Search

Background: Heterogeneity of cerebral atrophic rate commonly exists in mild cognitive impairment (MCI), which may be associated with microglia-involved neuropathology and have an influence on cognitive outcomes., Objective: We aim to explore the heterogeneity of cerebral atrophic rate among MCI and its association with plasma proteins related to microglia activity, with further investigation of their interaction effects on long-term cognition., Subjects: A total of 630 MCI subjects in the ADNI database were included, of which 260 subjects were available with baseline data on plasma proteins., Methods: Group-based multi-trajectory modeling (GBMT) was used to identify the latent classes with heterogeneous cerebral atrophic rates. Associations between latent classes and plasma proteins related to microglia activity were investigated with generalized linear models. Linear mixed effect models (LME) were implemented to explore the interaction effects between proteins related to microglia activity and identified latent classes on longitudinal cognitive changes., Results: Two latent classes were identified and labeled as the slow-atrophy class and the fast-atrophy class. Associations were found between such heterogeneity of atrophic rates and plasma proteins related to microglia activity, especially AXL receptor tyrosine kinase (AXL), CD40 antigen (CD40), and tumor necrosis factor receptor-like 2 (TNF-R2). Interaction effects on longitudinal cognitive changes showed that higher CD40 was associated with faster cognitive decline in the slow-atrophy class and higher AXL or TNF-R2 was associated with slower cognitive decline in the fast-atrophy class., Conclusions: Heterogeneity of atrophic rates at the MCI stage is associated with several plasma proteins related to microglia activity, which show either protective or adverse effects on long-term cognition depending on the variability of atrophic rates., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Regular physical activity prevents and treats cancer patients by assisting and improving the immune system. Co-stimulatory molecules that activate the immune system have been studied in cancer, such as immune checkpoint molecules of the CD40/CD40L pathway. This study aimed to characterize plasma levels of soluble CD40 (sCD40) and CD40 ligand (sCD40L) in older people with gastrointestinal tract (GIT) cancer and associate results with physical activity. This prospective and exploratory cohort study was performed with 24 older people with GIT cancer and 23 healthy elderly individuals as controls. Physical activity level was classified as active or sedentary according to the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Plasma levels of sCD40 and sCD40L were determined using Enzyme-Linked Immunosorbent Assay. Plasma levels of sCD40 were higher, while sCD40L were lower (p = 0.0171) in older people with GIT cancer than controls (p = 0.0038). Regarding physical activity, active older people with GIT cancer presented lower plasma levels of sCD40 and sCD40L than those sedentary with GIT cancer (p = 0.0228 and p = 0.0236), respectively. Our findings suggest that GIT cancer stimulates the immune system in older people, elevates levels of sCD40, and reduces levels of sCD40L. Physical activity may be a protective factor for the immune system of these patients since it acts on sCD40/sCD40L pathway., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality. Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 spike protein engaged the CD42b receptor to activate platelets via 2 distinct signaling pathways and promoted platelet-monocyte communication through the engagement of P selectin/PGSL-1 and CD40L/CD40, which led to proinflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation, and a cytokine storm are correlated in patients severely affected by COVID-19 and suggest a potential target for therapeutic intervention.

Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a B cell- and antibody-mediated autoimmune disease which may be regulated by CD40/CD40L signaling pathway. we enrolled anti-NMDARE patients and measured the serum CD40 and CD40L concentrations. The serum concentration of CD40 was decreased, while CD40L was increased in anti-NMDARE patients compared with that of healthy controls. The concentrations of CD40 and CD40L were both elevated in the acute stage of anti-NMDARE and were reduced during remission. Serum CD40L levels were positively correlated with serum CD40 levels. These results revealed that the CD40/CD40L signaling pathway might contribute to the pathogenesis of anti-NMDARE., (Copyright © 2021. Published by Elsevier B.V.)

Background: In colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk., Methods: We measured 84 angiogenic and inflammatory markers in serum sampled at the time of diagnosis within the population-based cohort of 122 stage I-III patients. In a stepwise manner, the statistically strongest proteins associated with time to development of liver metastasis were analysed in the corresponding serum samples from 273 stage II-III rectal cancer patients in three independent cohorts., Results: We identified the soluble form of the costimulatory immune checkpoint receptor cluster of differentiation molecule 40 (sCD40) as a marker of liver metastasis risk across all patient cohorts-the higher the sCD40 level, the shorter time to liver metastasis. In patients receiving neoadjuvant treatment, the sCD40 value remained an independent variable associated with progression to liver metastasis along with the local treatment response. Of note, serum sCD40 was not associated with progression to lung metastasis., Conclusions: Circulating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice., (© 2021. The Author(s).)

The current standard biomarker for myocardial infarction (MI) is high-sensitive troponin. Although powerful in clinical setting, search for new markers is warranted as early diagnosis of MI is associated with improved outcomes. Extracellular vesicles (EVs) attracted considerable interest as new blood biomarkers. A training cohort used for diagnostic modelling included 30 patients with STEMI, 38 with stable angina (SA) and 30 matched-controls. Extracellular vesicle concentration was assessed by nanoparticle tracking analysis. Extracellular vesicle surface-epitopes were measured by flow cytometry. Diagnostic models were developed using machine learning algorithms and validated on an independent cohort of 80 patients. Serum EV concentration from STEMI patients was increased as compared to controls and SA. EV levels of CD62P, CD42a, CD41b, CD31 and CD40 increased in STEMI, and to a lesser extent in SA patients. An aggregate marker including EV concentration and CD62P/CD42a levels achieved non-inferiority to troponin, discriminating STEMI from controls (AUC = 0.969). A random forest model based on EV biomarkers discriminated the two groups with 100% accuracy. EV markers and RF model confirmed high diagnostic performance at validation. In conclusion, patients with acute MI or SA exhibit characteristic EV biomarker profiles. EV biomarkers hold great potential as early markers for the management of patients with MI., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Aims: A high proportion of patients develop chronic kidney disease (CKD) after liver transplantation (LT). We aimed to develop clinical/protein models to predict future glomerular filtration rate (GFR) deterioration in this population., Approach and Results: In independent multicenter discovery (CTOT14) and single-center validation (BUMC) cohorts, we analyzed kidney injury proteins in serum/plasma samples at month 3 after LT in recipients with preserved GFR who demonstrated subsequent GFR deterioration versus preservation by year 1 and year 5 in the BUMC cohort. In CTOT14, we also examined correlations between serial protein levels and GFR over the first year. A month 3 predictive model was constructed from clinical and protein level variables using the CTOT14 cohort (n = 60). Levels of β-2 microglobulin and CD40 antigen and presence of hepatitis C virus (HCV) infection predicted early (year 1) GFR deterioration (area under the curve [AUC], 0.814). We observed excellent validation of this model (AUC, 0.801) in the BUMC cohort (n = 50) who had both early and late (year 5) GFR deterioration. At an optimal threshold, the model had the following performance characteristics in CTOT14 and BUMC, respectively: accuracy (0.75, 0.8), sensitivity (0.71, 0.67), specificity (0.78, 0.88), positive predictive value (0.74, 0.75), and negative predictive value (0.76, 0.82). In the serial CTOT14 analysis, several proteins, including β-2 microglobulin and CD40, correlated with GFR changes over the first year., Conclusions: We have validated a clinical/protein model (PRESERVE) that early after LT can predict future renal deterioration versus preservation with high accuracy. This model may help select recipients at higher risk for subsequent CKD for early, proactive renal sparing strategies., (© 2019 by the American Association for the Study of Liver Diseases.)

Aim: To evaluate the serum concentrations of inflammatory mediators in patients with type 2 diabetes mellitus (T2DM) with or without renal alteration (RA) function., Methods: Serum samples from 76 patients with T2DM and 24 healthy individuals were selected. Patients with T2DM were divided into two groups according to eGFR (> or < 60mL/min/1.73m2). Cytokines, chemokines and adipokines levels were evaluated using the Multiplex immunoassay and ELISA., Results: TNFR1 and leptin were higher in the T2DM group with RA than in the T2DM group without RA and control group. All patients with T2DM showed increased resistin, IL-8, and MIP-1α compared to the control group. Adiponectin were higher and IL-4 decreased in the T2DM group with RA compared to the control group. eGFR positively correlated with IL-4 and negatively with TNFR1, TNFR2, and leptin in patients with T2DM. In the T2DM group with RA, eGFR was negatively correlated with TNFR1 and resistin. TNFR1 was positively correlated with resistin and leptin, as well as resistin with IL-8 and leptin., Conclusion: Increased levels of TNFR1, adipokines, chemokines and decrease of IL-4 play important role in the inflammatory process developed in T2DM and decreased renal function. We also suggest that TNFR1 is a strong predictor of renal dysfunction in patients with T2DM., Competing Interests: The authors have declared that no competing interests exist.

