Characterization of natural human antagonistic soluble CD40 isoforms produced through alternative splicing

Eshel, Dani; Toporik, Amir; Efrati, Tali; Nakav, Sigal; Chen, Aviva; Douvdevani, Amos

doi:10.1016/j.molimm.2008.08.280

Cited by 28 publications

(23 citation statements)

References 41 publications

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“…Therefore, we next compared the mRNA expression of CD40 in B-lymphoblastoid cell lines of known genotype. Several isoforms of human CD40 transcripts resulting from alternative splicing may exist 27 . In the RefSeq database, two isoforms of CD40, a longer isoform using all exons and a shorter one lacking exon 5, have been deposited.…”

Section: 8mentioning

confidence: 99%

“…6a). The truncated protein lacks the transmembrane domain and is shed as a soluble form of CD40 that potentially acts as an inhibitor of CD40-CD40L signaling 27 . Through resequencing of the CD40 gene region and analyses of correlation between genotypes of the identified SNPs and frequency of exon 6 skipping, we focused on three candidate SNPs plausibly responsible for regulation of this alternative splicing event (rs73622651, rs3746821 and rs3765456; Supplementary Fig.…”

Section: 8mentioning

confidence: 99%

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A genome-wide association study identifies three new risk loci for Kawasaki disease

et al. 2012

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We performed a genome-wide association study (GWAS) of Kawasaki disease in Japanese subjects using data from 428 individuals with Kawasaki disease (cases) and 3,379 controls genotyped at 473,803 SNPs. We validated the association results in two independent replication panels totaling 754 cases and 947 controls. We observed significant associations in the FAM167A-BLK region at 8p22-23 (rs2254546, P = 8.2 × 10(-21)), in the human leukocyte antigen (HLA) region at 6p21.3 (rs2857151, P = 4.6 × 10(-11)) and in the CD40 region at 20q13 (rs4813003, P = 4.8 × 10(-8)). We also replicated the association of a functional SNP of FCGR2A (rs1801274, P = 1.6 × 10(-6)) identified in a recently reported GWAS of Kawasaki disease. Our findings provide new insights into the pathogenesis and pathophysiology of Kawasaki disease.

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Section: 8mentioning

confidence: 99%

Section: 8mentioning

confidence: 99%

A genome-wide association study identifies three new risk loci for Kawasaki disease

et al. 2012

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“…The mechanism of increased sCD40 level in ASC is still elusive. It was reported that sCD40 was produced by either alternative splicing or the proteolytic cleavage of membrane-anchored CD40 by a tumor necrosis factor-converting enzyme (TACE) [35,36,37]. In liver diseases, Schmilovitz-Weiss et al suggested that sCD40 probably derive from the liver [19].…”

Section: Discussionmentioning

confidence: 99%

Association of CD40 -1C/T Polymorphism in the 5′-Untranslated Region with Chronic HBV Infection

Zhou

Jin

Tang

et al. 2015

Cell Physiol Biochem

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Background: CD40 is an important costimulatory molecule in both celluar and humoral immune responses, involved in the pathogenic processes of chronic inflammatory diseases. Few studies were performed on the association of CD40 single nucleotide polymorphism (SNP) with chronic hepatitis B virus (HBV) infection. In this study, we studied whether the CD40-1C/T polymorphism had any effect on the progression of chronic HBV infection in Chinese population. Methods: CD40 -1C/T polymorphism in the 5′-untranslated region was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 453 chronic HBV carriers, who were divided into asymptomatic HBV carriers (ASC), moderate chronic hepatitis B group (MCHB) and severe chronic hepatitis B group (SCHB). 202 healthy individuals in the same region were enrolled in this study as the controls. The CD40 expression on B lymphocytes was detected by flow cytometry. The concentrations of soluble CD40 (sCD40) in sera were assayed by a commercial ELISA kit. Results: Our results showed the frequencies of TT genotype and T allele of CD40-1C/T polymorphism were higher significantly in ASC than those in controls (P< 0.05), while this result was not found in either MCHB or SCHB. On the surface of B lymphocytes, the CD40 expression levels in the individuals with TT genotype were significantly lower than those with CC and CT genotypes in either ASC group or healthy controls (P<0.001). The sCD40 levels in the sera of ASC, MCHB and SCHB groups were significantly higher than the controls (P<0.001). Conclusions: The CD40 -1C/T polymorphism may contribute to the susceptibility of asymptomatic HBV carriers through its effect on cell-surface CD40 expression, which indicated CD40 signaling was involved in immune tolerance of chronic HBV infection.

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“…Previous studies have demonstrated that when compared with large control datasets, identification of expression outliers in peripheral whole blood can contribute to the detection of disease-causing variants (Zeng et al, 2015;Zhao et al, 2016). As well as gene expression levels, perturbations in the relative abundance of specific isoforms is a driving force in the genesis of many diseases (Chen et al, 2010;Kim et al, 2018) as isoforms can have differential function (Takeda et al, 2010), or, in some cases, can be antagonistic (Eshel et al, 2008). Through RNASeq or exon junction spanning probe-based capture, changes in isoform balance can also be resolved.…”

Section: Rna In Diagnosticsmentioning

confidence: 99%

Exploring the RNA Gap for Improving Diagnostic Yield in Primary Immunodeficiencies

2019

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Challenges in diagnosing primary immunodeficiency are numerous and diverse, with current whole-exome and whole-genome sequencing approaches only able to reach a molecular diagnosis in 25-60% of cases. We assess these problems and discuss how RNA-focused analysis has expanded and improved in recent years and may now be utilized to gain an unparalleled insight into cellular immunology. We review how investigation into RNA biology can give information regarding the differential expression, monoallelic expression, and alternative splicing-which have important roles in immune regulation and function. We show how this information can inform bioinformatic analysis pipelines and aid in the variant filtering process, expediting the identification of causal variants-especially those affecting splicing-and enhance overall diagnostic ability. We also demonstrate the challenges, which remain in the design of this type of investigation, regarding technological limitation and biological considerations and suggest potential directions for the clinical applications.

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Characterization of natural human antagonistic soluble CD40 isoforms produced through alternative splicing

Cited by 28 publications

References 41 publications

A genome-wide association study identifies three new risk loci for Kawasaki disease

A genome-wide association study identifies three new risk loci for Kawasaki disease

Association of CD40 -1C/T Polymorphism in the 5′-Untranslated Region with Chronic HBV Infection

Exploring the RNA Gap for Improving Diagnostic Yield in Primary Immunodeficiencies

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