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Background Vestibular schwannoma is the third most common benign intracranial tumor that can occur sporadically or be associated with neurofibromatosis type 2 (neurofibromatosis type 2 vestibular schwannoma [NF2-VS]). The aim of this study is to provide a comprehensive bioinformatic analysis of methylated-differentially expressed genes (MDEGs) in NF2-VS. Methods Transcriptional sequencing datasets (GSE141801 and GSE108524) and gene methylation microarrays (GSE56598) from the Gene Expression Omnibus database were used to identify and analyze MDEGs in NF2-VS. A protein–protein interaction (PPI) network was built, and the hub genes and modules were identified. Finally, potential pharmacotherapy targeting MDEGs were extracted for NF2-VS. Results A total of 57 hypermethylation–low expression genes and 88 hypomethylation–high expression genes were identified. Pathways associated with aberrantly MDEGs included P13K-AKT, MAPK, and Ras, which were also involved in NF2-VS. Six hub genes (EGFR, CCND1, CD53, CSF1R, PLAU, and FGFR1) were identified from the PPI network. Modification of the aforementioned genes altered cell-to-cell communication, response to stimulus, cellular regulation, and membrane and protein bindings. Thirty drugs targeting these pathways were selected based on the hub genes. Conclusions Analysis of MDEGs may enrich the understanding of the molecular mechanisms of NF2-VS pathogenesis and lay the groundwork for potential biomarkers and therapeutic targets for NF2-VS.

The involvement of aberrantly expressed genes in the pathogenesis and progression of various human malignancies has been widely reported, including clear cell renal cell carcinoma (ccRCC). This study aimed to identify potential crucial genes in ccRCC and further investigate the role of these genes in ccRCC prognosis. Three gene expression profiles (GSE3, GSE6344 and GSE53000) were downloaded from GEO database. GEO2R was performed to identify the differentially expressed genes (DEGs) between ccRCC and normal samples. GO analysis and KEGG pathway enrichment analysis were applied for the function analysis. The DEGs were mapped into the PPI network, then the hub genes were identified and verified using the ONCOMINE database. Kaplan–Meier plotter was used to evaluate of the prognostic value of the identified hub genes. A total of 113 DEGs were identified from the three gene expression profiles, including 64 up-regulated genes and 69 down-regulated genes. DEGs were observed to be enriched in biological processes related to the progress and pathogenesis of human cancers. According to PPI network, 5 hub genes were collected, including TYROBP, C1QB, ITGB2, CD53 and FCER1G. Among them, CD53 was newly identified, and Kaplan–Meier survival curves suggested that high expression of CD53 was significantly associated with poor survival in ccRCC patients (log-rank P

Background. Neuropathic pain (NP) is a devastating complication following nerve injury, and it can be alleviated by regulating neuroimmune direction. We aimed to explore the neuroimmune mechanism and identify some new diagnostic or therapeutic targets for NP treatment via bioinformatic analysis. Methods. The microarray GSE18803 was downloaded and analyzed using R. The Venn diagram was drawn to find neuroimmune-related differentially expressed genes (DEGs) in neuropathic pain. Gene Ontology (GO), pathway enrichment, and protein-protein interaction (PPI) network were used to analyze DEGs, respectively. Besides, the identified hub genes were submitted to the DGIdb database to find relevant therapeutic drugs. Results. A total of 91 neuroimmune-related DEGs were identified. The results of GO and pathway enrichment analyses were closely related to immune and inflammatory responses. PPI analysis showed two important modules and 8 hub genes: PTPRC, CD68, CTSS, RAC2, LAPTM5, FCGR3A, CD53, and HCK. The drug-hub gene interaction network was constructed by Cytoscape, and it included 24 candidate drugs and 3 hub genes. Conclusion. The present study helps us better understand the neuroimmune mechanism of neuropathic pain and provides some novel insights on NP treatment, such as modulation of microglia polarization and targeting bone resorption. Besides, CD68, CTSS, LAPTM5, FCGR3A, and CD53 may be used as early diagnostic biomarkers and the gene HCK can be a therapeutic target.