Background: An altered immune response and decreased vaccine response are observed in patients with chronic renal failure. A preliminary study of 15 non-immunised patients, despite appropriate previous hepatitis B vaccination, showed a 60% seroconversion rate after 3 months of dialysis with a polymethylmethacrylate (PMMA) membrane. This response was associated with circulating soluble CD40 (CD40s) decrease, a natural inhibitor of the humoral immune response. The aim of the study is to confirm these results in a randomised study., Methods: We conducted a multicentre randomised intention-to-treat superiority clinical trial comparing polysulfone and a PMMA membrane in 2 parallel patient groups. The primary end point was the vaccine response rate, as defined by an anti-HBs antibodies titre of >10 IU/L, 1 month after the last vaccination with a double dose of Engerix B20®, performed at weeks 12, 16, 20, and 36., Results: Twenty-five patients were randomised and included in an intention-to-treat analysis. They were dialysed on polysulfone (n = 11) or PMMA (n = 14) for 40 weeks. Fifty percent of the PMMA patients versus 54.5% of the polysulfone patients achieved seroconversion (p = 1.00). The median anti-HBs antibody titre in responders at week 40 was 496 (92-750) versus 395 (43-572) UI/mL for PMMA and polysulfone, respectively (p = 0.46). The median CD40s titre at week 12 was 306 (193-448) versus 491 (281-515) pg/mL (p = 0.21). The CD40s median variation between week 0 and week 12 was 5 (-105 to 90) versus 64 (-63 to 123) pg/mL (p = 0.55). The CD40s level at week 12 in non-responders was slightly inferior to that of the responders: median 193 (168-331) versus 413 (281-512) pg/mL (p = 0.08)., Conclusion: We did not observe a better vaccine response with the PMMA membrane compared to high-flux polysulfone. The PMMA membrane did not decrease the CD40s more than the polysulfone membrane probably because the titre was previously low in the 2 groups., (© 2019 S. Karger AG, Basel.)

Atherosclerosis (AS) is one of the leading causes of death, with variable frequencies in different populations. To this end, we examined whether AS is associated with the miR-145 rs353291 polymorphism and specific rs353291 alleles. The distribution of the rs353291 C allele and CC genotypes was significantly higher in AS patients than in controls. Compared to individuals with the rs353291 TT genotype, carriers of the rs353291 C allele showed a significant increase in the plasma levels of sCD40L, IL-6 and MCP-1 and a decrease in miR-145 expression. After ox-LDL administration, the peripheral blood mononuclear cells (PBMCs) of rs353291 C allele carriers showed significantly increased CD40 and MCP-1 expression compared with those of individuals with the rs353291 TT genotype. These data suggest that the rs353291 C allele may increase susceptibility to atherosclerosis.

Objective: The aim of this study was to systematically review evidence regarding the association between CD40 polymorphisms and systemic lupus erythematosus and between soluble CD40 (sCD40) and CD40 ligand (sCD40L) levels and systemic lupus erythematosus., Methods: We performed a meta-analysis on the association between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and systemic lupus erythematosus risk and sCD40/sCD40L levels in patients with systemic lupus erythematosus and controls., Results: Fourteen studies were included. Ethnicity-specific meta-analysis indicated a significant association between the T allele of CD40 rs4810485 polymorphism and systemic lupus erythematosus in Europeans (odds ratio = 0.715, 95% confidence interval = 0.641-0.832, p  < 0.001) and a trend toward an association between the T allele and systemic lupus erythematosus in Asians (odds ratio = 1.255, 95% confidence interval = 0.978-1.810, p  = 0.074). Furthermore, a significant association was reported between systemic lupus erythematosus and the C allele of CD40 rs1883832 polymorphism (odds ratio = 1.235, 95% confidence interval = 1.087-1.405, p  = 0.001) and A allele of CD40 rs3765456 polymorphism and systemic lupus erythematosus in Asians (odds ratio = 1.184, 95% confidence interval = 1.040-1.348, p  = 0.011). sCD40 and sCD40L levels were significantly higher in SLE than in controls (standardized mean difference = 1.564, 95% confidence interval = 0.256-2.872, p  = 0.019 and standardized mean difference = 1.499, 95% confidence interval = 1.031-1.967, p  < 0.001, respectively). Stratification based on ethnicity revealed higher sCD40L levels in the systemic lupus erythematosus group among European, Asian, North American, and Arab populations., Conclusions: Our meta-analyses found associations between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and systemic lupus erythematosus susceptibility and significantly higher sCD40 and sCD40L levels in patients with systemic lupus erythematosus than in controls.

Platelet transfusion is a safe process, but during or after the process the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). Platelet concentrate transfusion may be liable for significant absence of beneficial response. Danger may manifest clinically or biologically; in the latter case, manifestations are frequently an absence of the expected response to the blood component by the recipient. Blood platelets exert roles in inflammation, especially through the immunomodulator complex CD40/CD40L (sCD40L). In this review, we concentrate on the inflammatory potential of platelets and their participation to SARs in transfusion., (Copyright © 2019. Published by Elsevier Masson SAS.)

Acute coronary syndrome (ACS) can be triggered by the presence of inflammatory factors which promote the activation of immune cells by costimulatory molecules such as CD40 and its ligand CD40L. Environmental and genetic factors are involved in the etiology of the ACS. The aim of this study was to explore the gene and protein expression associated with CD40 and CD40L genetic variants in ACS patients from the western Mexican population. A total of 620 individuals from western Mexico were recruited: 320 ACS patients and 300 individuals without a history of ischemic cardiopathy were evaluated. The genotype was determined using TaqMan SNP genotyping assays. CD40 and CD40L expressions at the mRNA level were quantified using TaqMan Gene Expression Assays. Soluble protein isoforms were measured by enzyme-linked immunosorbent assay. We did not find evidence of association between CD40 (rs1883832, rs4810485, and rs11086998) and CD40L (rs3092952 and rs3092920) genetic variants and susceptibility to ACS, although rs1883832 and rs4810485 were significantly associated with high sCD40 plasma levels. Plasma levels of sCD40L can be affected by gender and the clinical spectrum of acute coronary syndrome. Our results do not suggest a functional role of CD40 and CD40L genetic variants in ACS. However, they could reflect the inflammatory process and platelet activation in ACS patients, even when they are under pharmacological therapy. Due to the important roles of the CD40-CD40L system in the pathogenesis of ACS, longitudinal studies are required to determine if soluble levels of CD40 and CD40L could be clinically useful markers of a recurrent cardiovascular event after an ACS.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with immune dysregulation and increased risk of infections. The presence of autoantibodies and immunoglobulin abnormalities indicates B-cell and antibody-secreting cell (ASC) dysfunction. We hypothesize that soluble factors associated with B-cell and ASC activity are decreased in RA patients and that this is linked to higher susceptibility to infections., Methods: Using the Johns Hopkins Arthritis Cohort and Biorepository, we contrasted serum protein levels of soluble factors involved in B-cell activation (CD40, CD40L) and B-cell/ASC homing (CXCL10, CXCL11, and CXCL13) or survival (BAFF, APRIL, TACI, and BCMA) in 10 healthy subjects and 23 adult RA patients (aged 24-65 years). We subdivided RA patients into those with ( n = 17) and those without infections ( n = 6) within a 2-year period. In order to reduce the effect of RA treatment, we only included patients receiving methotrexate monotherapy or no RA treatments at baseline. Soluble serum protein levels of B-cell/ASC factors were quantified by multiplex immunoassays., Results: We identified that (1) serum levels of soluble BCMA, APRIL, CD40, and CD40L were significantly decreased in RA patients relative to healthy individuals; (2) serum soluble BCMA, predominantly released by ASC, correlated with serum concentrations of class-switched immunoglobulins, IgG and IgA; and (3) RA patients with a history of infections had significantly lower soluble BCMA levels compared with healthy donors and with RA patients without infections., Conclusions: Our study using soluble factors linked to B-cell/ASC activation and survival suggests that there is a paucity of ASC in a subset of RA patients and that this may be linked to altered antibody production and increased risk of infections. Further delineating the link between ASC and infection susceptibility in RA may optimize disease management and provide novel insights into disease pathogenesis that are susceptible to intervention.

