Circulating CD40
            <sup>+</sup>
            and CD86
            <sup>+</sup>
            B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke

Mantani, Polyxeni T.; Ljungcrantz, Irena; Andersson, Linda; Alm, Ragnar; Hedblad, Bo; Björkbacka, Harry; Nilsson, Jan; Fredrikson, Gunilla Nordin

doi:10.1161/atvbaha.113.302667

Cited by 48 publications

(32 citation statements)

References 57 publications

(75 reference statements)

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“…Similar to our observations regarding the memory B cells, it has previously been shown that patients with high CD40 + B‐cell percentages exhibit a lower stroke risk 22. Accordingly, we also observed a lower rate of cerebrovascular events in patients with high memory cell numbers (0.6%) compared with patients with low numbers (3.6%).…”

Section: Discussionsupporting

confidence: 91%

“…Categorical variables were indicated as percentages and compared by chi‐square or Fisher's exact tests where appropriate. As confounders, we selected variables that associate with CVD risk, but also influence B‐cell numbers and have been established as confounders in literature, including age, sex, smoking, history of coronary artery disease, and glomerular filtration rate 22, 44, 45, 46, 47. We also tested for a sex interaction between the association of B cells and cardiovascular end points.…”

Section: Methodsmentioning

confidence: 99%

“…In patients with acute myocardial infarction (MI), high levels of the B‐cell specific cytokines, chemokine (C‐C motif) ligand 7 and B‐cell activating factor, predict increased risk of death and recurrent MI 21. In addition, hypertensive patients with high percentages of CD40 + B cells were at lower risk for stroke,22 whereas high numbers of CD86 + B cells showed higher risk for stroke 22. A larger body of evidence is derived from elaborate mouse studies, which identified a subset‐specific role for B lymphocytes in atherosclerosis 23, 24, 25.…”

Section: Introductionmentioning

confidence: 99%

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High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

Meeuwsen

Duijvenvoorde

Gohar

et al. 2017

JAHA

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BackgroundAtherosclerosis is an inflammatory lipid disorder and the main underlying pathology of acute ischemic events. Despite a vast amount of data from murine atherosclerosis models, evidence of B‐cell involvement in human atherosclerotic disease is limited. We therefore investigated the association of circulating B‐cell subtypes with the occurrence of secondary cardiovascular events in advanced atherosclerotic disease.Methods and ResultsThis cohort study consists of 168 patients who were included in the Athero‐Express biobank between 2009 and 2011. Before surgery, peripheral blood mononuclear cells were isolated and stored in liquid nitrogen. After gentle thawing of the peripheral blood mononuclear cells, different B‐cell subtypes including naïve, (un)switched memory, and CD27+ CD43+ B1‐like B cells, were analyzed by flow cytometry. Univariable and multivariable Cox proportional hazard models were used to analyze associations between B‐cell subtypes, circulating antibodies and secondary cardiovascular manifestations during the 3‐year follow‐up period. Mean age was 70.1±9.6 years, males represented 62.8% of the population, and 54 patients had secondary manifestations during follow‐up. High numbers of unswitched memory cells were protective against secondary outcome (hazard ratio, 0.30 [95% CI, 0.13–0.69]; P<0.01). Similar results were obtained for the switched memory cells that also showed to be protective against secondary outcome (hazard ratio, 0.33 [95% CI, 0.14–0.77]; P=0.01).ConclusionsA high number of (un)switched memory B cells is associated with better outcome following carotid artery endarterectomy. These findings suggest a potential role for B‐cell subsets in prediction and prevention of secondary cardiovascular events in patients with atherosclerosis.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

Meeuwsen

Duijvenvoorde

Gohar

et al. 2017

JAHA

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“…19 Blocking CD28 post stroke reduces infarct size, improves behavioral outcomes, and reduces the inflammatory response. 20,21 Our study suggests that a decrease in let7i may promote this detrimental immune response post stroke by increasing expression of CD86.…”

