A gain‐of‐function mutation in TNFRSF13B is a candidate for predisposition to familial or sporadic immune thrombocytopenia

Peng, Hongling; Zhang, Yang; Sun, Nannan; Yin, Yuqin; Wang, Ye-Wei; Zhao, Cheng; Yan, Wenzhe; Liu, Su‐fang; Xu, Yunxiao; Xiao, Xiang; Zhang, Guang‐sen

doi:10.1111/jth.13806

Cited by 14 publications

(9 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutated cases had upregulated cytokine-cytokine receptor interaction, increased serum TNFα, IL-17α, IFNγ, and BAFF levels, and enhanced binding capacity of APRIL ligand to B cells. Moreover, B cells transfected with the G76S mutation could induce human megakaryocyte apoptosis in vitro (117).…”

Section: Studies On Inflammatory Cytokinesmentioning

confidence: 98%

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

Fattizzo

Barcellini

2020

Front. Oncol.

View full text Add to dashboard Cite

Autoimmune cytopenias, particularly autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), complicate up to 25% of chronic lymphocytic leukemia (CLL) cases. Their occurrence correlates with a more aggressive disease with unmutated VHIG status and unfavorable cytogenetics (17p and 11q deletions). CLL lymphocytes are thought to be responsible of a number of pathogenic mechanisms, including aberrant antigen presentation and cytokine production. Moreover, pathogenic B-cell lymphocytes may induce T-cell subsets imbalance that favors the emergence of autoreactive B-cells producing anti-red blood cells and anti-platelets autoantibodies. In the last 15 years, molecular insights into the pathogenesis of both primary and secondary AIHA/ITP has shown that autoreactive B-cells often display stereotyped B-cell receptor and that the autoantibodies themselves have restricted phenotypes. Moreover, a skewed T-cell repertoire and clonal T cells (mainly CD8+) may be present. In addition, an imbalance of T regulatory-/T helper 17-cells ratio has been involved in AIHA and ITP development, and correlates with various cytokine genes polymorphisms. Finally, altered miRNA and lnRNA profiles have been found in autoimmune cytopenias and seem to correlate with disease phase. Genomic studies are limited in these forms, except for recurrent mutations of KMT2D and CARD11 in cold agglutinin disease, which is considered a clonal B-cell lymphoproliferative disorder resulting in AIHA. In this manuscript, we review the most recent literature on AIHA and ITP secondary to CLL, focusing on available molecular evidences of pathogenic, clinical, and prognostic relevance.

show abstract

Section: Studies On Inflammatory Cytokinesmentioning

confidence: 98%

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

Fattizzo

Barcellini

2020

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…According to Koopmans, the heterozygotes of C104R mutation were phenotypically different, ranging from asymptomatic to ill health (38). Peng reported an ITP pedigree with two familial ITPs and three sporadic ITPs with G76S mutations in the TNFRSF13B gene, which showed ITP-rather than CVID-related symptoms (39). The present study showed five patients with TNFRSF13B mutations-two (40%) presented with the same monoallelic nonsense mutation: R84T.…”

Section: Discussionmentioning

confidence: 48%

Screening for Genetic Mutations for the Early Diagnosis of Common Variable Immunodeficiency in Children With Refractory Immune Thrombocytopenia: A Retrospective Data Analysis From a Tertiary Children's Center

et al. 2020

Front. Pediatr.

View full text Add to dashboard Cite

Aim: This study aimed to identify common variable immunodeficiency (CVID) by high-throughput next-generation sequencing (NGS) in children with refractory immune thrombocytopenia (RITP) to facilitate early diagnosis.Methods: CVID-related genetic mutations were explored in patients with RITP during 2016–2019. They were tested consecutively through NGS by the ITP team of the tertiary children hospital in China. An evaluation system was devised based on the phenotype, genetic rule, and serum immunoglobulins (Igs) of all patients with RITP. The patients were divided into highly suspicious, suspicious, and negative groups using the evaluation system.Results: Among 176 patients with RITP, 16 (9.1%) harbored CVID-related genetic mutations: 8 (4.5%) were highly suspicious of CVIDs. Five had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), one in lipopolysaccharide responsive beige-like anchor protein (LRBA), one in nuclear factor kappa-B2 (NF-κB2), and one in caspase recruitment domain11 (CARD11). Others were classified into the suspicious group because the clinical phenotype and pedigree were suggestive, yet insufficient, for diagnosis. Repeated infection existed in all patients. Two had an allergic disease. Positive autoimmune serologies were noted in 62.5%. Five had a definite positive family history. The median serum immunoglobulin (Ig)A, IgG, and IgM levels were 0.3875, 6.14, and 0.522 g/L, respectively. Nearly 85.7% of patients had insufficient serum IgA levels, while 37.5% had low IgG and IgM levels.Conclusions: High-throughput NGS and a thorough review of the medical history are beneficial for the early diagnosis of patients without any significant clinical characteristics, distinguishing them from those with primary pediatric ITP. The cases suspicious of CVID need further investigation and follow-up to avoid deterioration.

