CD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function

Bandala‐Sanchez, Esther; Bediaga, Naiara G.; Goddard‐Borger, Ethan D.; Ngui, Katrina; Naselli, Gaetano; Stone, Natalie L.; Neale, Alana M.; Pearce, Lesley A.; Wardak, Ahmad; Czabotar, P.E.; Haselhorst, Thomas; Maggioni, Andrea; Hartley-Tassell, Lauren A; Adams, Timothy E.; Harrison, Leonard C.

doi:10.1073/pnas.1722056115

Cited by 56 publications

(65 citation statements)

References 26 publications

(58 reference statements)

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“…Studies have shown that Siglec-10 plays an important role in regulating the immune balance of in ammatory diseases. For example, the interaction of Siglec-10 and CD24 reduces the in ammatory response associated with the damage-associated molecular patterns (DAMPs) by inhibiting the activation of high mobility group box 1 (HMGB1) and NF-κB [15][16][17][18]. The interaction between Siglec-10 expressed on human DC and pseudaminic acid can increase the expression of IL-10 through MyD88 and p38 MAPK signaling pathway to promote anti-in ammatory function [19].…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: Long-term Elevated Siglec-10 in Cerebral Spinal Fluid Heralds Better Prognosis for Patients with Aneurysmal Subarachnoid Hemorrhage

S¹,

Peng²,

Chen³

et al. 2020

Preprint

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Background The presence of aneurysmal subarachnoid hemorrhage (aSAH) is usually accompanied by excessive inflammatory response leading to the destruction of central nervous system, while the sialic acid-binding Ig-like lectin 10 (Siglec-10) is a factor recognized as having the ability to modify the inflammatory microenvironment, indicating a potential protective effect in aSAH. Methods We collected the cerebrospinal fluid (CSF) of control group and aSAH patients at different time points, measured the Siglec-10 concentration by the enzyme-linked immunosorbent assay (ELISA), and evaluated the changes of Glasgow Outcome Scale (GOS) and Glasgow Coma Scale (GCS) in the disease progression. Results Our data showed that the Siglec-10 level in CSF could respond to aSAH and quickly rose to a peak, then fell back to a stable range slightly higher than the normal range. Severely impaired patients were likely to maintain high levels of Siglec-10 for longer periods. Generally, having high-level and long-term Siglec-10 indicated a better prognosis. Conclusions These results suggested that Siglec-10 could possibly reduce the degree of inflammatory response related to the damage-associated molecular patterns (DAMPs) by regulating the balance between pro-inflammatory and anti-inflammatory, thereby improving the patient's prognosis. These findings might provide new treatment perspectives for aSAH and other inflammation-related diseases.

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Section: Introductionmentioning

confidence: 99%

“…Since the in ammatory response is an important progress in aSAH, in which excessive reaction usually causes serious harm [18], Siglec-10, an anti-in ammatory factor, may affect the recovery of aSAH patients by adjusting the balance of pro-in ammatory and anti-in ammatory. This has not been proved in vivo or in vitro.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Long-term Elevated Siglec-10 in Cerebral Spinal Fluid Heralds Better Prognosis for Patients with Aneurysmal Subarachnoid Hemorrhage

S¹,

Peng²,

Chen³

et al. 2020

Preprint

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“…CD52 is an important immune regulator on T-cell activation as previous reports, which can modulate T-cell activation either by its intracellular signal pathways or by the interaction of soluble CD52 and Siglec-10 expressing on T cells (30,31). Functional enrichment analysis of 933 differential expression genes in CD52 high and CD52 low found that DEGs were significantly enriched in terms of T cell activation, which is consistent with previous reports.…”

Section: Discussionmentioning

confidence: 70%

High expression of CD52 predicts poor prognosis of cytogenetic normal acute myeloid leukemia