Section: Neurology 87 November 22 2016mentioning

confidence: 99%

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

et al. 2016

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Objective: To evaluate microRNA let7i in ischemic stroke and its regulation of leukocytes.Methods: A total of 212 patients were studied: 106 with acute ischemic stroke and 106 controls matched for risk factors. RNA from circulating leukocytes was isolated from blood collected in PAXgene tubes. Let7i microRNA expression was assessed using TaqMan quantitative reverse transcription PCR. To assess let7i regulation of gene expression in stroke, messenger RNA (mRNA) from leukocytes was measured by whole-genome Human Transcriptome Array Affymetrix microarray. Given microRNAs act to destabilize and degrade their target mRNA, mRNAs that inversely correlated with let7i were identified. To demonstrate let7i posttranscriptional regulation of target genes, a 39 untranslated region luciferase assay was performed. Target protein expression was assessed using ELISA.Results: Let7i was decreased in patients with acute ischemic stroke (fold change 21.70, p , 0.00001). A modest inverse correlation between let7i and NIH Stroke Scale score at admission (r 5 20.32, p 5 0.02), infarct volume (r 5 20.21, p 5 0.04), and plasma MMP9 (r 5 20.46, p 5 0.01) was identified. The decrease in let7i was associated with increased expression of several of its mRNA targets, including CD86, CXCL8, and HMGB1. In vitro studies confirm let7i posttranscriptional regulation of target genes CD86, CXCL8, and HMGB1. Functional analysis predicted let7i regulates pathways involved in leukocyte activation, recruitment, and proliferation including canonical pathways of CD86 signaling in T helper cells, HMGB1 signaling, and CXCL8 signaling.Conclusions: Let7i is decreased in circulating leukocytes of patients with acute ischemic stroke.Mechanisms by which let7i regulates inflammatory response post stroke include targeting CD86, CXCL8, and HMGB1. Neurology ® 2016;87:2198-2205 GLOSSARY cDNA 5 complementary DNA; HTA 5 Human Transcriptome Array; IL 5 interleukin; mRNA 5 messenger RNA; NIHSS 5 NIH Stroke Scale; 39UTR 5 39 untranslated region; TNF-a 5 tumor necrosis factor a.Ischemic stroke remains a leading cause of disability. Although early reperfusion therapy can improve outcomes, it is available to a minority of stroke patients. Specific therapies are needed to reduce brain injury and improve outcomes after stroke. The immune system responds rapidly following cerebral ischemia. A range of damage-associated molecular patterns, cytokines, and chemokines are released to activate circulating leukocytes, vasculature, and brain cells.

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“…The authors also identified CD4 + IL-21 + T cells in human post-mortem ischemic brain tissues. Mantani et al in their recent clinical stroke study focused on B lymphocytes and identified the role of two B-cell subsets CD19 + CD40 + (decreasing) and CD19 + CD86 + (increasing) altering the risk for development of a stroke event [43].…”

Section: Adaptive Immune Responses and Role Of Bridge Cellsmentioning

confidence: 99%

Recent and near-future advances in nucleic acid-based diagnosis of stroke

Baird

Soper

Pullagurla

et al. 2015

Expert Review of Molecular Diagnostics

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Stroke is a leading cause of death and disability in adults, but at present, treatment for ischemic stroke reaches only a small percentage of patients. This is because of the very short time window for treatment and the time-consuming evaluation involved. Intense efforts are underway to find novel approaches to expedite stroke diagnosis and treatment. In this review, we provide the rationale for the use of blood-based nucleic acid biomarkers to advance stroke diagnosis. We describe mRNA markers identified in genomic profiling of circulating leukocytes and then outline technological issues involved in the application of these results. We then describe the novel point-of-care technology that is in development for the rapid detection of multiple mRNA molecules in circulating leukocytes.

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Circulating CD40 ⁺ and CD86 ⁺ B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke

Abstract: + CD86+ B cells were associated with higher risk for development of a stroke event and increased release of proinflammatory cytokines from mononuclear leukocytes. Conclusions-These

Cited by 48 publications

References 57 publications

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

Recent and near-future advances in nucleic acid-based diagnosis of stroke

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Circulating CD40 + and CD86 + B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke

Abstract: + CD86+ B cells were associated with higher risk for development of a stroke event and increased release of proinflammatory cytokines from mononuclear leukocytes. Conclusions-These

Cited by 48 publications

References 57 publications

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

Recent and near-future advances in nucleic acid-based diagnosis of stroke

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Product

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Circulating CD40 ⁺ and CD86 ⁺ B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke