in the galactosylation of immunoglobulin G (IgG). Autoantibodies against IgG lacking galactose frequently appear in RA patients and this change has been demonstrated to be associated with disease activities in RA. Although the precise mechanism is still not known, it is likely that the abnormal glycosylation processes may pathologically associate with RA. We hypothesize that this kind of glycosylation abnormalities occurs in the development of immune competent cells in the bone marrow (BM). Ochi et al reported an abnormality of BM cells contributes to the pathogenesis of RA in human and animal models (Arthritis Res Ther. 2007). Especially, they reported the presence of abnormal myeloid cells expressing the difucosyl type 2 chain structure (a specific marker of human undifferentiated cells) in RA patients' BM. This fact encouraged us to focus on bone marrow cells.ObjectivesThis study is to clarify the abnormal expression of glycosylation-related genes in bone marrow cells of RA patients and to analyze the network regulation of immune and inflammatory responses related to glycosylation abnormalities in RA.MethodsComprehensive gene expression analysis was conducted using DNA microarray on the BM cells of 28 RA patients and 11 healthy individuals (HI). According to the gene lists based on the Glyco Gene Database (GGDB) and Lectin Frontier Database (LfDB), glycosylation-related genes were extracted among the differentially expressed genes in RA compared with HI. Network analysis was performed using Ingenuity Pathway AnalysisR (IPA).Results1416 down regulated and 1673 up regulated genes were identified by more than two-fold change in the expression in RA compared to HI. In these differentially expressed genes, 50 glycosylation related genes decreased and 54 genes increased significantly. The decreased genes included A4GALT, B4GALT (encoding galactosyltransferases), UGCG (glucosyltransferase), FUT8 (fucosyltransferase) and EXT1,2 (exostoses) listed as top-five changed genes. On the other hand, the increased genes included many lectin genes such as ITGAL (encoding integrin), LGAL (galectin) and SIGLEC (sialic acid binding lectin). IPA analysis showed that the differentially expressed genes composed networks with inflammatory cytokines including TNF and IL-1. Moreover, they composed a network relevant to a dendritic cells and NK cells functions.ConclusionsThis is the first report that abnormal expression of glycosylation related genes in the bone marrow cells of RA patients. The down-regulation of genes of glycan synthesis and up-regulation of lectin genes might associate with the pathogenesis of RA.Disclosure of InterestNone declared

• Publisher: Elsevier Limited