Inhaled mometasone was shown to improve pain scores and decrease soluble vascular cell adhesion molecule (sVCAM) concentration in a randomized controlled trial of nonasthmatic patients with sickle cell disease. We sought to explore potential changes in systemic inflammation as a mechanism underlying this effect. Serum samples from 41 trial participants (15 placebo- and 26 mometasone-treated) were analyzed using a 92 inflammatory marker panel at baseline and after 8 weeks of mometasone therapy. Individual marker analysis and correlation analysis were conducted. Adjusted for age, the mometasone-treated group decreased the concentration of CXCL9, CXCL11, CD40, IL-10, and IL-18 relative to placebo-treated participants. Hierarchical clustering and correlation analysis identified additional evidence for a decrease in cytokines linking to macrophage signaling and migration. There was no statistically significant change in markers of asthma and allergy, indicating that the improvement was unlikely mediated by modulation of occult reactive airway disease. This analysis of inflammatory markers suggests that decrease in macrophage activity may be involved in the mediation of the clinical benefit seen with use of inhaled mometasone in nonasthmatic patients with sickle cell disease.Trial registration: clinicaltrials.gov identifier: NCT02061202.

Background and Aims: There is a strong association between primary sclerosing cholangitis [PSC] and ulcerative colitis [UC], but the immunological link between the two diseases is obscure. We compared serum cytokine profiles of patients with PSC-UC and UC, and investigated a number of selected cytokines in colonic biopsy samples. We also assessed the presence and activation of T cells in peripheral blood and colonic mucosa., Methods: Serum samples from 22 patients with PSC-UC, 28 patients with UC, and 19 controls were analysed by a proximity extension assay including 92 inflammatory cytokines. Biopsies from caecum, sigmoid colon, and rectum were collected from the same patients. Quantitative analysis for IFN-γ, IL-2, IL-4, IL-5, IL-13, IL-17A/ E/F, IL-21, IL-22, IL-23, and IL-27 was carried out on tissue homogenates. T cell phenotype was evaluated by flow cytometry., Results: By multivariate analysis we identified a cluster of serum cytokines with higher levels in PSC-UC, and sCD40 in particular was strongly associated with this patient group. In contrast, colonic cytokines were only modestly increased in PSC-UC, whereas several Th1-, Th2-, and Th17-associated cytokines were increased in UC. Patients with PSC-UC had increased colonic levels of CXCR3-positive CD8+ T cells but fewer CD25-positive CD4+ T cells. An increased CRTH2/CXCR3-quote indicated a predominance of Th-2 type CD4+ T cells in UC patients., Conclusions: Our study reveals different cytokine profiles and T cell profiles in PSC-UC and UC, with higher systemic levels of cytokines in PSC-UC, and a more pronounced colonic inflammation in UC. Serum sCD40 could potentially be investigated as a marker for PSC in UC., (Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder of unknown etiology. Considerable evidence supports a genetic basis for susceptibility to SLE. Genetic and functional data suggested the CD40 receptor (CD40) and CD40 ligand (CD40L) as strong candidate genes for SLE., Aim: To investigate whether CD40 gene rs1883832 C/T single-nucleotide polymorphism (SNP) and/or soluble CD40 (sCD40) are associated with SLE in the Egyptian population., Subjects and Methods: The study included a hundred SLE patients, and a fifty age- and gender-matched healthy control subjects. CD40 gene rs1883832 C/T genotyping was carried out using restriction fragment length polymorphism (RFLP), while sCD40 levels were measured by ELISA., Results: CD40 rs1883832C/T genotypes (CC, TT, and CT) as well as CD40 alleles (C and T) did not differ between SLE patients and normal control (p = 0.63, 0.37, and 0.31 respectively). Though did not reach statistical significance, carriers of genotype CT had 1.5 times more chance to develop SLE compared to wild homozygous CC genotype carriers (OR 1.44), while carriers of genotype TT had ~ 2 times more chance to have SLE than CC carries (OR 1.96). Accordingly, the carriers of the T allele had ¬ 1.5 times more chance to get SLE compared to the carriers of the C allele (OR 1.4). The serum sCD40 level was significantly higher in SLE patients compared to healthy control (3.4 vs. 0.8 ng/mL, p < 0.001). In SLE patients, using CC as the reference genotype, serum sCD40 level was significantly higher in the carriers of the homozygous genotype TT (3.8 ± 1.3 vs. 2.9 ± 1.9, p = 0.0001), and T allele (3.6 ± 1.4 vs. 3.0 ± 1.5, p = 0.003). Moreover, sCD40 could discriminate SLE patients from normal subjects at a cutoff value of 0.885 ng/mL with 98% sensitivity and 96% specificity (AUC = 0.999, p < 0.001)., Conclusions: The study did not prove CD40 gene (rs1883832 C/T) polymorphism as a clear risk factor of SLE in this cohort of Egyptian patients, though it was highly likely associated with the carriers of T allele. In the same context, significant high sCD40 levels were observed in the T allele carriers.

Objective: Ankylosing spondylitis (AS) is a common clinical autoimmune disease, the pathogenesis of which, however, is not yet elucidated. In this study, we aim to explore the effect of B cells in the development and progression of AS and its underlying mechanism., Patients and Methods: B cells were isolated from peripheral blood of AS patients and normal controls. Surface expression of CD40 in B cells was detected by flow cytometry. Expressions of downstream genes in MAPK pathway were detected by Western blot. Moreover, IL-10 expressions in peripheral blood of AS patients and normal controls were detected by ELISA., Results: No difference was found in the surface expression of CD40 in B cells between AS patients and normal controls. However, CD40 expression was inhibited after B cells in peripheral blood were specifically stimulated by lipopolysaccharide (LPS) in vitro. Abnormal activated B cells, dysregulated p38 expressions and decreased serum expressions of IL-10 were also observed in AS patients., Conclusions: Abnormal surface expression of CD40 inn B cells of AS patients may lead to abnormal activation of B cells, thereby interfering the p38 MAPK pathway and reducing the IL-10 secretion.

Objectives: Altered platelet function has been proposed as an underlying mechanism to explain increased risk of myocardial infarction in people living with HIV associated with use of the nucleoside reverse transcriptase inhibitor abacavir (ABC). We aimed to examine changes in platelet biomarkers in people living with HIV switching from ABC., Methods: In a prospective, 48-week substudy of virally suppressed HIV-1-positive subjects randomized to remain on ABC/lamivudine (ABC/3TC) or switch to tenofovir disoproxil fumarate/emtricitabine, we measured soluble glycoprotein VI (sGPVI), soluble P-selectin, soluble CD40 ligand and von Willebrand factor in plasma collected over time and assessed differences using mixed effect models., Results: Of 312 randomized participants, 310 were included in the analysis. Mean (SD) age 46.4 (9.3) years, 262 (85%) men and 201 (65%) white. At baseline, there was no significant between-group difference in sGPVI [tenofovir disoproxil fumarate/emtricitabine 3.75 (0.25) versus ABC/3TC 3.61 (0.22) ng/ml, P = 0.69]. Greater increases in sGPVI from baseline to week 48 occurred in those switched from ABC/3TC (effect size +0.57 ng/ml; 95% confidence interval, 0.2-0.94; P = 0.003). There was no significant baseline difference or change overtime in soluble P-selectin, soluble CD40 ligand or von Willebrand factor between groups., Conclusion: The significant increases in sGPVI that occur with a switch from ABC/3TC are suggestive of changes in platelet function centred on platelet/collagen interactions and potentially represent an underlying mechanism to explain increased risk of myocardial infarction with ABC.

Sepsis is a severe and progressive disease characterized by systemic inflammatory response syndrome (SIRS). CD40 serves as a vital link between immune response and inflammation. This study was designed to investigate the potential association between a functional single-nucleotide polymorphism (SNP) of CD40 (rs1883832) and susceptibility to sepsis. We first performed a case-control study to explore the relationship between the CD40 rs1883832 polymorphism and sepsis. CD40 mRNA expression and protein expression were determined by real-time PCR and western blotting, respectively, in peripheral blood mononuclear cells (PBMCs) from sepsis patients and healthy controls. The plasma sCD40L levels in the two groups were measured by ELISA. The results showed that the frequencies of the TT genotype and the CD40 rs1883832 T allele were significantly higher in sepsis patients than in healthy controls. Plasma sCD40L levels were also significantly increased in sepsis patients. In addition, TT genotype carriers among sepsis patients displayed the highest CD40 expression at both the mRNA and protein levels, accompanied by the highest plasma sCD40L concentrations. In conclusion, the CD40 rs1883832 T allele acts as a risk factor for increased susceptibility to sepsis and may be involved in the process of sepsis through regulation of CD40 expression and plasma sCD40L levels.