show abstract

“…While research on ITP on this issue is lacking, it has been reported that furin protease dysregulation is associated with increased levels of BAFF and APRIL in immune cells of patients with advanced atherosclerotic plaque [29]. The second possible reason is that some surface platelet APRIL shed into the plasma due to unknown pathophysiological reasons [14,17]. If this reason can be confirmed in the future, we can say that surface platelet APRIL is another source of soluble APRIL increase in plasma in ITP patients.…”

Section: Discussionmentioning

confidence: 97%

“…Gu et al proposed that APRIL originates from increased gene expression. By studying the predisposing gene in familial or sporadic ITP, Peng et al show that the p.G76S mutation on the TNFRSF13B gene in ITP patients may lead to enhanced binding ability of APRIL ligands to B cells as well as increased BAFF levels [17]. In contrast, Kamhieh-Milz et al conclude that APRIL has nothing to do with increased gene expression [15].…”

Section: Introductionmentioning

confidence: 99%

Aberrant Expression of a Proliferation-Inducing Ligand Underlies Autoimmune Mechanisms in Immune Thrombocytopenia

Hao

Yang

Zhou

2018

Blood

View full text Add to dashboard Cite

Background: Immunological thrombocytopenia (ITP) is an antibody-mediated autoimmune disease characterized by accelerated platelet destruction and suboptimal platelet production. The proliferation-inducing ligand (APRIL or TNFSF13), a member of the TNF superfamily, is structurally and functionally related to the TNF family of B cell activating factors (BAFF, TNFSF13b) and has been shown to regulate lymphocyte survival by interacting with its receptors. And activation. Transmembrane activators and calcium regulate cyclophilin ligand interactors (TACI) and B cell mature antigens (BCMA). APRIL is secreted by various cells as soluble factors, including inactive B cells, T cells, monocytes, neutrophils, macrophages and dendritic cells, as well as epithelial cells, osteoclasts and megakaryocytes. Recent studies have shown that APRIL not only participates in normal immune responses, but also plays an important role in the establishment and/or maintenance of autoimmune and inflammatory diseases. Aims: Based on the relationship between APRIL, which promotes proliferation and regulates immunity, and the development of autoimmunity, we hypothesize that APRIL may play a role in the pathogenesis of ITP. Methods:1. The EDTA anticoagulated whole blood was collected, and peripheral blood mononuclear cells (PBMC) were separated by Ficoll density gradient centrifugation. The APRIL levels on the surface of T cells, B cells, DC cells and platelets were detected by flow cytometry.Detection of plasma APRIL levels in patients with ITP by ELISA.Real time quantitative PCR were used for detecting the level of APRIL and its receptors BCMA and TACI from PBMC of healthy controls and ITP patients.Use soluble APRIL or BLyS protein and APRIL inhibitors to examine the effect of APRIL inhibition on IL-10 secretion by B cells. Flow cytometry and intracellular staining were used to evaluate B10 cells. Resoult: 1. The APRIL on the platelet surface of patients with ITP was significantly lower than that of the normal control group (p<0.01). In the ITP patients of 10 patients with complete remission, the content of APRIL on the platelet surface was significantly increased after treatment (p=0.02), and there was no significant change in the treatment-ineffective group. . The levels of APRIL and its receptors BCMA and TACI on B cells and DC cells in ITP patients were higher than those in normal controls, and the difference was statistically significant. APRIL is not expressed on CD4 + T cells, CD8 + T cells.The expression of APRIL mRNA in PBMNCs was significantly higher in ITP patients than in the normal control group (p <0.01). There was no difference in BCMA and TACI expression in PBMNC of ITP patients compared to normal controls.Plasma APRIL levels were significantly higher in ITP patients than in the normal control group, p = 0.04, and negatively correlated with platelet count, p = 0.029.In 10 patients with ITP, the percentage of CD19 + B cells remained similar between patients, and the results showed that the amount of B10 cells in the medium supplemented with APRIL was greater than that of B10 cells containing BLyS and control medium (p<0.01; p= 0.01), and the use of APRIL inhibitors resulted in a decrease in B10 cells. Conclusion: Our study shows that aberrant expression of APRIL is involved in the autoimmune response of ITP, and the effect of treatment can be assessed by measuring changes in the level of APRIL on the platelet surface. We also speculate that APRIL inhibits, rather than promotes, an immune-mediated inflammatory response in the pathogenesis of ITP. Our current observations support that the immunomodulatory effects of APRIL may be due, at least in part, to stimulation of IL-10 producing B cells. Disclosures No relevant conflicts of interest to declare.

show abstract

A gain‐of‐function mutation in TNFRSF13B is a candidate for predisposition to familial or sporadic immune thrombocytopenia

Cited by 14 publications

References 25 publications

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

Screening for Genetic Mutations for the Early Diagnosis of Common Variable Immunodeficiency in Children With Refractory Immune Thrombocytopenia: A Retrospective Data Analysis From a Tertiary Children's Center

Aberrant Expression of a Proliferation-Inducing Ligand Underlies Autoimmune Mechanisms in Immune Thrombocytopenia

Contact Info

Product

Resources

About