International audience; T cells depend on the phosphatase CD45 to initiate T cell receptor signaling. Although the critical role of CD45 in T cells is established, the mechanisms controlling function and localization in the membrane are not well understood. Moreover, the regulation of specific CD45 isoforms in T cell signaling remains unresolved. By using unbiased mass spectrometry, we identify the tetraspanin CD53 as a partner of CD45 and show that CD53 controls CD45 function and T cell activation. CD53-negative T cells (Cd53-/-) exhibit substantial proliferation defects, and Cd53-/- mice show impaired tumor rejection and reduced IFNγ-producing T cells compared with wild-type mice. Investigation into the mechanism reveals that CD53 is required for CD45RO expression and mobility. In addition, CD53 is shown to stabilize CD45 on the membrane and is required for optimal phosphatase activity and subsequent Lck activation. Together, our findings reveal CD53 as a regulator of CD45 activity required for T cell immunity.

Background: Regulatory T cells (Tregs) have shown to be protective against the development of atherosclerosis, a major pathological cause for cardiovascular events. Here, we aim to explore the roles of Tregs-related genes in atherosclerosis deterioration.Methods and Results: We downloaded the gene expression profile of 29 atherosclerotic samples from the Gene Expression Omnibus database with an accession number of GSE28829. The abundance of Tregs estimated by the CIBERSORT algorithm was negatively correlated with the atherosclerotic stage. Using the limma test and correlation analysis, a total of 159 differentially expressed Tregs-related genes (DETregRGs) between early and advanced atherosclerotic plaques were documented. Functional annotation analysis using the DAVID tool indicated that the DETregRGs were mainly enriched in inflammatory responses, immune-related mechanisms, and pathways such as complement and coagulation cascades, platelet activation, leukocyte trans-endothelial migration, vascular smooth muscle contraction, and so on. A protein-protein interaction network of the DETregRGs was then constructed, and five hub genes (PTPRC, C3AR1, CD53, TLR2, and CCR1) were derived from the network with node degrees ≥20. The expression patterns of these hub DETregRGs were further validated in several independent datasets. Finally, a single sample scoring method was used to build a gene signature for the five DETregRGs, which could distinguish patients with myocardial infarction from those with stable coronary disease.Conclusion: The results of this study will improve our understanding about the Tregs-associated molecular mechanisms in the progression of atherosclerosis and facilitate the discovery of novel biomarkers for acute cardiovascular events.

BackgroundAlthough more and more evidence has supported psoriasis is prone to atherosclerosis, the common mechanism of its occurrence is still not fully elucidated. The purpose of this study is to further explore the molecular mechanism of the occurrence of this complication.MethodsThe gene expression profiles of psoriasis (GSE30999) and atherosclerosis (GSE28829) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis and atherosclerosis, three kinds of analyses were performed, namely functional annotation, protein‐protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis.ResultsA total of 94 common DEGs (24 downregulated genes and 70 upregulated genes) was selected for subsequent analyses. Functional analysis emphasizes the important role of chemokines and cytokines in these two diseases. In addition, lipopolysaccharide-mediated signaling pathway is closely related to both. Finally, 16 important hub genes were identified using cytoHubba, including LYN, CSF2RB, IL1RN, RAC2, CCL5, IRF8, C1QB, MMP9, PLEK, PTPRC, FYB, BCL2A1, LCP2, CD53, NCF2 and TLR2.ConclusionsOur study reveals the common pathogenesis of psoriasis and atherosclerosis. These common pathways and hub genes may provide new ideas for further mechanism research.

Tetraspanin proteins are expressed in various immune cells, and they play an important role in tuberculosis formation. CD53 is a protein in the tetraspanin family that is expressed in many white blood cells. In particular, it plays an important role in cytokine regulation and interaction between natural killer (NK) cells and antigen-presenting cells (APCs). The purpose of this study was to investigate whether the single nucleotide polymorphisms (SNPs) difference of CD53 gene could affect TB case. In this study, we investigated the effects of genetic polymorphism of CD53 on the pathogenesis of tuberculosis based on Korean Association Resource (KARE) data. Logistic regression analysis was used to determine the effect of SNPs of the CD53 gene on tuberculosis in TB cases and control groups. We also examined the effect of SNPs on tuberculosis in gene expression. Eight SNPs of CD53 were found to be associated with TB case. The SNP showing the greatest significance in this association was rs4839583 (odds ratio = 0.83, 95% confidence interval 0.72–0.96, p = 0.010). These genetic variants might be involved in cytokine regulation through the Jun pathway, and are thought to affect the immune responses and pathogenesis of TB. CD53 is a type of tetraspanin that is expressed on various immune cells. In this study, we identified eight statistically significant SNPs in CD53 gene, confirming that it could be involved in the regulation of CD53 gene expression. Associations between genetic variants and tuberculosis facilitated better understanding of the differences in the incidence of tuberculosis in various populations.