Objective: To determine whether exposure of workers handling engineered nanoparticles (ENPs) may result in increased inflammation and changes in lung function., Methods: A prospective panel study compared changes in several markers of inflammation for ENP handling and non-ENP handling control workers. Nanoparticle exposure was measured during ENP handling and for controls. Lung function, fraction of exhaled nitric oxide (FeNO), C-reactive protein (CRP), blood cell counts and several serum cytokines were measured at baseline, at the end of the shift and at the end of the working week., Results: Nanoparticle exposure was not higher when ENPs were being handled; nanoparticle counts were higher in offices and in ambient air than in laboratories. There were no differences at baseline in lung function, FeNO, haemoglobin, platelet, white cell counts or CRP levels between those who handled nanoparticles and those who did not, with or without asthmatic participants. There were statistically significant increases in sCD40 and sTNFR2 over the working day for those who handled ENPs. The changes were larger and statistically significant over the working week and sCD62P also showed a statistically significant difference. The changes were slightly smaller and less likely to be statistically significant for atopic than for non-atopic participants., Conclusions: Even at low ENP exposure, increases in three cytokines were significant over the week for those who handled nanoparticles, compared with those who did not. However, exposure to low and transient levels of nanoparticles was insufficient, to trigger measurable changes in spirometry, FeNO, CRP or blood cell counts., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Soluble CD40 ligand (sCD40L) has been implicated in the development of renal injury. The CD40 receptor exists in a soluble form, sCD40R, and has been shown to function as a competitive antagonist against CD40 activation. We analyzed whether plasma levels of sCD40L and sCD40R predict changes in renal function in an all-cause chronic kidney disease (CKD) cohort. Stratification of subjects based on sCD40L and sCD40R individually, as well as in combination, demonstrated that sCD40L was directly associated with declines in estimated glomerular filtration rate (eGFR). sCD40R was negatively associated with declines in eGFR. Baseline characteristics following stratification, including systolic blood pressure, history of diabetes mellitus or peripheral vascular disease, primary renal disease classification, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker usage were not significantly different. High sCD40L and low sCD40R were both found to be independent predictors of a decline in eGFR at 1-year follow-up (-7.57%, p = 0.014; -6.39%, p = 0.044). Our data suggest that circulating levels of sCD40L and sCD40R are associated with changes in renal function in patients with CKD. The CD40 decoy receptor, sCD40R, may serve as a potential therapeutic target to attenuate renal function decline.

Rationale: The pathogenesis of respiratory syncytial virus (RSV) bronchiolitis in infants remains poorly understood. Mouse models implicate pulmonary T cells in the development of RSV disease. T cell responses are initiated by dendritic cells (DCs), which accumulate in lungs of RSV-infected mice. In infants with RSV bronchiolitis, previous reports have shown that DCs are mobilised to the nasal mucosa, but data on lower airway DC responses are lacking., Objective: To determine the presence and phenotype of DCs and associated immune cells in bronchoalveolar lavage (BAL) and peripheral blood samples from infants with RSV bronchiolitis., Methods: Infants intubated and ventilated due to severe RSV bronchiolitis or for planned surgery (controls with healthy lungs) underwent non-bronchoscopic BAL. Immune cells in BAL and blood samples were characterised by flow cytometry and cytokines measured by Human V-Plex Pro-inflammatory Panel 1 MSD kit., Measurements and Main Results: In RSV cases, BAL conventional DCs (cDCs), NK T cells, NK cells and pro-inflammatory cytokines accumulated, plasmacytoid DCs (pDCs) and T cells were present, and blood cDCs increased activation marker expression. When stratifying RSV cases by risk group, preterm and older (≥4 months) infants had fewer BAL pDCs than term born and younger (<4 months) infants, respectively., Conclusions: cDCs accumulate in the lower airways during RSV bronchiolitis, are activated systemically and may, through activation of T cells, NK T cells and NK cells, contribute to RSV-induced inflammation and disease. In addition, the small population of airway pDCs in preterm and older infants may reveal a distinct endotype of RSV bronchiolitis with weak antiviral pDC responses., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose: We investigated the level of pro- and anti-inflammatory biomarkers before and after 8 weeks of unsupervised physical activity (PA) initiated by employer., Methods: During autumn 2014, background data, blood samples and self-reported exercise level were collected from 76 men and 41 women in a Norwegian road maintenance company. Monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), leptin, adiponectin, p-selectin and CD40 ligand (CD40L) were analyzed. [Formula: see text] was measured in a subgroup of 50 subjects., Results: With reference point of exercise ≤1 time/week, we found that participants who exercised 2-3 times/week had higher [Formula: see text] values (5.6 mL kg -1  min -1 ; 95% CI [1.3, 9.9]). MCP-1 was lower in those who exercised ≥ 4 times/week (-81.98 pg/ml [-142.9, -21.0]). IL-6 and p-selectin levels were lower in females who exercised ≥4 times/week (-1.04 pg/ml [-2.04, -0.03] and -13.75 ng/ml [-24.03, -3.48]). Leptin was lower in participants who exercised 2-3 times/week (-0.39 µg/ml ln [-0.68, -0.09]) and ≥4 times/week (-0.69 µg/ml ln [-1.10, -0.28]). During follow-up, [Formula: see text] increased (2.9 mL kg -1  min -1 [1.5, 4.3]), while p-selectin and CD40L decreased (-2.33 ng/ml [-3.78, -0.87] and 718.14 ng/ml [-1368, -68]). MCP-1 levels decreased among men (-32.70 pg/ml [-51.21, -14.19]). A joint analysis of all biomarkers (inversed adiponectin) showed that those who exercised ≥4 times/week at baseline had lower total levels of biomarkers and that total biomarker levels decreased during follow-up., Conclusions: Exercising several times a week was associated with less inflammation compared to exercising once a week or less. During the 8-week follow-up, total levels of biomarkers of inflammation improved.

Coronary heart disease (CHD), characterized by inflammation and accumulation of plaques mainly comprised of lipids, calcium and inflammatory cells in the walls of coronary arteries. CHD is exacerbated by specific cardiovascular risk factors, such as obesity, diabetes mellitus, and hypertension. The current review focuses on the critical role of traditional inflammatory biomarkers, including interleukin-6, C-reactive protein (CRP), complement, CD40 and myeloperoxidase (MPO), in the pathogenesis of CHD.

Rationale: Patients with chronic kidney disease (CKD) develop hyperhomocysteinemia and have a higher cardiovascular mortality than those without hyperhomocysteinemia by 10-fold., Objective: We investigated monocyte differentiation in human CKD and cardiovascular disease (CVD)., Methods and Results: We identified CD40 as a CKD-related monocyte activation gene using CKD-monocyte -mRNA array analysis and classified CD40 monocyte (CD40 + CD14 + ) as a stronger inflammatory subset than the intermediate monocyte (CD14 ++ CD16 + ) subset. We recruited 27 patients with CVD/CKD and 14 healthy subjects and found that CD40/CD40 classical/CD40 intermediate monocyte (CD40 + CD14 + /CD40 + CD14 ++ CD16 - /CD40 + CD14 ++ CD16 + ), plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine levels were higher in CVD and further elevated in CVD+CKD. CD40 and CD40 intermediate subsets were positively correlated with plasma/cellular homocysteine levels, S-adenosylhomocysteine and S-adenosylmethionine but negatively correlated with estimated glomerular filtration rate. Hyperhomocysteinemia was established as a likely mediator for CKD-induced CD40 intermediate monocyte, and reduced S-adenosylhomocysteine/S-adenosylmethionine was established for CKD-induced CD40/CD40 intermediate monocyte. Soluble CD40 ligand, tumor necrosis factor (TNF)-α/interleukin (IL)-6/interferon (IFN)-γ levels were elevated in CVD/CKD. CKD serum/homocysteine/CD40L/increased TNF-α/IL-6/IFN-γ-induced CD40/CD40 intermediate monocyte in peripheral blood monocyte. Homocysteine and CKD serum-induced CD40 monocyte were prevented by neutralizing antibodies against CD40L/TNF-α/IL-6. DNA hypomethylation was found on nuclear factor-κB consensus element in CD40 promoter in white blood cells from patients with CKD with lower S-adenosylmethionine / S-adenosylhomocysteine ratios. Finally, homocysteine inhibited DNA methyltransferase-1 activity and promoted CD40 intermediate monocyte differentiation, which was reversed by folic acid in peripheral blood monocyte., Conclusions: CD40 monocyte is a novel inflammatory monocyte subset that appears to be a biomarker for CKD severity. Hyperhomocysteinemia mediates CD40 monocyte differentiation via soluble CD40 ligand induction and CD40 DNA hypomethylation in CKD., (© 2016 American Heart Association, Inc.)

