Serum sCD40L Levels Research Articles

Soluble CD40 Ligand as a Predictor of Coronary Artery Disease and Long-Term Clinical Outcomes in Stable Patients Undergoing Coronary Angiography

Background: In patients with acute coronary syndrome (ACS), elevated levels of soluble CD40 ligand (sCD40L) are associated with increased risk of cardiovascular events. We evaluated sCD40L levels and future cardiovascular events in patients not experiencing ACS. Methods: Serum sCD40L levels were measured in 909 patients undergoing angiography. A three-way matching scheme (age, gender and catheterization time period) identified 303 patients with coronary artery disease (CAD) who experienced a cardiac event within 1 year (CAD/event), 303 patients with CAD free of events (CAD/no event) and 303 patients without CAD and free of events (no CAD). Results: Average age was 64 ± 11 years; 74% were males. Median (± SE) sCD40L levels were higher for no CAD patients (335 ± 60 pg/ml) compared to CAD (248 ± 65 pg/ml, p = 0.01) and to CAD/event (233 ± 63 pg/ml, p < 0.001). There was no significant difference in median sCD40L levels between CAD/no event and CAD/event patients. Higher sCD40L quartiles were associated with a significant decrease in the risk of CAD/event versus no CAD (quartile 4 versus quartile 1: odds ratio = 0.59, p = 0.03). There was a nonsignificant trend towards a decreased risk of CAD as compared to no CAD, and for CAD/event versus CAD. Conclusions: In non-ACS patients, higher sCD40L levels were associated with a decreased risk of CAD. This novel interaction of sCD40L raises interesting questions for CAD pathogenesis.

Silent Brain Infarction and Platelet Activation in Obstructive Sleep Apnea

Silent brain infarction (SBI) and increased levels of soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) are associated with an increased risk of cerebrovascular disease. The aim of this study was to evaluate whether SBI and serum levels of sCD40L and sP-selectin are increased in patients with obstructive sleep apnea (OSA). SBI was studied by brain magnetic resonance images in 50 male patients with OSA and 15 obese male control subjects who were free of comorbidities. In addition, the effects of 3 months of treatment with nasal continuous positive airway pressure (nCPAP) on serum parameters were studied in 24 patients with moderate to severe OSA. The percentage of SBI in patients with moderate to severe OSA (25.0%) was higher than that of obese control subjects (6.7%) or patients with mild OSA (7.7%). Serum levels of sCD40L and sP-selectin were significantly higher in patients with moderate to severe OSA than in obese control subjects (p < 0.05) or patients with mild OSA (p < 0.05). In addition, nCPAP significantly decreased serum levels of sCD40L (p < 0.03) and sP-selectin (p < 0.01) in patients with moderate to severe OSA. These results suggest that serum levels of sCD40L and sP-selectin are elevated and SBI is more common in patients with moderate to severe OSA, leading to elevated cerebrovascular morbidity. Moreover, nCPAP may be useful for decreasing risk in patients with moderate to severe OSA.

High serum levels of soluble CD40-L in patients with undifferentiated nasopharyngeal carcinoma: pathogenic and clinical relevance.

BackgroundEngagement of CD40 promotes survival of undifferentiated nasopharyngeal carcinoma (UNPC) cells and similar effects are induced by the EBV oncoprotein LMP-1 that is expressed in a fraction of cases. Considering that CD40 may be activated also by the soluble isoform of CD40L (sCD40L), we investigated the serum levels of sCD40L in a series of 61 UNPC patients from Italy, a non-endemic area for this disease.ResultsAt diagnosis, serum samples of UNPC patients contained significantly higher levels of sCD40L than age-matched healthy controls (p < 0.001). High levels of sCD40L (i.e., >18 ng/ml) were more frequently found in patients <40 years of age (p = 0.03) and with distant metastases at presentation (p = 0.03). Serum levels of sCD40L were inversely associated with the expression of the EBV oncoprotein LMP-1 (p = 0.03), which mimics a constitutively activated CD40. The amount of sCD40L decreased in a fraction of patients treated with local radiotherapy alone. Moreover, CD40L+ lymphoid cells admixed to neoplastic UNPC cells were detected in cases with high serum levels of sCD40L, suggesting that sCD40L is probably produced within the tumor mass.ConclusionsCD40L may contribute to CD40 activation in UNPC cells, particularly of LMP-1-negative cases, further supporting the crucial role of CD40 signalling in the pathogenesis of UNPC. sCD40L levels may be useful to identify UNPC patients with occult distant metastases at presentation.