Breast cancer (BC) is the second leading cause of cancer death in women worldwide, and settings of specific prognostic factors and efficacious therapies are made difficult by phenotypic heterogeneity of BC subtypes. Therefore, there is a current urgent need to define novel predictive genetic predictors that may be useful for stratifying patients with distinct prognostic outcomes. Here, we looked for novel molecular signatures for triple negative breast cancers (TNBCs). By a bioinformatic approach, we identified a panel of genes, whose expression was positively correlated with disease-free survival in TNBC patients, namely IL18R1, CD53, TRIM, Jaw1, LTB, and PTPRCAP, showing specific immune expression profiles linked to survival prediction; most of these genes are indeed expressed in immune cells and are required for productive lymphocyte activation. According to our hypothesis, these genes were not, or poorly, expressed in different TNBC cell lines, derived from either primary breast tumours or metastatic pleural effusions. This conclusion was further supported in vivo, as immuno-histochemical analysis on biopsies of TNBC invasive ductal carcinomas highlighted differential expression of these six genes in cancer cells, as well as in intra- and peri-tumoral infiltrating lymphocytes. Our data open to the possibility that inter-tumour heterogeneity of immune markers might have predictive value; further investigations are recommended in order to establish the real power of cancer-related immune profiles as prognostic factors. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-021-00401-0.

Background: Atherosclerotic cardiovascular diseases accounted for a quarter of global deaths. Most of these fatal diseases like coronary atherosclerotic disease (CAD) and stroke occur in the advanced stage of atherosclerosis, during which candidate therapeutic targets have not been fully established. This study aims to identify hub genes and possible regulatory targets involved in treatment of advanced atherosclerotic plaques.Material/Methods: Microarray dataset GSE43292 and GSE28829, both containing advanced atherosclerotic plaques group and early lesions group, were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was conducted to identify advanced plaque-related modules. Module conservation analysis was applied to assess the similarity of advanced plaque-related modules between GSE43292 and GSE28829. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these modules were performed by Metascape. Differentially expressed genes (DEGs) were mapped into advanced plaque-related modules and module membership values of DEGs in each module were calculated to identify hub genes. Hub genes were further validated for expression in atherosclerotic samples, for distinguishing capacity of CAD and for potential functions in advanced atherosclerosis.Results: The lightgreen module (MElightgreen) in GSE43292 and the brown module (MEbrown) in GSE28829 were identified as advanced plaque-related modules. Conservation analysis of these two modules showed high similarity. GO and KEGG enrichment analysis revealed that genes in both MElightgreen and MEbrown were enriched in immune cell activation, secretory granules, cytokine activity, and immunoinflammatory signaling. RBM47, HCK, CD53, TYROBP, and HAVCR2 were identified as common hub genes, which were validated to be upregulated in advanced atherosclerotic plaques, to well distinguish CAD patients from non-CAD people and to regulate immune cell function-related mechanisms in advanced atherosclerosis.Conclusions: We have identified RBM47, HCK, CD53, TYROBP, and HAVCR2 as immune-responsive hub genes related to advanced plaques, which may provide potential intervention targets to treat advanced atherosclerotic plaques.

The importance of tetraspanin proteins in regulating migration has been demonstrated in many diverse cellular systems. However, the function of the leukocyte-restricted tetraspanin CD53 remains obscure. We therefore hypothesized that CD53 plays a role in regulating leukocyte recruitment and tested this hypothesis by examining responses of CD53-deficient mice to a range of inflammatory stimuli. Deletion of CD53 significantly reduced neutrophil recruitment to the acutely inflamed peritoneal cavity. Intravital microscopy revealed that in response to several inflammatory and chemotactic stimuli, absence of CD53 had only minor effects on leukocyte rolling and adhesion in postcapillary venules. In contrast, Cd53−/− mice showed a defect in leukocyte transmigration induced by TNF, CXCL1 and CCL2, and a reduced capacity for leukocyte retention on the endothelial surface under shear flow. Comparison of adhesion molecule expression in wild-type and Cd53−/− neutrophils revealed no alteration in expression of β2 integrins, whereas L-selectin was almost completely absent from Cd53−/− neutrophils. In addition, Cd53−/− neutrophils showed defects in activation-induced cytoskeletal remodeling and translocation to the cell periphery, responses necessary for efficient transendothelial migration, as well as increased α3 integrin expression. These alterations were associated with effects on inflammation, so that in Cd53−/− mice, the onset of neutrophil-dependent serum-induced arthritis was delayed. Together, these findings demonstrate a role for tetraspanin CD53 in promotion of neutrophil transendothelial migration and inflammation, associated with CD53-mediated regulation of L-selectin expression, attachment to the endothelial surface, integrin expression and trafficking, and cytoskeletal function.