Objective: Beyond their eminent role in hemostasis and thrombosis, platelets are recognized as mediators of inflammation. Platelet cluster of differentiation 40 (CD40) ligand (CD40L and CD154) plays a key role in mediating platelet-induced inflammation in atherosclerosis. CD40, the receptor for CD40L, is present on platelets; however, the role of CD40 on this cell type is until now undefined., Approach and Results: We found that in both mice and humans, platelet CD40 mediates the formation of platelet-leukocyte aggregates and the release of chemokine (C-X-C motif) ligand 4. Leukocytes were also less prone to adhere to CD40-deficient thrombi. However, platelet CD40 was not involved in platelet aggregation. Activated platelets isolated from Cd40(-/-)Apoe(-/-) mice adhered less to the endothelium upon injection into Apoe(-/-) mice when compared with CD40-sufficient platelets. Furthermore, lack of CD40 on injected platelets led to reduced leukocyte recruitment to the carotid artery as assayed by intravital microscopy. This was accompanied by a decrease in endothelial vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule, VE-cadherin, and P-selectin expression. To investigate the effect of platelet CD40 in atherosclerosis, Apoe(-/-) mice received thrombin-activated Apoe(-/-) or Cd40(-/-)Apoe(-/-) platelets every 5 days for 12 weeks, starting at the age of 17 weeks, when atherosclerotic plaques had already formed. When compared with mice that received Apoe(-/-) platelets, those receiving Cd40(-/-)Apoe(-/-) platelets exhibited a >2-fold reduction in atherosclerosis. Plaques of mice receiving CD40-deficient platelets were less advanced, contained less macrophages, neutrophils, and collagen, and displayed smaller lipid cores., Conclusions: Platelet CD40 plays a crucial role in inflammation by stimulating leukocyte activation and recruitment and activation of endothelial cells, thereby promoting atherosclerosis., (© 2016 American Heart Association, Inc.)

Objective: To investigate the association of SNP of CD40 gene and its serum levels with ischemic stroke (IS)., Methods: A total of 202 IS patients from a hospital of Baise city were enrolled in case group from May 2013 to November 2014. At the same time, 109 healthy people who had physical check-ups in the outpatient department at the same hospital were enrolled in the control group. All participants were from Guangxi Zhuang Autonomous Region and unrelated to each other. 3 ml venous blood were collected on the premise of informed consent. The single nucleotide polymorphisms of CD40 gene rs1883832 C/T, rs13040307 C/T, rs752118 C/T and rs3765459 G/A were analyzed using a Snapshot SNP genotyping assays, and the serum levels of CD40 were tested by ELISA. t-test was used to compare the serum levels of CD40 between the case and control group, and the genotypes at different locuses in case group; χ(2) test was used to compare the distribution differences of the CD40 gene locuses in different genotypes and allele between the case group and the control group; alleles was established as independent variables, the occurrence of the IS as dependent variable, and expressed relative risk with OR (95%CI) value., Results: In the case group, the frequency of CC, CT and TT genotypes in CD40 gene rs1883832 C/T were 21.78% (44/202), 49.51% (100/202) and 28.71% (58/202), respectively, and 33.17% (66/199), 48.74% (97/199), 18.09% (36/199) in the control group, respectively, the differences between the two groups was significant (χ(2)=9.57, P=0.008). The CD40 serum levels were (62.7 ± 24.5) pg/ml in the case group, which was higher than that in the control group (45.3 ± 17.2) pg/ml (t=8.97, P<0.001). The serum levels of TT and CT genotypes in CD40 gene were (65.9 ± 26.3) and (64.3 ± 25.9) pg/ml, respectively, and the differences were significant when comparing with CC genotype (t equaled 5.34 and 5.03, respectively, P<0.001). The risk of developing IS was 1.56 times higher in 1883832 T allele carriers than that in rs1883832 C allele carriers (OR=1.56, 95% CI: 1.18-2.06); Combined genotype analysis displayed that CD40 gene rs1883832 C/T, rs13040307 C/T, rs752118 C/T and rs3765459 G/A polymorphisms showed strong linkage disequilibrium, the case group TCCA haplotype was tested to be associated with a significantly increased risk of IS as compared with that in the control group(OR=2.49; 95%CI: 1.13-5.48)., Conclusion: CD40 gene rs1883832 C/T polymorphism and its TCCA haplotype were possibly associated with ischemic stroke, and the susceptibility gene for ischemic stroke may be rs1883832 T allele.

Introduction: CD154 is a surface glycoprotein present on activated platelets, lymphocytes and mast cells. It mediates the transmission of information between cells and initiates an inflammatory response. The interaction of CD154 with its receptor CD40 leads to increase in concentrations of soluble forms of both molecules (sCD154, sCD40), which has an important prognostic value in cardiovascular complications. The metabolic disorders in chronic kidney disease (CKD), chronic inflammation, increased oxidative stress and type of renal replacement therapy may influence on the balance of sCD154/sCD40 in plasma and blood platelets. The purpose of the reasearch was to analyse the concentrations of sCD154 antigen and sCD40 receptor in platelet pure plasma (PPP) and platelet rich plasma (PRP) of patients with CKD treated conservatively, haemodialysed and on petitoneal dialysis., Methods: The group examined comprised 141 patients with chronic kidney disease: in pre-dialysis stage (n = 68), haemodialysed (n = 38) and on peritoneal dialysis (n = 35). The concentrations of sCD154 and sCD40 in PRP and PPP were determined with an ELISA method. The biochemical parameters were obtained using colorimetric method., Results: The concentrations of sCD154 and sCD40 in PPP and PRP in examined group were significantly different depending on the method of renal replacement therapy. The haemodialysis procedure caused a significant increase in sCD40 concentration in PRP. The concentrations of sCD40 and sCD154 were correlated with lipid parameters., Conclusions: The type of renal replacement therapy influences on platelet activation which may be a factor contributing to increased cardiovascular complications in patients suffering from CKD., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

The instant blood-mediated inflammatory reaction (IBMIR) has been studied in whole blood models of human allo-islet transplantation for short periods (<6 h). Beyond this time frame the innate response to intraportally transplanted islets is less well described. A novel whole blood model was applied to study blood-islet-graft interactions up to 48 h. Heparinized polyvinyl chloride tubing was sealed into small bags containing venous blood together with allogeneic human islets and exocrine tissue, respectively. The bags were attached to a rotating wheel (37°C). Concentrated glucose and sodium hydrogen carbonate were added every 12 h to maintain physiological limits for sustained immune cell functions. Plasma was collected at repeated time points for analyses of coagulation/complement activation and chemokine/cytokine production. Immune cell infiltration was analyzed using immunohistochemistry. Coagulation and platelet activation markers, thrombin-antithrombin complex (TAT) and soluble CD40 ligand (sCD40L) showed early high concentrations (at 6-12 h). sC5b-9 steadily increased over 48 h. At 6 h neutrophils and monocytes surrounded the clotted cellular grafts with a following massive infiltration of neutrophils. High and increasing concentrations of CXCR1/2 ligands [IL-8 and growth-regulated oncogene α/β/γ (Gro-α/β/γ)] and IL-6 were produced in response to human islets and exocrine tissue. The CCR2 ligand monocyte chemoattractant protein 1 (MCP-1) exhibited increasing concentrations in response to exocrine tissue. The CXCR3 ligand interferon-inducible T cell α chemoattractant (I-TAC) was produced in response to both human islets and exocrine tissue from 6 h. Monokine induced by γ interferon (Mig) and interferon γ-induced protein 10 (IP-10) showed a later response, preferentially to exocrine tissue and with larger variations among preparations. An extended blood model of clinical islet transplantation allowed characterization of early immune activation in response to human islets and exocrine tissue. Increased production of chemokines targeting CXCR1/2, CCR2, and CXCR3 was observed, accompanied by massive intraislet neutrophil infiltration over 48 h. The model proved to be useful in exploring early blood-mediated reactions to cellular transplants and has relevance for evaluation of pharmacological interventions to prevent graft loss.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is caused by genetic and environmental factors. Current evidence shows that the CD40-CD40L system plays a crucial role in the development, progression and outcome of SLE. CD40, which stimulates lymphocyte proliferation and differentiation, is an important immunomodulator and is expressed in the thyroid follicular cells as well as antigen-presenting cells. The aim of the present study was to investigate whether CD40 gene polymorphism confers susceptibility to SLE and its impact on CD40 expression in Chinese. We analyzed four single nucleotide polymorphisms of CD40 gene rs1883832C/T, rs13040307C/T, rs752118C/T, and rs3765459G/A in 205 patients with SLE and 220 age- and sex-matched controls, using Snapshot SNP genotyping assays and DNA sequencing method. Soluble CD40 (sCD40) levels were measured by ELISA. There were significant differences in the genotype and allele frequencies of CD40 gene rs1883832 C/T polymorphism between the group of patients with SLE and the control group (P < 0.05). sCD40 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the CD40 rs1883832 T variant allele were associated with increased CD40 levels compared with the homozygous wild-type genotype in patients with SLE. The rs1883832 C/T polymorphism of CD40 and its sCD40 levels were associated with SLE in the Chinese population. These data suggest that CD40 gene may play an essential role in the development of SLE.

