DNA Microarray Analysis of Labial Salivary Glands in IgG4‐Related Disease: Comparison With Sjögren's Syndrome

Tsuboi, Hiroto; Nakai, Yuji; Iizuka, Mana; Asashima, Hiromitsu; Hagiya, Chihiro; Tsuzuki, Sayaka; Hirota, Tomoya; Miki, Haruka; Hagiwara, Shinji; Kondo, Yuya; Tanaka, Akihiko; Moriyama, Masafumi; Matsumoto, Isao; Nakamura, Seiji; Yoshihara, Toshio; Abe, Keiko; Sumida, Takayuki

doi:10.1002/art.38748

Cited by 36 publications

(47 citation statements)

References 34 publications

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“…We showed that the up-regulated sets of DEGs in patients with SS-encoded proteins that function in antigen processing and presentation of peptide antigen in the gene-annotation enrichment analysis, as we have reported previously [7]. We showed that the up-regulated sets of DEGs in patients with SS-encoded proteins that function in antigen processing and presentation of peptide antigen in the gene-annotation enrichment analysis, as we have reported previously [7].…”

Section: Discussionsupporting

confidence: 83%

“…In SS patients, 1785 up-regulated probe sets (corresponding to 1320 up-regulated genes) and 1771 down-regulated probe sets (corresponding to 1321 down-regulated genes) were identified as DEGs (FDR < 0Á05, compared with IgG4-RD) (Supporting information, Table S1). Geneannotation enrichment analysis by the Web tool DAVID and QuickGO showed that significantly enriched Gene Ontology (GO) terms (FDR-corrected P-value < 0Á0001) found in highly expressed probe sets in SS compared with IgG4-RD included protein glycosylation, immune response, antigen processing and presentation of peptide antigen via major histocompatibility complex (MHC) class I, Golgi vesicle transport, co-translational protein targeting to membrane, endoplasmic reticulum (ER) unfolded protein response and response to virus, as reported previously by our group [7]. In contrast, gene-annotation enrichment analysis by GO annotation showed that the down-regulated set of DEGs in SS encoded proteins that function in wound healing, response to inorganic substance, skeletal system development, muscle organ development, heart development, angiogenesis, cell morphogenesis involved in cDNA microarray identifies NR4A2 in SS V C 2017 British Society for Immunology, Clinical and Experimental Immunology, 190: 96-109 differentiation, cell projection organization, muscle contraction, extracellular matrix organization, actin cytoskeleton organization, cell-matrix adhesion, regulation of cell migration, regulation of cell-substrate adhesion, positive regulation of cell adhesion, regulation of cell proliferation, enzyme linked receptor protein signalling pathway, regulation of inflammatory response and translational elongation, as shown in our previous report [7].…”

Section: Cdna Microarray Analysissupporting

confidence: 74%

“…The reason that we selected only females was that an overwhelming majority of SS patients are female [21]. The methods of isolation and purification of total RNA for the cDNA microarray analysis were described in detail in our previous report [7]. All microarray data were minimum information about a microarray-compliant experiment (MIAME) and have been deposited in a MIAME-compliant database; the National Center for Biotechnology Information Gene Expression Omnibus (GEO Series Accession number: GSE40568), as detailed on the Microarray and Gene Expression Data (MGED) Society website.…”

Section: Cdna Microarray Analysismentioning

confidence: 99%

“…We compared previously the LSG gene expression profiles of IgG4-RD and SS [7]. The results showed differences in the gene expression patterns and differentially expressed genes (DEGs) between the two conditions and, accordingly, we then analysed those in LSGs of IgG4-RD [7]. In the present study, we focused on the gene expression in LSGs of SS and performed analyses of genes that are specific to the pathology of SS.…”

Section: Introductionmentioning

confidence: 99%

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cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjögren's syndrome

Takahashi

Tsuboi

Asashima

et al. 2017

Clinical and Experimental Immunology

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To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) in comparison with those of patients with immunoglobulin (Ig)G4-related disease (IgG4-RD), and to identify the genes involved in the pathogenesis of SS. Gene expression in LSGs of SS patients, IgG4-RD patients and healthy controls (HC) was analysed by cDNA microarray. Quantitative polymerase chain reaction (qPCR) was used to validate the up-regulation of differentially expressed genes (DEGs) in SS. Protein production of the validated gene in LSGs was examined by immunofluorescence (IF) assay. The association of molecular functions of the gene with the pathological conditions in SS was examined using peripheral blood lymphocytes. Among 1320 DEGs up-regulated in SS, qPCR confirmed the up-regulation of NR4A2 in LSGs of SS compared with IgG4-RD. IF staining showed higher production of NR4A2 in nuclei of CD4 T cells and interleukin (IL)-17-producing cells in LSGs of SS, compared with IgG4-RD. Over-expression of NR4A2 mRNA was observed in peripheral CD4 T cells of SS patients, compared with HC. Nuclear NR4A2 expression in T helper type 17 (Th17)-polarized CD4 T cells determined by cellular IF was significantly higher in SS than in HC. Importazole, an inhibitor of importin-β, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4 T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression. NR4A2 seems to promote Th17 polarization via increased expression and intranuclear localization in CD4 T cells of SS patients, which could play a critical role in the pathogenesis of SS.

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Section: Discussionsupporting

confidence: 83%

Section: Cdna Microarray Analysissupporting

confidence: 74%

Section: Cdna Microarray Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjögren's syndrome

Takahashi

Tsuboi

Asashima

et al. 2017

Clinical and Experimental Immunology

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“…The roles of chemotactic factors in the immunopathology of IgG4-RD are poorly understood, with only less than a dozen chemotactic factors known to be upregulated (e.g., CXCL13, CCL18, and CCR4) [114,115]. A critical question is which chemotactic factors are involved in creating a milieu rich in Th2 and Tregs.…”

Section: Chemokines and Chemokine Receptorsmentioning

confidence: 99%

IgG4-related sclerosing cholangitis: all we need to know

2016

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Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a ''benign'' disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell-or immunoglobulin-related (Fc-gamma receptormediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.

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IgG4‐Related Disease: Clinical and Laboratory Features in One Hundred Twenty‐Five Patients

Wallace

Deshpande

Mattoo

et al. 2015

Arthritis & Rheumatology

533

466

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Purpose IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. No detailed clinical and laboratory assessments have been reported in large numbers of patients with IgG4-RD diagnoses established by strict clinicopathological correlation. Methods We reviewed the baseline features of 125 patients with biopsy-proven disease. The diagnosis was confirmed by pathology review according to consensus diagnostic criteria. Disease activity and damage were assessed by the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts. Results Of the 125 patients, 103 had active disease and 86 were on no treatment. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher RI, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 (P<0.01 for all comparisons). The correlation between IgG4+ plasmablast level and RI (R=0.45, P=0.003) was stronger than that of total plasmablasts and RI. Seventy-six (61%) of the patients were male, but no significant differences according to gender were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Glucocorticoids failed to produce sustained remission in the majority of patients. Conclusion Nearly 50% of this patient cohort with biopsy-proven, clinically-active IgG4-RD had normal serum IgG4 concentrations. Serum IgG4 elevation identify a subset with more inflammatory features. IgG4+ plasmablasts correlate well with disease activity.

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DNA Microarray Analysis of Labial Salivary Glands in IgG4‐Related Disease: Comparison With Sjögren's Syndrome

Cited by 36 publications

References 34 publications

cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjögren's syndrome

cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjögren's syndrome

IgG4-related sclerosing cholangitis: all we need to know

IgG4‐Related Disease: Clinical and Laboratory Features in One Hundred Twenty‐Five Patients

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