Atherosclerosis risk factors in children of parents with the metabolic syndrome

Background Metabolic syndrome is a constellation of disorders that produces a high risk of atherosclerosis. Endothelial dysfunction is the key event in atherosclerosis and already present even in the childhood. The aim of the present study is to investigate inflammatory and radiological signs of atherosclerosis in children who have parents with the metabolic syndrome. Design and methods Fifty children of parents with the metabolic syndrome and 38 age- and sex-matched controls were studied. Anthropometric measurements, blood pressure assessment, echocardiography, flow-mediated vasodilatation (FMD) which is a non-invasive test for the evaluation of endothelial function and fasting blood measurements including blood glucose, insulin, total cholesterol, HDL cholesterol, triglyceride, hsCRP and soluble CD40 ligand were performed. Results Serum sCD40L and hsCRP levels were significantly higher in the study group compared to the controls. FMD values did not differ between the study and control groups. Increased serum sCD40L levels were positively correlated with body mass index, waist hip ratio, LDL/HDL cholesterol ratio, and the number of metabolic syndrome components in parents, whereas showed negative correlation with the serum HDL cholesterol levels. High hsCRP levels were positively correlated with body mass index and the number of metabolic syndrome components. Multiple regression analysis demonstrated that the number of metabolic syndrome components in parents presented as being a significant predictor of the serum sCD40L and hsCRP levels of their children. Conclusion Our results suggest that children of patients with metabolic syndrome have higher values of the serum markers of inflammation, which may be associated with increased risk for development of cardiovascular disease.

SCD40 Ligand Determined in Maternal and Umbilical Cord Blood in Pregnancies Complicated by Pre-Eclampsia with and without Intrauterine Growth Retardation

Objective: The aim of this study was determination and comparative analysis of the maternal and umbilical cord sCD40L serum levels in pregnancies complicated by pre-eclampsia with and without intrauterine growth retardation (IUGR) and in normotensive pregnancies. Patients and Methods: The study was carried out on 16 patients with singleton pregnancies complicated by severe pre-eclampsia with appropriate-for-gestational-age weight infants and 14 pregnant patients with severe pre-eclampsia complicated by IUGR. The control group consisted of 13 healthy normotensive delivering patients. Five milliliters of blood were taken by venipuncture from each pre-eclamptic patient and from each woman from the control group before active phase of labor and 5 ml of umbilical vein blood were taken immediately after delivery and collected in sterile tubes. Maternal and umbilical serum sCD40L concentrations were estimated using a sandwich ELISA assay. Results and Conclusions: Our results reveal the higher levels of maternal and umbilical sCD40L serum levels in pregnancy complicated by pre-eclampsia with and without IUGR. The mean maternal values were 4.022 ± 2.399 ng/ml in group P, 3.914 ± 2.824 ng/ml in group PI and 0.885 ± 0.064 ng/ml in healthy controls. The mean umbilical values were 2.633 ± 1.984 ng/ml in group P, 2.703 ± 1.996 ng/ml in group PI and 1.112 ± 0.436 ng/ml in the control group. It seems that these higher concentrations of sCD40L protect maternal immune cells bearing CD40 receptor from Fas-mediated apoptosis. Our findings may suggest also enhanced platelet activation in pre-eclamptic patients. It may be one of the factors responsible for the enhanced procoagulatory and proinflammatory properties, and increased cytokine production, and endothelial cell dysfunction in pregnancies complicated by pre-eclampsia.

The levels of sCD30 and of sCD40L in a group of patients with systemic lupus erythematodes and their diagnostic value

CD30/CD30L and CD40/CD40L are molecules from the tumor necrosis factor (TNF) superfamily. They have a major effect on communications between the B and T cells, which leads to control of maturation, proliferation, and apoptosis of those cells. The aim of this study was to compare the levels of a soluble form of CD30 (sCD30) and a soluble ligand CD40 (sCD40L) in patients with systemic lupus erythematosus (SLE) (n=65) and healthy controls (sCD30 n=20, sCD40L n=10) with other parameters of SLE activity. Patients were divided into subgroups according to presence or absence of lupus nephritis (LN; 33 with LN, 32 without LN). The serum levels of selected parameters were assessed also in the subgroups with low active disease characterized by European Lupus Activity Measure (ECLAM) at most 3(n=29) and active disease with ECLAM more than 3 (n=36). The serum levels of sCD30 were 66.0+/-40.2 UI/ml in the whole group. The mean serum levels were 60.0+/-45.2 UI/ml in the subgroups with LN, 67.1+/-38.9 UI/ml in the subgroup without LN, 80.2+/-51.9 UI/ml in the subgroup with active disease, 55.4+/-24.1 UI/ml in the subgroup with low active disease, and finally, 40.1+/-19.2 U/ml in the controls. Significant differences were found between the SLE patients and controls (p=0.0001) and between the active and nonactive groups (p=0.002). A correlation was found between levels of CD30 and ECLAM (r=0.25, p<or=0.05), SLEDAI (SLE Disease Activity Index) (r=0.25, p<or=0.05), C4 component of the complement system (r=0.24, p=0.02), and anti-C1q antibodies (r=0.42, p=0.0001). The levels of sCD40L were 7.4+/-6.7 ng/ml in whole SLE group, 7.0+/-8.1 ng/ml in the subgroup with LN, 8.0+/-4.9 ng/ml in the subgroup without LN, 7.1+/-5.0 ng/ml in the group of patients with active disease, 7.73+/-7.8 ng/ml in the subgroup with low activity, and 2.96+/-1.39.0 ng/ml in the controls. The difference in sCD40L serum levels between patients with SLE and controls was statistically significant (p=0.02). A correlation was found with the anti-C1q antibodies (r=0.21, p=0.05); no other correlations were found. These findings indicate some potential role of both serum parameters in measurement or SLE disease activity, although their usage in the diagnostic of disease requires further investigation.