Background: Anti-tumor necrosis factor (TNF) therapy has become a standard therapy for severe inflammatory bowel diseases (IBD), but its effect on B lymphocytes is largely unexplored. In this study we investigated peripheral blood B cells, B-cell subsets, and CD40 expression in patients with IBD before and during anti-TNF therapy with infliximab (IFX)., Methods: Blood was taken from healthy controls (n = 52) and patients with active IBD before (n = 46) and/or during anti-TNF therapy (n = 55). B-cell markers were detected by immunofluorescent staining and FACS analysis. Patients were classified as responders or nonresponders to anti-TNF therapy., Results: We found a numerical deficiency of circulating CD19 B cells, a lower activation state (CD40 expression) and lower proportions of CD5 B cells and IgMIgDCD27 preswitched memory cells among B cells in active patients with IBD before IFX therapy compared with healthy controls. IFX treatment increased CD19 B-cell numbers as well as the proportions of named B-cell subsets in responders but not in nonresponders. IFX more effectively upregulated CD40 expression in responders than in nonresponders. Restoration of B cells correlated with the biological response to therapy (C-reactive protein). Trough serum levels of IFX correlated with the number of B cells during therapy., Conclusions: A lower number of circulating B cells, a low CD40 expression, and a decrease in the proportion of CD5 and in the preswitched memory subset characterize active IBD. Restoration of these abnormalities correlates with the clinical response to anti-TNF therapy. The mechanism for this effect on B cells should be further explored.

Background: Current evidence shows that the CD40-CD40 ligand (CD40-CD40L) system plays a crucial role in the development, progression and outcome of systemic lupus erythematosus (SLE). The aim of this study was to investigate whether a CD40 gene single nucleotide polymorphism (SNP) is associated with SLE and CD40 expression in the Chinese population. We included controls (n = 220) and patients with either SLE (n =205) in the study., Methods: The gene polymorphism was measured using Snapshot SNP genotyping assays and confirmed by sequencing. We analyzed three single nucleotide polymorphisms of CD40 gene rs1883832C/T, rs1569723A/C and rs4810485G/T in 205 patients with SLE and 220 age-and sex-matched controls. Soluble CD40 (sCD40) levels were measured by ELISA., Results: There were significant differences in the genotype and allele frequencies of CD40 gene rs1883832C/T polymorphism between the group of patients with SLE and the control group (P < 0.05). sCD40 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the CD40 rs1883832 C/T variant allele were associated with increased CD40 levels compared to the homozygous wild-type genotype in patients with SLE. The rs1883832C/T polymorphism of CD40 and its sCD40 levels were associated with SLE in the Chinese population., Conclusions: Our results suggest that CD40 gene may play a role in the development of SLE in the Chinese population.

Unlabelled: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta  = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta  = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta  = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta  = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71)  ≤ Pmeta  ≤ 9.92 × 10(-7) )., Conclusion: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease., (© 2015 by the American Association for the Study of Liver Diseases.)

Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is B cell-dependent, although how particular B cell subsets modulate immunopathogenesis remains unknown. Although their phenotype remains controversial, regulatory B cells (Bregs ), play a role in immunological tolerance via interleukin (IL)-10. Putative CD19(+) CD24(hi) CD38(hi) and CD19(+) CD24(hi) CD27(+) Bregs were evaluated in addition to their CD5(+) subsets in 69 patients with ANCA-associated vasculitis (AAV). B cell IL-10 was verified by flow cytometry following culture with CD40 ligand and cytosine-phosphate-guanosine (CpG) DNA. Patients with active disease had decreased levels of CD5(+) CD24(hi) CD38(hi) B cells and IL-10(+) B cells compared to patients in remission and healthy controls (HCs). As IL-10(+) and CD5(+) CD24(hi) CD38(hi) B cells normalized in remission within an individual, ANCA titres decreased. The CD5(+) subset of CD24(hi) CD38(hi) B cells decreases in active disease and rebounds during remission similarly to IL-10-producing B cells. Moreover, CD5(+) B cells are enriched in the ability to produce IL-10 compared to CD5(neg) B cells. Together these results suggest that CD5 may identify functional IL-10-producing Bregs . The malfunction of Bregs during active disease due to reduced IL-10 expression may thus permit ANCA production., (© 2014 British Society for Immunology.)

Introduction: Unstable atherosclerotic plaques are prone to rupture, which leads to atherothrombosis. Endothelial progenitor cells (EPCs) are bone marrow-derived precursor cells that may repair vascular injury in atherosclerosis. Chemokine (C-C motif) receptor 5 (CCR5) promotes mobilization of EPCs. In this study, we investigated the therapeutic potential of CCR5-overexpressing EPCs on plaque stabilization in an apolipoprotein E (ApoE)-/- mouse model., Methods: The expression of CCR5 and its cognate ligand chemokine (C-C motif) ligand 5 (CCL5) was examined in atherosclerotic aortas of humans and mice by immunohistochemistry. Splenectomized ApoE-/- C57BL/6 J mice fed a high-fat diet for 24 weeks were intravenously injected with EPCs transfected with CCR5 overexpression lentivirus. The recruitment of EPCs over the atherosclerotic plaques was evaluated by immunofluorescence. The content of lipid, smooth muscle cells, monocytes/macrophages, and endothelial cells in atherosclerotic plaques was assayed by specific immunostaining. The serum levels of atherosclerosis-related inflammatory factors in ApoE-/- mice were measured by mouse atherosclerosis antibody array I., Results: CCR5 and CCL5 are highly expressed in atherosclerotic plaques in both humans and mice. The ApoE-/- mice with CCR5-overexpressing EPC treatment demonstrated a more stable plaque formation with enhanced recruitment of EPC, reduced lipid, and macrophage content in the atherosclerotic plaques. CCR5-overexpressing EPC treatment also increased the content of endothelial cells and nitric oxide production in the plaques. In addition, the serum levels of interleukin-3 (IL-3), IL-5, IL-6, IL-13, CD40, and tumor necrosis factor-alpha and the plaque contents of IL-6 and matrix metalloproteinase-9 were reduced in mice with CCR5-overexpressing EPC treatment., Conclusions: These findings suggest that CCR5 is a novel therapeutic target in EPC treatment for stabilization of atherosclerotic plaques.