Cai¹,

Cai²,

Xu³

et al. 2020

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Background: The prognosis of cytogenetic normal acute myeloid leukemia (CN-AML) varies. Finding new biomarkers affecting the prognosis of these patients may bring a new strategy for precise classification and treatment. CD52 play a significant role in chronic lymphocytic leukemia (CLL). However, the potential role of CD52 in CN-AML remains largely elusive. Methods: We analyzed the prognostic role of different expression levels of CD52 in 58 CN-AML from The Cancer Genome Atlas (TCGA) dataset and validate these results with 345 CN-AML patients from Gene Expression Omnibus (GEO) dataset. Results: CN-AML patients with high CD52 mRNA expression have a poorer prognosis compared to low CD52 expression ( event-free survival [EFS], P =0.056; overall survival [OS], P=0.043; log-rank test) and the results was verified by GSE12417 (OS, P=0.0197; log-rank test) and GSE71014 (OS, P=0.0197; log-rank test). Hematopoietic stem cell transplantation (HSCT) may improve prognosis of patients with CD52 high . Multivariate cox regression analysis show that the expression level of CD52 (HR=1.503; 95%CI:1.158-1.949 ; P=0.002) was a prognostic factor independent of age (HR=3.045; 95%CI:1.524-6.086; P=0.002) and FLT3 mutation status (HR=2.219; 95%CI:1.123-4.382; P=0.022). CD52 gene expression show a predictive effect on EFS (1-year survival- area under the curve [AUC]:0.685, 2-year survival-AUC:0.752) and OS (1-year survival-AUC: 0.717, 2-year survival-AUC:0.770). Besides, we also found that there is a significant negative correlation between CD52 mRNA expression and DNA methylation . CD52 DNA demethylation may responsible for the high level of CD52 mRNA. Functional enrichment analysis of differentially expressed genes in CD52 high and CD52 low suggests that leukemia cell adhesion-related pathways may be associated with poor prognosis in CD52 high patients . Conclusions: CD52 gene mRNA overexpression is an independent adverse prognostic factor for CN-AML, which could be reversed by HSCT. CD52 DNA demethylation may responsible for the high level of CD52 mRNA. The poor prognosis of patients with CD52 high may involves in leukemia cell adhesion-related pathways. Whether CD52 monoclonal antibodies play a role in high risk patients need further research.

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“…CD52 is an important immune regulator on T-cell activation as previous reports, which can modulate T-cell activation either by its intracellular signal pathways or by the interaction of soluble CD52 and Siglec-10 expressing on T cells (31,32). Functional enrichment analysis of differential expression genes in CD52 high and CD52 low found that DEGs were significantly enriched in terms of T cell activation, which is consistent with previous reports.…”

Section: Discussionmentioning

confidence: 70%

High expression of CD52 mRNA predicts poor prognosis for cytogenetic normal acute myeloid Leukemia patients

Cai¹,

Cai²,

Xu³

et al. 2020

Preprint

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Background: The prognosis of cytogenetic normal acute myeloid leukemia (CN-AML) varies. Finding new biomarkers affecting the prognosis of these patients may bring a new strategy for precise classification and treatment. CD52 plays a significant role in chronic lymphocytic leukemia (CLL). However, the potential role of CD52 in CN-AML remains largely elusive. Methods: We analyzed the prognostic role of different expression levels of CD52 in 58 CN-AML from The Cancer Genome Atlas (TCGA) dataset and validated these results with 345 CN-AML patients from Gene Expression Omnibus (GEO) dataset. Results: CN-AML patients with high CD52 mRNA expression had a poorer prognosis compared to low CD52 expression ( event-free survival [EFS], P =0.056; overall survival [OS], P=0.043; log-rank test) and the results was verified by GSE12417 (OS, P=0.020; log-rank test) and GSE71014 (OS, P=0.020; log-rank test). Hematopoietic stem cell transplantation (HSCT) may improve prognosis of patients with CD52 high . Regression analysis shows that the expression level of CD52 (HR=1.503; 95%CI:1.158-1.949 ; P=0.002) is a prognostic factor independent of age (HR=3.045; 95%CI:1.524-6.086; P=0.002) and FLT3 mutation status (HR=2.219; 95%CI:1.123-4.382; P=0.022). CD52 gene expression shows a predictive effect on EFS (1-year survival- area under the curve [AUC]:0.685, 2-year survival-AUC:0.752) and OS (1-year survival-AUC: 0.717, 2-year survival-AUC:0.770). Besides, we also found that there is a significant negative correlation between CD52 mRNA expression and DNA methylation . Accordingly, we speculated that CD52 DNA hypomethylation may responsible for the high level of CD52 mRNA. Functional enrichment analysis of differentially expressed genes in CD52 high and CD52 low suggests that adhesion molecule deregulation maybe also the potential pathological mechanism of CD52. Conclusions: CD52 gene mRNA overexpression is an independent adverse prognostic factor for CN-AML. CD52 DNA hypomethylation may responsible for the high level of CD52 mRNA. Adhesion molecule deregulation maybe potential pathological mechanism of CD52. Whether CD52 monoclonal antibodies play a role in high risk patients need further research.

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CD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function

Cited by 56 publications

References 26 publications

WITHDRAWN: Long-term Elevated Siglec-10 in Cerebral Spinal Fluid Heralds Better Prognosis for Patients with Aneurysmal Subarachnoid Hemorrhage

WITHDRAWN: Long-term Elevated Siglec-10 in Cerebral Spinal Fluid Heralds Better Prognosis for Patients with Aneurysmal Subarachnoid Hemorrhage

High expression of CD52 predicts poor prognosis of cytogenetic normal acute myeloid leukemia

High expression of CD52 mRNA predicts poor prognosis for cytogenetic normal acute myeloid Leukemia patients

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