Blocking I Ag7 class II major histocompatibility complex by drug-like small molecules alleviated Sjögren's syndrome in NOD mice

Gupta, Shivai; Li, Danmeng; Ostrov, David A.; Nguyen, Cuong Q.

doi:10.1016/j.lfs.2021.120182

Cited by 7 publications

(7 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 59 Administration of small molecules inhibitor targeting MHC II could reduce the infiltration of Th1 and Th17 cells in the exocrine glands, and improve SS-like symptoms, such as SS-related dry eye, in NOD mice. 60 Consistent with these findings, our study proved that 858 upregulated DEGs in LGs of 8-, 12- and 16-week-old groups were closely related to T cell immune response, such as positive regulation of T cell activation and peptide antigen assembly with MHC class II protein complex, 58 , 61 , 62 indicating that these upregulated genes may contribute to SS-related dry eye by directly promoting T cell activation or acting on MHC class II molecules in LGs to indirectly drive T cell response.…”

Section: Discussionmentioning

confidence: 99%

Integrated DNA Methylation and Transcriptomics Analyses of Lacrimal Glands Identify the Potential Genes Implicated in the Development of Sjögren’s Syndrome-Related Dry Eye

Sun,

Wei,

Zhang

et al. 2023

JIR

View full text Add to dashboard Cite

Purpose Sjögren’s syndrome-related dry eye (SS-related dry eye) is an intractable autoimmune disease characterized by chronic inflammation of lacrimal glands (LGs), where epigenetic factors are proven to play a crucial role in the pathogenesis of this disease. However, the alteration of DNA methylation in LGs and its role in the pathogenesis of SS-related dry eye is still unknown. Here, we performed an integrated analysis of DNA methylation and RNA-Seq data in LGs to identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in the pathogenesis of SS-related dry eye. Methods The DNA methylation and transcription profiles of LGs in NOD mice at different stages of SS-related dry eye (4-, 8-, 12- and 16 weeks old) were generated by reduced representation bisulfite sequencing (RRBS) and RNA-Seq. The differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were analyzed by MethylKit R package and edgeR. Correlation analysis between methylation level and mRNA expression was conducted with R software. The functional correlation of DMGs and DEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, LG tissues from another litter of NOD mice were collected for methylation-specific polymerase chain reaction (MSP) and quantitative real-time PCR (qRT-PCR) to validate the methylation and expression levels of key genes. CD4 + cell infiltration of LGs was detected by immunofluorescence staining. Results Hypermethylation of LGs was identified in NOD mice with the progression of SS-related dry eye and the DMGs were mainly enriched in the GTPases activation and Ras signaling pathway. RNA-seq analysis revealed 1321, 2549, and 3712 DEGs in the 8-, 12- and 16-week-old NOD mice compared with 4-week-old normal control mice. For GO analysis, the DEGs were mainly enriched in T cell immune responses. Further, a total of 140 MeDEGs were obtained by integrated analysis of methylome and transcriptome, which were primarily enriched in T cell activation, proliferation and differentiation. Based on the main GO terms and KEGG pathways of MeDEGs, 8 genes were screened out. The expression levels of these key genes, especially Itgal, Vav1, Irf4 and Icosl , were verified to elevate after the onset of SS-related dry eye in NOD mice and positively correlated with the extent of inflammatory cell infiltration in LGs. Immunofluorescence assay revealed that CD4 + cell infiltration dramatically increased in LGs of SS-related dry eye mice compared with the control mice. And the expression levels of four genes showed significantly positive correlation with the extent of CD4 + cell infiltration in LGs. MSP showed the hypomethylation of the Irf 4 and Itgal promoters in NOD mice with SS-related dry eye compared to...

show abstract

Section: Discussionmentioning

confidence: 99%

Integrated DNA Methylation and Transcriptomics Analyses of Lacrimal Glands Identify the Potential Genes Implicated in the Development of Sjögren’s Syndrome-Related Dry Eye

Sun,

Wei,

Zhang

et al. 2023

JIR

View full text Add to dashboard Cite

show abstract

“…NOD mice are commonly used as spontaneous SS model mice 21–23 . Female 8‐week‐old NOD mice were obtained from Beijing HFK Bio‐Technology Co. Ltd.…”

Section: Methodsmentioning

confidence: 99%

“…NOD mice are commonly used as spontaneous SS model mice. 21 , 22 , 23 Female 8‐week‐old NOD mice were obtained from Beijing HFK Bio‐Technology Co. Ltd. The housing conditions involve maintaining the temperature at 25 ± 1°C and the humidity at 45%–55%, with a 12 h light/dark cycle.…”

Section: Methodsmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cells improve disease characterization of Sjogren's syndrome in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity

Zou,

Xiao,

Liu

et al. 2024

Immunity Inflam & Disease

View full text Add to dashboard Cite

BackgroundFor the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs‐exo) have exhibited promising results in treating SS.ObjectThis study aimed to investigate the effect and mechanism of human umbilical cord MSCs (UC‐MSCs) on SS.MethodsNonobese Diabetic (NOD) mouse splenic T cells were co‐cultured with UC‐MSCs and UC‐MSCs‐exo, and interferon‐gamma (IFN‐γ), interleukin (IL)‐6, IL‐10, prostaglandin E2 (PGE2), and transforming growth factor‐β1 (TGF‐β1) levels in the supernatant were assessed by quantitative real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay. Co‐cultured T cells were injected into NOD mice via the tail vein. The inflammatory cell infiltration in the intestine and the submandibular gland was characterized by hematoxylin‐eosin staining. Treg/Th17 homeostasis within the spleen was determined by flow cytometry. Gut microbiota was detected by 16S rRNA sequencing, and the relationship between differential microbiota and Treg/Th17 cytokines was analyzed by the Pearson correlation coefficient.ResultsUC‐MSCs, UC‐MSCs‐exo, and NOD mouse splenic T cells were successfully cultured and identified. After T cells were co‐cultured with UC‐MSCs and UC‐MSCs‐exo, both IFN‐γ and IL‐6 were decreased while IL‐10, PGE2, and TGF‐β1 were increased in transcriptional and translational levels. UC‐MSCs and UC‐MSCs‐exo partially restored salivary secretion function, reduced Ro/SSA antibody and α‐Fodrin immunoglobulin A levels, reduced inflammatory cell infiltration in the intestine and submandibular gland, raised proportion of Treg cells, decreased IFN‐γ, IL‐6, IL‐2, IL‐17, lipopolysaccharide, and tumor necrosis factor‐alpha levels, and raised IL‐10, Foxp3, and TGF‐β1 levels by affecting co‐cultured T cells. The intervention of UC‐MSCs and UC‐MSCs‐exo improved intestinal homeostasis in NOD mice by increasing microbiota diversity and richness. Additionally, differential microbiota was significantly associated with Treg/Th17 cytokine levels.ConclusionHuman UC‐MSCs and UC‐MSCs‐exo improved disease characterization of SS in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.

show abstract

“…Other researchers have mitigated pSS by blocking MHC class II IAg7 antigen presentation in NOD mice to prevent pathogenic T cells from recognizing their antigens. The results showed that tetraazatricyclo-dodecane (TATD) and 8-azaguanine (8-AZA) alleviated symptoms by improving saliva and lacrimal gland secretion, reducing autoantibody levels, and reducing the severity of lymphocyte infiltration in saliva and lacrimal glands ( 203 ).…”

Section: Treatmentmentioning

confidence: 99%

Composition and regulation of the immune microenvironment of salivary gland in Sjögren’s syndrome

Tan

Wang

2022

Front. Immunol.

View full text Add to dashboard Cite

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by exocrine gland dysfunction and inflammation. Patients often have dry mouth and dry eye symptoms, which seriously affect their lives. Improving dry mouth and eye symptoms has become a common demand from patients. For this reason, researchers have conducted many studies on external secretory glands. In this paper, we summarize recent studies on the salivary glands of pSS patients from the perspective of the immune microenvironment. These studies showed that hypoxia, senescence, and chronic inflammation are the essential characteristics of the salivary gland immune microenvironment. In the SG of pSS, genes related to lymphocyte chemotaxis, antigen presentation, and lymphocyte activation are upregulated. Interferon (IFN)-related genes, DNA methylation, sRNA downregulation, and mitochondrial-related differentially expressed genes are also involved in forming the immune microenvironment of pSS, while multiple signaling pathways are involved in regulation. We further elucidated the regulation of the salivary gland immune microenvironment in pSS and relevant, targeted treatments.

show abstract

Blocking I Ag7 class II major histocompatibility complex by drug-like small molecules alleviated Sjögren's syndrome in NOD mice

Cited by 7 publications

References 60 publications

Integrated DNA Methylation and Transcriptomics Analyses of Lacrimal Glands Identify the Potential Genes Implicated in the Development of Sjögren’s Syndrome-Related Dry Eye

Integrated DNA Methylation and Transcriptomics Analyses of Lacrimal Glands Identify the Potential Genes Implicated in the Development of Sjögren’s Syndrome-Related Dry Eye

Human umbilical cord mesenchymal stem cells improve disease characterization of Sjogren's syndrome in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity

Composition and regulation of the immune microenvironment of salivary gland in Sjögren’s syndrome

Contact Info

Product

Resources

About