Objective: Hypothalamic-pituitary-adrenal system dysfunction, serotonergic system alterations, and enhanced platelet activity may contribute to the increased cardiac risk in depression. This exploratory study examined associations between cortisol parameters, platelet serotonin (5-HT) content, and platelet activity markers in patients with newly diagnosed major depression (MD) and/or Type 2 diabetes (T2DM) compared with healthy controls., Methods: We compared cortisol awakening response (CAR), diurnal decrease in salivary cortisol concentrations (slope), platelet 5-HT, and platelet markers (CD40, CD40 ligand [CD40L], soluble CD40L, CD62P, β-thromboglobulin, and platelet factor-4) in 22 T2DM patients, 20 MD patients, 18 T2DM patients with MD, and 24 healthy controls., Results: Platelet markers were elevated in MD (F(6,60) = 11.14, p < .001) and T2DM (F(6,60) = 13.07, p < .001). Subgroups did not differ in 5-HT or cortisol slope, whereas T2DM patients without depression had significantly lower CAR than did healthy controls (F(1,61) = 7.46, p = .008). In healthy controls, cortisol slope correlated with platelet activity for CD40 (r = -0.43, p = .048) and 5-HT was correlated with CD40L (r = 0.53, p = .007). In patients with both T2DM and MD, 5-HT and CD62P were correlated (r = 0.52, p = .033)., Conclusions: Increased platelet activity in T2DM and MD may play a role in the association between diabetes, depression, and coronary artery disease. The present data suggest that group differences in cortisol or 5-HT as well as group-specific associations of cortisol or 5-HT with platelet markers might be of limited importance in the shared pathways of T2DM and depression in the pathophysiology of coronary artery disease.

Background: CD40 is an important costimulatory molecule in both cellular 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., (© 2015 S. Karger AG, Basel.)

Objective: This paper aims to investigate the interaction mechanism between pioglitazone/simvastatin and the CD40-CD40 ligand (CD40-CD40L) system and to determine their interaction effects on atherosclerosis in rabbits., Materials and Methods: Forty rabbits were randomly divided into five groups of eight: normal control, hyperlipidemia model, pioglitazone, simvastatin, and pioglitazone combined with simvastatin therapy. The rabbits were raised for 16 weeks. Blood samples and the aortic length were taken after 16 weeks with the following indicators: (1) blood lipid measurement [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)] were measured; (2) measurement of serum high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble CD40 ligand (sCD40L), and matrix metallopeptidase-9 (MMP-9) by enzyme-linked immunosorbent assay; (3) aortic pathological observation and measurement of the area ratios for plaque/intimal; and (4) expression determination of CD40L in plaque parts by immunohistochemistry., Results: In the treatment groups, the levels of TC, TG, LDL-C, hsCRP, sVCAM-1, sICAM-1, sCD40L, and MMP-9 increased, and HDL-C level, plaque/intimal area ratio, and CD40 expression in the plaque parts decreased. Improved effects were also found in the combination treatment group., Conclusions: Pioglitazone and simvastatin may inhibit different functions, such as inflammatory response and lipid regulation, by inhibiting the CD40-CD40L signaling pathway to suppress the formation of atherosclerosis. Therefore, the combined application of pioglitazone and simvastatin has synergistic effects.

Myeloid dendritic cells (mDC) are key mediators of innate and adaptive immunity to virus infection, but the impact of HIV infection on the mDC response, particularly early in acute infection, is ill-defined. We studied acute pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques to address this question. The mDC in blood and bone marrow were depleted within 12 days of intravenous infection with SIVmac251, associated with a marked proliferative response. In lymph nodes, mDC were apoptotic, activated and proliferating, despite normal mDC numbers, reflecting a regenerative response that compensated for mDC loss. Blood mDC had increased expression of MHC class II, CCR7 and CD40, whereas in lymph nodes these markers were significantly decreased, indicating that acute infection induced maturation of mDC in blood but resulted in accumulation of immature mDC in lymph nodes. Following SIV infection, lymph node mDC had an increased capacity to secrete tumour necrosis factor-α upon engagement with a Toll-like receptor 7/8 ligand that mimics exposure to viral RNA, and this was inversely correlated with MHC class II and CCR7 expression. Lymph node mDC had an increased ability to capture and cleave soluble antigen, confirming their functionally immature state. These data indicate that acute SIV infection results in increased mDC turnover, leading to accumulation in lymph nodes of immature mDC with an increased responsiveness to virus stimulation., (© 2014 John Wiley & Sons Ltd.)

The pathophysiological pathways linking particulate air pollution to cardiovascular disease are still not fully understood. We examined the association between ambient air pollutants and blood markers of inflammation and coagulation/fibrinolysis in three potentially susceptible populations. Three panels of non-smoking individuals were examined between 3/2007 and 12/2008: 1) with type 2 diabetes mellitus (T2D, n=83), 2) with impaired glucose tolerance (IGT, n=104), and 3) with a potential genetic predisposition which could affect detoxifying and inflammatory pathways (n=87) defined by the null polymorphism for glutathione S-transferase M1 (GSTM1) in combination with a certain single nucleotide polymorphism on the C-reactive protein (CRP) or the fibrinogen gene. Study participants had blood drawn up to seven times every four to six weeks. In total, 1765 blood samples were analysed for CRP, interleukin (IL)-6, soluble CD40 ligand (sCD40L), fibrinogen, myeloperoxidase (MPO), and plasminogen activator inhibitor-1 (PAI-1). Hourly mean values of particulate air pollutants, particle number concentrations in different size ranges and gaseous pollutants were collected at fixed monitoring sites and individual 24hour averages calculated. Associations between air pollutants and blood markers were analysed for each panel separately and taking the T2D panel and the IGT panel together, using additive mixed models adjusted for long-term time trend and meteorology. For the panel with potential genetic susceptibility, CRP and MPO increased for most lags, especially with the 5-day average exposure (% change of geometric mean and 95% confidence interval: 22.9% [12.0;34.7] for CRP and 5.0% [0.3;9.9] for MPO per interquartile range of PM2.5). Small positive associations were seen for fibrinogen while sCD40L, PAI-1 and IL-6 mostly decreased in association with air pollution concentrations. Except for positive associations for fibrinogen we did not see significant results with the two other panels. Participants with potential genetic susceptibility showed a clear association between inflammatory blood biomarkers and ambient air pollutants. Our results support the hypothesis that air pollution increases systemic inflammation especially in susceptible populations which may aggravate atherosclerotic diseases and induce multi-organ damage., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Adherence to the Mediterranean diet (MD) is associated with reduced morbidity and mortality due to cardiovascular disease. However, how the MD exerts its effects is not fully known., Aim: To assess the 12-month effects of two enhanced MDs compared to a low-fat diet on inflammatory biomarkers related to atherosclerosis and plaque vulnerability in a subcohort of the PREDIMED (Prevención con Dieta Mediterránea) study., Methods: A total of 164 participants at high risk for cardiovascular disease were randomized into three diet groups: MD supplemented with 50mL/d of extra virgin olive oil (MD+EVOO) or 30 g/d of nuts (MD+Nuts) and a low-fat diet. Changes in classical cardiovascular risk factors, inflammatory biomarkers of atherosclerosis and plaque vulnerability were measured after 12 months of intervention., Results: Compared to participants in the low-fat diet group, those receiving MD+EVOO and MD+Nuts showed a higher decrease in systolic (6mmHg) and diastolic (3mmHg) blood pressure (P = 0.02; both), as well as a reduction of 10% and 8% in LDL-cholesterol (P = 0.04), respectively. Patients in the MD+Nuts group showed a significant reduction of 34% in CD40 expression on monocyte surface compared to low-fat diet patients (P = 0.03). In addition, inflammatory biomarkers related to plaque instability such as C-reactive protein and interleukin-6 were reduced by 45% and 35% and 95% and 90% in the MD+EVOO and MD+Nuts groups, respectively (P<0.05; all) compared to the low-fat diet group. Likewise, sICAM and P-selectin were also reduced by 50% and 27%, respectively in the MD+EVOO group (P = 0.04) and P-selectin by 19% in MD+Nuts group (P = 0.04) compared to the low-fat diet group., Conclusions: Adherence to the MD is associated with an increase in serum markers of atheroma plaque stability which may explain, at least in part, the protective role of MD against ischemic heart disease., Trial Registration: www.controlled-trials.com ISRCTN35739639.