Acute rejection (AR) in kidney transplants remains a major cause of allograft failure. This study investigates the association between gene networks and AR in human kidney transplant biopsies with weighted gene co-expression network analysis (WGCNA). The gene expression profiles of 403 (training set) and 702 (validation set) kidney transplant patients' biopsies were analyzed. WGCNA was conducted, and 11 co-regulated gene modules were identified. Each module was investigated with a t-test for AR and survival analysis for graft loss. The association between modules and AR molecular subtypes was also evaluated. Three transcriptional gene modules were associated with AR and graft loss of kidney transplant. One module constitutes unregulated immune response genes in AR and is associated with shorter graft survival (HR = 4.22, p-value = 4.29 × 10-6). This module is more significantly up-regulated in T cell-mediated acute rejection (TCMR) than in non-TCMRs. Hub genes such as HLA-DMA, CORO1A, PYCARD, and CD53 were identified. The expression of the other two modules was down-regulated in AR patients and associated with a good graft prognosis (HR = 0.41 and 0.24, respectively). A systems biology network approach may help uncover gene networks in kidney transplant biopsies associated with AR and contribute to identifying new biomarkers.

Summary Tetraspanins regulate key processes in immune cells; however, the function of the leukocyte-restricted tetraspanin CD53 is unknown. Here we show that CD53 is essential for lymphocyte recirculation. Lymph nodes of Cd53−/− mice were smaller than those of wild-type mice due to a marked reduction in B cells and a 50% decrease in T cells. This reduced cellularity reflected an inability of Cd53−/− B and T cells to efficiently home to lymph nodes, due to the near absence of L-selectin from Cd53−/− B cells and reduced stability of L-selectin on Cd53−/− T cells. Further analyses, including on human lymphocytes, showed that CD53 stabilizes L-selectin surface expression and may restrain L-selectin shedding via both ADAM17-dependent and ADAM17-independent mechanisms. The disruption in lymphocyte recirculation in Cd53−/− mice led to impaired immune responses dependent on antigen delivery to lymph nodes. Together these findings demonstrate an essential role for CD53 in lymphocyte trafficking and immunity., Graphical Abstract, Highlights • CD53 is essential for lymph node cellularity as Cd53−/− lymph nodes lack T and B cells • CD53 is essential for lymphocyte homing to lymph nodes • CD53 stabilizes L-selectin cell surface expression and may restrain shedding • Impaired lymphocyte homing leads to diminished immune responses in Cd53−/− mice, Molecular Mechanism of Behavior; Immunology; Immune Response; Specialized Functions of Cells

Maintenance of quiescence is necessary for optimal hematopoietic stem cell (HSC) function. The absence of fine-tuned cycling regulation of HSCs can result in impaired hematopoiesis, bone marrow (BM) failure, or malignant transformation. While various factors, including inflammatory cytokines and chemotherapy, have been identified to induce HSC cycling, the mechanisms regulating HSC return to quiescence are unclear. Herein, we profiled HSCs in response to a variety of inflammatory stressors (cytokines, toll-like receptor agonists, mobilizing agents, and chemotherapeutics) and found markedly upregulated expression of CD53 in both mouse and human HSCs, in some cases by as much as 70-fold higher expression over vehicle-treated controls. CD53 is a tetraspanin, a type of transmembrane protein involved in plasma membrane organization and regulation of processes such as cellular migration, adhesion, and signaling. CD53 has been shown to be asymmetrically segregated in HSCs, with CD53-enriched HSCs believed to be more stem-like; however, there is no current proposed mechanism to explain the association between CD53 and stem cell quality. To understand the role of CD53 in HSC quality, we generated a CD53 knockout mouse, and profiled HSC phenotype and function. Under homeostatic conditions, Cd53 -/- HSC number and frequency are normal as compared to wild type (WT) mice. However, we found Cd53 -/-HSCs to have significantly impaired function, particularly in response to inflammatory stimuli. Cd53 -/- BM failed to engraft as well as WT BM (45% chimerism vs 63%, p Transcriptomic sequencing revealed significant upregulation of genes associated with cell cycling and division in G-CSF-treated Cd53 -/- HSCs compared to WT controls. Notably, these differentially expressed genes are targets of the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex, a newly described transcriptional regulator that represses cell cycling-associated genes, suggesting that CD53 promotes DREAM-mediated quiescence in stressed HSCs. We performed CUT&Tag profiling of Rbl2/p130, a DREAM complex subunit, in HSCs and found that loss of CD53 was associated with decreased complex binding (consistent with enhanced transcription of cell cycle genes). Proximity labeling studies demonstrated that CD53 interacts with cell cycle machinery proteins, including Rbl2/p130, and Western blots of sorted HSCs from Cd53 -/- and WT mice treated with G-CSF showed decreased expression of DREAM complex components (Rbl1/p107 and Rbl2/p130) in the absence of CD53. Finally, enforced activation of DREAM and HSC quiescence using the CDK4/6 inhibitor palbociclib rescued the Cd53 -/-HSC repopulating defect. Together, these data derive a novel mechanism whereby CD53 regulates HSC quiescence through regulating DREAM complex binding during stress-induced cycling. Disclosures No relevant conflicts of interest to declare.

Background Chronic periodontitis (CP) is a multifactorial inflammatory disease. For the diagnosis of CP, it is necessary to investigate molecular biomarkers and the biological pathway of CP. Although analysis of mRNA expression profiling with microarray is useful to elucidate pathological mechanisms of multifactorial diseases, it is expensive. Therefore, we utilized pooled microarray gene expression data on the basis of data sharing to reduce hybridization costs and compensate for insufficient mRNA sampling. The aim of the present study was to identify molecular biomarker candidates and biological pathways of CP using pooled datasets in the Gene Expression Omnibus (GEO) database. Methods Three pooled transcriptomic datasets (GSE10334, GSE16134, and GSE23586) of gingival tissue with CP in the GEO database were analyzed for differentially expressed genes (DEGs) using GEO2R, functional analysis and biological pathways with the Database of Annotation Visualization and Integrated Discovery database, Protein-Protein Interaction (PPI) network and hub gene with the Search Tool for the Retrieval of Interaction Genes database, and biomarker candidates for diagnosis and prognosis and upstream regulators of dominant biomarker candidates with the Ingenuity Pathway Analysis database. Results We shared pooled microarray datasets in the GEO database. One hundred and twenty-three common DEGs were found in gingival tissue with CP, including 81 upregulated genes and 42 downregulated genes. Upregulated genes in Gene Ontology were significantly enriched in immune responses, and those in the Kyoto Encyclopedia of Genes and Genomes pathway were significantly enriched in the cytokine-cytokine receptor interaction pathway, cell adhesion molecules, and hematopoietic cell lineage. From the PPI network, the 12 nodes with the highest degree were screened as hub genes. Additionally, six biomarker candidates for CP diagnosis and prognosis were screened. Conclusions We identified several potential biomarkers for CP diagnosis and prognosis (e.g., CSF3, CXCL12, IL1B, MS4A1, PECAM1, and TAGLN) and upstream regulators of biomarker candidates for CP diagnosis (TNF and TGF2). We also confirmed key genes of CP pathogenesis such as CD19, IL8, CD79A, FCGR3B, SELL, CSF3, IL1B, FCGR2B, CXCL12, C3, CD53, and IL10RA. To our knowledge, this is the first report to reveal associations of CD53, CD79A, MS4A1, PECAM1, and TAGLN with CP. Electronic supplementary material The online version of this article (10.1186/s12903-019-0738-0) contains supplementary material, which is available to authorized users.

Red-spotted grouper nervous necrosis virus (RGNNV) has threatened aquaculture of the Asian seabass (Lates calcarifer) in many countries of the Asia-Pacific for decades. To understand the pathogenesis of RGNNV, a transcriptome analysis of the head kidney, a major fish lymphoid tissue which performs important immune functions and is involved in the hematopoiesis was undertaken. RNA from the head kidney of RGNNV infected fish was sequenced and compared RNA from uninfected control fish at two and 15-days post infection. Functional analysis revealed a number of differentially expressed genes implicated in autophagy (beclin-1 and inositol 1,4,5-trisphosphate receptor), superoxide production (cytochrome b-245 light chain, C3a anaphylatoxin chemotactic receptor and neutrophil cytosol factor 2-like), inflammation (leukocyte surface antigen CD53), antigen presentation (MHC class I alpha chain), antiviral activity (cholesterol 25-hydroxylase) and other immune functions (oxysterol-binding protein 1, dipeptidyl peptidase I, interleukin-5 receptor subunit alpha-like and tyrosine-protein kinase BTK). This is the first description of the change in L. calcarifer head kidney mRNA expression as a consequence of RGNNV infection and the information will serve as the rational basis for future investigations into the pathophysiology of NNV infection of fish.

Reproductive ability, especially prolificacy, impacts sheep profitability. Hu sheep, a unique Chinese breed, is recognized for its high prolificacy (HP), early sexual maturity, and year-round estrus. However, little is known about the molecular mechanisms underlying HP in Hu sheep. To explore the potential mRNAs and long non-coding RNAs (lncRNAs) involved in Hu sheep prolificacy, we performed an ovarian genome-wide analysis of mRNAs and lncRNAs during the follicular stage using Hu sheep of HP (litter size = 3; three consecutive lambings) and low prolificacy (LP, litter size = 1; three consecutive lambings). Plasma luteinizing hormone (LH) concentration was higher in the HP group than in the LP group (P

International audience; Mast cells (MCs) are innate immune cells that are scattered in tissues throughout the organism being particularly abundant at sites exposed to the environment such as the skin and mucosal surfaces. Generally known for their role in IgE-mediated allergies, they have also important functions in the maintenance of tissue integrity by constantly sensing their microenvironment for signals by inflammatory triggers that can comprise infectious agents, toxins, hormones, alarmins, metabolic states, etc. When triggered their main function is to release a whole set of inflammatory mediators, cytokines, chemokines, and lipid products. This allows them to organize the ensuing innate immune and inflammatory response in tight coordination with resident tissue cells, other rapidly recruited immune effector cells as well as the endocrine and exocrine systems of the body. To complete these tasks, MCs are endowed with a large repertoire of receptors allowing them to respond to multiple stimuli or directly interact with other cells. Here we review some of the receptors expressed on MCs (ie, receptors for Immunoglobulins, pattern recognition receptors, nuclear receptors, receptors for alarmins, and a variety of other receptors) and discuss their functional implication in the immune and inflammatory response focusing on non-IgE-mediated activation mechanisms.© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Aims Limited information exists about the impact of cytogenetic alterations on the protein expression profiles of individual meningioma cells and their association with the clinicohistopathological characteristics of the disease. The aim of this study is to investigate the potential association between the immunophenotypic profile of single meningioma cells and the most relevant features of the tumour. Methods Multiparameter flow cytometry (MFC) was used to evaluate the immunophenotypic profile of tumour cells (n = 51 patients) and the Affymetrix U133A chip was applied for the analysis of the gene expression profile (n = 40) of meningioma samples, cytogenetically characterized by interphase fluorescence in situ hybridization. Results Overall, a close association between the pattern of protein expression and the cytogenetic profile of tumour cells was found. Thus, diploid tumours displayed higher levels of expression of the CD55 complement regulatory protein, tumours carrying isolated monosomy 22/del(22q) showed greater levels of bcl2 and PDGFRβ and meningiomas carrying complex karyotypes displayed a greater proliferation index and decreased expression of the CD13 ectoenzyme, the CD9 and CD81 tetraspanins, and the Her2/neu growth factor receptor. From the clinical point of view, higher expression of CD53 and CD44 was associated with a poorer outcome. Conclusions Here we show that the protein expression profile of individual meningioma cells is closely associated with tumour cytogenetics, which may reflect the involvement of different signalling pathways in the distinct cytogenetic subgroups of meningiomas, with specific immunophenotypic profiles also translating into a different tumour clinical behaviour.

Contains fulltext : 174451.pdf (Publisher’s version ) (Closed access) Activation of B cells by the binding of antigens to the B cell receptor (BCR) requires the protein kinase C (PKC) family member PKCbeta. Because PKCs must translocate to the plasma membrane to become activated, we investigated the mechanisms regulating their spatial distribution in mouse and human B cells. Through live-cell imaging, we showed that BCR-stimulated production of the second messenger diacylglycerol (DAG) resulted in the translocation of PKCbeta from the cytosol to plasma membrane regions containing the tetraspanin protein CD53. CD53 was specifically enriched at sites of BCR signaling, suggesting that BCR-dependent PKC signaling was initiated at these tetraspanin microdomains. Fluorescence lifetime imaging microscopy studies confirmed the molecular recruitment of PKC to CD53-containing microdomains, which required the amino terminus of CD53. Furthermore, we showed that Cd53-deficient B cells were defective in the phosphorylation of PKC substrates. Consistent with this finding, PKC recruitment to the plasma membrane was impaired in both mouse and human CD53-deficient B cells compared to that in their wild-type counterparts. These data suggest that CD53 promotes BCR-dependent PKC signaling by recruiting PKC to the plasma membrane so that it can phosphorylate its substrates and that tetraspanin-containing microdomains can act as signaling hotspots in the plasma membrane.

