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Gene expression patterns in IgG4-RD before and after steroid treatment and healthy control groups

ABSTRACT: Transcriptome analysis in patients with IgG4-RD and healthy controls IgG4-related disease (IgG4-RD) is a new emerging disease entity characterized by elevated serum IgG4 concentrations and tissue tumefaction or infiltration by IgG4-positive plasma cells. At present, however, it is not clear whether IgG4-RD is caused by abnormalities in acquired immunity, like autoimmune diseases, or whether the excess production of IgG4 is a true cause of IgG4-RD or an epiphenomenon associated with inflammatory and/or allergic reactions. We therefore attempted to identify genes related to the pathogenesis or clinicopathology of IgG4-RD. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IgG4-RD before and after steroid therapy and from healthy controls. Total RNA was extracted and DNA microarray analysis was performed to screen for genes showing changes in expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66465 | GEO | 2015/03/03

SECONDARY ACCESSION(S): PRJNA277019

REPOSITORIES: GEO

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Project description:<Objective> To compare gene expression in labial salivary glands (LSG) of IgG4-related disease (IgG4-RD) with SjM-CM-6grenM-bM-^@M-^Ys syndrome (SS). <Methods> Gene expression was analyzed by DNA microarray in LSG of IgG4-RD (n=5), SS (n=5), and healthy controls (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. Validation of the result was performed by quantitative PCR using LSG from IgG4-RD (n=9), SS (n=10), and controls (n=4). <Results> Gene expression patterns in IgG4-RD, SS, and healthy controls were quite different with each other in hierarchical clustering as well as principal component analysis. In IgG4-RD, 1771 up-regulated probe sets (corresponding to 1321 up-regulated genes) and 1785 down-regulated probe sets (corresponding to 1320 down-regulated genes) were identified as DEGs (false discovery rate <0.05). GO term analysis indicated that the up-regulated set of DEGs in IgG4-RD encoded proteins that function in cell proliferation, extracellular matrix organization, and organ development. PCR validated significantly higher expression of lactotransferrin (LTF) in IgG4-RD than SS (P<0.05), and chemokine (C-C motif) ligand 18 (CCL18) in IgG4-RD than SS and controls (P<0.05). <Conclusion> The results clearly showed that the gene expression pattern in LSG of IgG4-RD is different from that of SS. LSG samples were collected from 5 Japanese patients with IgG4-RD, as well as from 5 Japanese patients with SS who had been followed up at University of Tsukuba Hospital (Ibaraki, Japan). All patients with IgG4-RD satisfied the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) 2011 proposed by the All Japan IgG4 team [3]. The diagnosis of IgG4-RD was based on the presence of all three items; 1) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs, 2) Hematological examination shows elevated serum IgG4 concentrations (135 mg/dl), 3) Histopathologic examination shows: (1) Marked lymphocyte and plasmacyte infiltration and fibrosis. (2) Infiltration of IgG4+ plasma cells: ratio of IgG4+/IgG+ cells > 40% and >10 IgG4+ plasma cells/HPF. All patients with SS satisfied the Japanese Ministry of Health criteria for the diagnosis of SS (1999) [4]. These criteria included four clinicopathological findings: lymphocytic infiltration of the salivary or lacrimal glands, dysfunction of salivary secretion, keratoconjunctivitis sicca, and presence of anti-SS-A or SS-B antibodies. The diagnosis of SS was based on the presence of two or more of the above four items. Approval for this study was obtained from the local ethics committee and a signed informed consent was obtained from each subject.

Project description:Objective: This study aimed to investigate plasma exosome profiling of IgG4-RD and its potential role in B cell differentiation and tissue damage. Methods: One hundred untreated IgG4-RD patients and 135 sex, age matched healthy controls (HCs) were enrolled in this study. A combination of liquid chromatography-tandem mass spectroscopy (LC-MS/MS) and TMT label quantitation was used to detect exosome and B cell profiling. To validate differentially expressed proteins, western blot and ELISA were performed. RT-qPCR was used to detect gene expression after exosome stimulation. Flowcytometry was used to measure B cell activation, apoptosis, differentiation and reactive oxygen species (ROS) expression. Besides, correlation analysis between differentially expressed complement protein and laboratory parameters was also performed. Results: In total, 82 proteins were upregulated and 96 proteins were downregulated in exosome of IgG4-RD patients compared with HCs. Pathway analysis revealed that complement cascade pathway in exosome of IgG4-RD was activated, together with reduced C3 complement and C5 complement. Validation by ELISA and WB, exosome C3 and C5 was decrease in IgG4-RD compared with HCs. Stimulation of B cells with exosome, naïve B cells decreased, while memory B cells and plasmablast were increased together with increased CYCS with activation of downstream complement system. ROS was increased in B cells of IgG4-RD compared with HC. In affected submandibular glands, BCR signaling pathway was activated and exosome may potentially participate in tissue damage. Conclusion: There were 82 differentially expressed upregulated proteins and 96 downregulated proteins in IgG4-RD exosome compared with HCs. Differentially expressed proteins were enriched in exosome, complement function and immune response indicating complement activation in exosome may be related to IgG4-RD. Reduced C3 and C5 expression in exosome of IgG4-RD may indicate the disease severity. Our research suggests that IgG4-RD exosomes can participate in the differentiation B cells into plasmablast, activate the B cell auto-oxidative damage pathway and potentially participate in the pathogenesis of IgG4-RD.

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Gene expression patterns in IgG4-RD before and after steroid treatment and healthy control groups

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