Post-stroke epilepsy (PSE) has a negative effect on stroke prognosis and quality of life. The CD40/CD40L system is reported to be involved in the progression of multiple disease states. We investigated the association between functional polymorphism of CD40 and PSE susceptibility, and we also explored the role of the CD40/CD40L system in PSE. A case-control study was performed in 410 ischemic stroke (IS) patients and in 389 PSE patients. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The CD40 mRNA and protein levels were determined by real-time PCR and western blotting, respectively. The plasma sCD40L level was detected using an ELISA kit. The frequency of the T allele in PSE patients was significantly higher than in IS patients (P<0.05). The plasma sCD40L level was significantly higher in the PSE patients than in the healthy controls and IS patients (P<0.01, P<0.05, respectively). The peripheral blood mononuclear cells (PBMCs) from PSE patients showed significantly higher CD40 mRNA and protein expression than the healthy controls and IS patients (P<0.01, P<0.05, respectively). In the PSE patients, the T-allele carriers showed increased plasma sCD40L levels and increased CD40 mRNA expression. Our study suggested that the T allele of the CD40 -1C/T polymorphism may be associated with PSE susceptibility. The CD40/CD40L system is involved in the process of PSE., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

CD40 receptor is activated by ligand CD40L (CD154) which is synthesized in inflammation by NK cells, monocytes and lymphocytes B. TRAF proteins are activated in cells by CD40 stimulation and next they stimulate different enzymatic pathways. High concentrations of CD40L stimulate CD40, and consequently STAT enzyme system inhibits the expression ofnonstructural proteins ofHCV NS3 and NS5A and E2 core in infected human hepatocytes. PURPOSE. The aim of the study was to evaluate the concentration of soluble components of the complex: sCD40 and sCD40L in the serum of patients infected with HCV and HCV/HIV-1 co-infected. The effect ofHCV genotype, HIV and HCV viral load and rs12979860 polymorphism on serum sCD40 and sCD40L was established among the patients. The influence of the number of CD3+, CD4+ and CD8+ on the concentrations of sCD40 and sCD40L was evaluated in the HIV-1 infected group MATERIALS AND METHODS. Serum concentrations of sCD40 and sCD40L were determined using ELISA in 68 HCV infected patients including 39 HCV monoinfected and 29 HCV/HIV-1 co-infected. RESULTS. Serum concentration of sCD40 and sCD40L was significantly higher in HCV and HCV/HIV coinfected patients compared to healthy subjects (25.7 and 23.2 v. 8.5 pg/ml and 12.7 and 7.3 v. 0.79 ng/ml). The concentration of sCD40L in patients with genotype CC rs12979860 was significantly higher compared to patients with Non-CC genotypes (11.8 v. 7.6 ng/ml, p < 0.018). CONCLUSIONS. High levels of sCD40 and sCD40L were detected among patients with chronic HCV and HCV/ HIV-1 infection The high concentration of sCD40L correlates with CC rs12979860 genotype.

In the present study, we aimed to characterize the predictive value of cytokines/chemokines in rectal cancer (RC) patients receiving chemoradiation therapy (CRT). Blood samples were obtained pre- and post-CRT from 35 patients with advanced RC, who received neoadjuvant CRT followed by surgery, and the correlation between plasma levels of cytokines/chemokines and the response to CRT was analyzed. The pre-CRT levels of soluble CD40-ligand (sCD40L) and the post-CRT levels of chemokine ligand-5 (CCL-5) were significantly associated with the depth of tumor invasion and with venous invasion. In addition, a significant decrease in sCD40L and CCL-5, as well as in platelet counts, was associated with a favorable response to CRT. A significant correlation between pre-CRT platelet counts and sCD40L was observed in patients with a favorable response. By contrast, higher post-CRT interleukin (IL)-6 was associated with a poor response. Platelets, immune system and cancer cells, cross-linked through various cytokines/chemokines, appear to play an important role in the response to CRT, and by understanding their roles, new approaches for the improvement of the therapy might be proposed.

Objective: To explore effects and action mechanism of warm moxibustion on regulation of blood lipids and anti-atherosclerosis., Methods: Forty-one male Japanese big-ear white rabbits were randomly divided into a blank group (10 rabbits), a model group (10 rabbits), a moxibustion group (10 rabbits) and a medication group (11 rabbits). Normal diet was applied in the blank group while high-cholesterol diet combined with injection of bovine serum albumin were applied in the rest groups to establish rabbit model of atherosclerosis. After establishment, the model group was not intervened and warm moxibustion was applied in the moxibustion group at "Zusan-li" (ST 36) and "Shenque" (CV 8), 10 min per acupoint per day for continuous 4 weeks. The medication group was treated with intragastric administration of lovastatin capsule (3.6 mg/kg) for continuous 4 weeks. The level of blood lipids, such as total cholesterol (TC), triglyceride (TG), and content of CD40 ligand (CD40L), soluble CD40 ligand (sCD40L) and expression of nuclear factor NF-kappaB were tested after 4 weeks., Results: Compared with the model group, the moxibustion group and medication group could effectively reduce the contents of TC and low density lipoprotein (all P < 0.05), lower the level of sCD40L [(8.310 +/- 1.221) ng/mL in the model group, (7.097 +/- 0.846) ng/mL in the moxibustion group and (7.354 +/- 0.631) ng/mL in the medication group], reduce expression of CD40L [(0.235 +/- 0.179) mm2 in the model group, (0.072 +/- 0.079) mm2 in the moxibustion group and (0.039 +/- 0.015) mm2 in the medication group] and NF-kappaB [(0.145 +/- 0.052)mm2 in the model group, (0.052 +/- 0.012) mm2 in the moxibustion group and (0.036 +/- 0.013) mm2 in the medication group], indicating the significant difference (P < 0.05, P < 0.001). There was no statistical difference between the moxibustion group and medication group (all P > 0.05)., Conclusion: The warm moxibustion has great effect on regulation of blood lipids and anti-atherosclerosis, in which lowering expression of CD40-CD40L could be one of possible mechanisms to take effect of anti-atherosclerosis.

Objective: Accumulating evidence shows that immune cells play an important role in atherosclerosis. Most attention has focused on the role of different T cell subsets, whereas the possible involvement of B cells has been less studied. In this study, we assessed the association of 2 different B cell subsets, CD19(+)CD40(+) and CD19(+)CD86(+) B cells, with risk for development of acute cardiovascular events., Approach and Results: The prospective study included 700 subjects randomly selected from the cardiovascular cohort of the Malmö Diet and Cancer study. Mononuclear leukocytes, stored at -140(○)C at the baseline investigation in 1991-1994, were thawed and B cell subsets analyzed by flow cytometry. Cytokine release from CD3/CD28-stimulated mononuclear leukocytes was measured with multiplex ELISA. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography, and clinical events were monitored through validated national registers during a median/mean follow-up time of 15 years. The subjects in the highest tertile of CD19(+)CD40(+) B cells had a significantly lower risk of incident stroke after adjustment for other risk factors. In contrast, CD19(+)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 observations provide evidence for an involvement of B cells in the incidence of stroke and suggest that both pathogenic and protective B cell subsets exist.

Background: Breast cancer is the most common cancer in women. T cell-based immunotherapy for cancer has attracted much attention recently. CD40 and CD40L occupy an important position of specific immune response. In this paper, we want to study the role of co-stimulatory molecules CD40/CD40L and their clinical significance in peripheral blood of patients with breast cancer., Methods: Thirty breast cancer patients served as observation group, who were diagnosed as having infiltrating ductal breast cancer histopathologically, and 30 healthy as control group. Flow cytometric analysis was conducted to detect the expression of CD40 and CD40L on B and T lymphocytes in peripheral blood. The relationship between the CD40/CD40L expression levels and pathological grades was analyzed., Results: The expression levels of CD40/CD40L on B cells and T cells in breast cancer patients were significantly higher than those in the controls (all P < 0.001), and CD40/CD40L levels had a significant positive relationship with pathological grades (all P < 0.001)., Conclusions: The upregulated levels of co-stimulators CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer.

We aimed to investigate whether atorvastatin influenced the CD40-CD40L pathway in atherosclerosis formation in rats fed a high cholesterol diet. Thirty-six male Wistar rats were divided among 4 groups as follows: control (C), statin (S), 5% cholesterol fed (HC), and statin-administered hypercholesterolemic (HCS). Serum levels of lipids, soluble CD40L, platelet factor 4, and interleukin-6 were assayed with commercial kits. The number of platelets expressing surface P-selectin, CD40, and CD40L were determined by flow cytometry. Aortas were examined for fatty streaks. In the HC group, we observed a significant increase in serum lipid levels and platelet activation markers compared with the control group. Rats in the HCS group had a significant decrease in lipid levels and downregulation in the number of platelets expressing surface P-selectin, CD40, and CD40L compared with the HC group. We observed decreased fatty streak formations in aortas in HCS rats. A positive correlation was found for platelet activation markers and atherosclerotic fatty streak formations. Regression analysis revealed that the predictor of atherosclerosis was CD40L. Our study suggests that in a rat hypercholesterolemic model, statin treatment may influence the CD40-CD40L dyad, and that this effect is parallelled by a suppression of progression of atherosclerotic plaque formation.