Contains fulltext : 176991.pdf (Publisher’s version ) (Open Access) Dendritic cells (DCs), which are essential for initiating immune responses, are comprised of different subsets. Tetraspanins organize dendritic cell membranes by facilitating protein-protein interactions within the so called tetraspanin web. In this study we analyzed expression of the complete tetraspanin superfamily in primary murine (CD4+, CD8+, pDC) and human DC subsets (CD1c+, CD141+, pDC) at the transcriptome and proteome level. Different RNA and protein expression profiles for the tetraspanin genes across human and murine DC subsets were identified. Although RNA expression levels of CD37 and CD82 were not significantly different between human DC subsets, CD9 RNA was highly expressed in pDCs, while CD9 protein expression was lower. This indicates that relative RNA and protein expression levels are not always in agreement. Both murine CD8alpha+ DCs and its regarded human counterpart, CD141+ DCs, displayed relatively high protein levels of CD81. CD53 protein was highly expressed on human pDCs in contrast to the relatively low protein expression of most other tetraspanins. This study demonstrates that tetraspanins are differentially expressed by human and murine DC subsets which provides a valuable resource that will aid the understanding of tetraspanin function in DC biology.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy, most commonly originating from the transformation of progenitor cells of the B cell lineage (B cell precursor-ALL; BCP-ALL). Treatment of patients with high-risk or relapsed disease is difficult and prognosis remains poor in pediatric patients, with an even worse survival rate for adult BCP-ALL. Previous studies have shown an association of enhanced CD53 expression with many B cell malignancies, suggesting upregulation of CD53 may be implicated in carcinogenesis or maintenance of malignant cells. CD53 is a member of the tetraspanin family of transmembrane proteins, classically involved in cell adhesion, proliferation, and survival, and expressed exclusively on hematopoietic cells. While several studies have implicated a role for CD53 in regulating mature B cell proliferation, its role in early B cell development is not yet known. To elucidate the contribution of CD53 to normal and malignant B cell development, we have generated a CD53 knockout mouse. In our CD53-/- mouse, we observe no differences in total white blood cell counts, yet the fraction of peripheral blood B cells is significantly reduced by 31% compared to wild-type (WT) controls (28.3% vs. 19.5%; p With the observed loss of both B cell progenitors and mature B cells in CD53-deficient mice, CD53-/- mice were recently crossed to Eμ-Myc transgenic mice, a model of B-lineage leukemia/lymphoma, to generate WT, CD53-/-, Eμ-Myc+;CD53+/+, and Eμ-Myc+;CD53-/- groups to assess whether loss of CD53 alters the pathology or survival of these mice. As observed in human patients, moribund Eμ-Myc+ mice significantly upregulate CD53 on malignant cells, suggesting a potential role for CD53 during pathogenesis. Ongoing experiments are aimed at elucidating the mechanism by which CD53 promotes homeostatic B cell development and determining the potential of CD53 as a therapeutic target for B lineage malignancies. Disclosures No relevant conflicts of interest to declare.

Background In this study, the association of asthma with CD53, a member of the tetraspanin family, was assessed for the first time in a mechanism-based study. Methods Genetic polymorphisms of CD53 were analyzed in 591 subjects and confirmed in a replication study of 1001 subjects. CD53 mRNA and protein levels were measured in peripheral blood leukocytes, and the effects of the promoter polymorphisms on nuclear factor binding were examined by electrophoretic mobility shift assay. Cellular functional studies were conducted by siRNA transfections. Results Among tagging SNPs of CD53, the − 1560 C>T in the promoter region was significantly associated with asthma risk. Compared with the CC genotype, the CT and TT genotypes were associated with a higher asthma risk, with odd ratios of 1.74 ( P = 0.009) and 2.03 ( P = 0.004), respectively. These findings were confirmed in the replication study with odd ratios of 1.355 ( P = 0.047) and 1.495 ( P = 0.039), respectively. The − 1560 C>T promoter SNP had functional effects on nuclear protein binding as well as mRNA and protein expression levels in peripheral blood leukocytes. When CD53 was knocked down by siRNA in THP-1 human monocytic cells stimulated with house dust mite, the production of inflammatory cytokines as well as NFκB activity was significantly over-activated, suggesting that CD53 suppresses over-activation of inflammatory responses. Conclusions The − 1560 C>T SNP is a functional promoter polymorphism that is significantly associated with population asthma risk, and is thought to act by directly modulating nuclear protein binding, thereby altering the expression of CD53, a suppressor of inflammatory cytokine production.

Intratumor heterogeneity presents a major hurdle in cancer therapy. Most current research studies consider tumors as single entities and overlook molecular diversity between heterogeneous state(s) of different cells assumed to be homogenous. The present approach was designed for fluorescence-activated cell sorting-based resolution of heterogeneity arising from cancer stem cell (CSC) hierarchies and genetic instability in ovarian tumors, followed by microarray-based expression profiling of sorted fractions. Through weighted gene correlation network analyses, we could assign enriched modules of co-regulated genes to each fraction. Such gene modules often correlate with biological functions; one such specific association was the enrichment of CD53 expression in CSCs, functional validation indicated CD53 to be a tumor-initiating cell- rather than quiescent CSC-marker. Another association defined a state of poise for stress-induced metastases in aneuploid cells. Our results thus emphasize the need for studying cell-specific functionalities relevant to regeneration, drug resistance and disease progression in discrete tumor cell fractions.

Thymocyte development and maintenance of peripheral T-cell numbers and functions are critically dependent on T-cell receptor (TCR) signal strength. SHP1 (Src homology region 2 domain-containing phosphatase-1), a tyrosine phosphatase, acts as a negative regulator of TCR signal strength. Moreover, germline SHP1 knockout mice have shown impaired thymic development. However, this has been recently questioned by an analysis of SHP1 conditional knockout mice, which reported normal thymic development of SHP1 deficient thymocytes. Using this SHP1 conditional knockout mice, in this issue of the European Journal of Immunology, Martinez et al. [Eur. J. Immunol. 2016. 46: 2103-2110] show that SHP1 indeed does have a role in the negative regulation of TCR signal strength in positively selected thymocytes, and in the final maturation of single positive thymocytes. They report that thymocyte development in such mice shows loss of mature, post-selection cells. This is due to increased TCR signal transduction in thymocytes immediately post positive-selection, and increased cell death in response to weak TCR ligands. Thus, SHP1-deficiency shows strong similarities to deficiency in the T-cell specific SHP1-associated protein Themis.

To cite this article: Peng WM, Yu CF, Kolanus W, Mazzocca A, Bieber T, Kraft S, Novak N. Tetraspanins CD9 and CD81 are molecular partners of trimeric FcɛRI on human antigen-presenting cells. Allergy 2011; 66: 605–611. Abstract Background: Most functions of tetraspanins are not related to cell-surface receptor ligand binding, but are mediated by direct interactions with their partner proteins. Functions of trimeric FcɛRI, expressed by antigen-presenting cells (APCs), range from amplification of allergic inflammatory reactions to their active suppression. Cell-type-specific protein–protein interactions might play a role in the regulation of these bidirectional tasks. Therefore, we intended to study the interactions of trimeric FcɛRI with tetraspanins. Methods: The expression levels of tetraspanins CD9, CD37, CD53, CD63, CD81, CD82, and CD151 on skin dendritic cells of atopic dermatitis (AD) patients or healthy individuals were detected by flow cytometry. Tetraspanin expression on FcɛRIpos and FcɛRIneg monocyte subpopulations was evaluated. Flow cytometry, confocal microscopy, immunoprecipitation, and immunoblotting experiments were performed to observe the relationship between tetraspanins CD9 and CD81 and FcɛRI. Furthermore, plate stimulation experiments were performed, and cytokines in the supernatants were detected. Results: We found that human FcɛRIpos APCs expressed high amounts of tetraspanins and that the tetraspanins CD9 and CD81 were associated with FcɛRI. Concomitant activation of FcɛRI and CD9 on human monocytes increased FcɛRI-mediated cytokine release. Conclusion: Taken together, we show for the first time that CD9 and CD81 act as molecular partners of trimeric FcɛRI on human APC, which might be of importance in allergic diseases such as AD.