Influence of pre-analytical and analytical factors on soluble CD40L measurements

The soluble form of CD40L (CD40 ligand), a pro-atherogenic mediator, has emerged as a diagnostic and prognostic marker for cardiovascular events. However, as platelets can shed CD40L upon activation, accurate measurement has proved challenging. The present study addresses the controversy regarding the appropriate specimen and preparation for laboratory evaluation of blood sCD40L (soluble CD40L). Serum and plasma (collected in EDTA, citrate or heparin) were collected from healthy volunteers (n=20), and sCD40L was analysed by ELISA immediately or after one to three freeze-thaw cycles and at different centrifugation speeds. Urine sCD40L levels were measured in subjects with low- and high-plasma sCD40L levels. Serum sCD40L levels (5.45+/-4.55 ng/ml; P<0.001) were higher than in citrate, EDTA or heparin plasma (1.03+/-1.07, 1.43+/-1.03 or 1.80+/-1.25 ng/ml respectively), with no significant differences between plasma preparations. Increasing g values (200-13000 g), which gradually deplete plasma of platelets, yielded lower sCD40L levels. Repeated freeze-thaw cycles significantly (P<0.05) increased sCD40L concentrations in platelet-rich, but not platelet-depleted, plasma (up to 2.4-fold). Bilirubin and haemoglobin interfered positively, and triacylglycerols (triglycerides) and cholesterol quenched CD40L signalling. No sCD40L was detected in urine samples. In conclusion, serum yields higher sCD40L concentrations than plasma; accurate measurements of sCD40L require exclusion of platelets and avoiding their post-hoc activation. Samples with high concentrations of bilirubin, haemoglobin and/or triacylglycerols should be excluded, as these substances interfere with the assay.

The clinical investigation of testing seven cycling markers in patients with coronary heart disease by flow cytometry

目的 探讨7种外周血循环标志物在不同类型冠心病患者中的临床应用价值.方法 对190例可疑冠心病患者,行选择性冠状动脉造影术,确定只少一支冠状动脉直径狭窄≥50%为冠状动脉造影阳性,其中冠状动脉造影阳性组144例,包括稳定性心绞痛(SAP)患者62例,ACS患者82例;冠状动脉造影阴性组46例.应用流式细胞术进行患者血清白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、sCD40L、单核细胞趋化蛋白-1(MCP-1)、可溶性P-选择素(P-selectin)、组织纤溶酶原激活剂(t-PA)、可溶性血管细胞黏附分子(sVCAM-1)的测定.结果 急性冠状动脉综合征组血清sCD40L水平(8.6±5.1)ng/L较稳定性心绞痛组(5.7±4.4)ng/L和冠状动脉造影阴性组(4.1±3.3)ng/L明显升高(P＜0.01),其余标志物在各组间均有统计学意义(P＜0.01).Logistic回归分析显示,冠脉造影阳性组和阴性组,OR值最大的是sCD40L(OR=1.41,95%CI 1.08～1.85);而在稳定性心绞痛组和急性冠脉综合征组间,OR值最大的是sP-selectin(OR=1.06,95%CI 1.02～1.10),而IL-6在两种分组中,也有统计学意义.结论 IL-6、sCD40L和sP-selectin作为冠心病严重程度的估计和监测可能优于其他几种标志物,同时也为进一步解释急性冠状动脉综合征患者斑块不稳定性的病理生理学机制提供有用的佐证。

Effects of atorvastatin and atorvastatin withdrawal on soluble CD40L and adipocytokines in patients with hypercholesterolaemia

Objective — Beyond lipid lowering, statins have pleiotropic effects with favourable benefits against atherogenesis.Withdrawal of statin therapy has been demonstrated to abrogate vascular protective activity and even increase the incidence of thrombotic vascular events.The purpose of this study is to investigate the serial changes of soluble CD40 ligand (sCD40L) and two adipocytokines, adiponectin and resistin, after short-term atorvastatin therapy and withdrawal in patients with hypercholesterolaemia.Methods and results — Thirty-two patients with hypercholesterolaemia received atorvastatin 10 mg/day for 3 months. Serum lipid profiles, and levels of sCD40L, adiponectin and resistin, were assessed before and immediately after 3 months’ statin therapy. Serum levels of sCD40L and adiponectin were also measured on the 3 consecutive days after statin withdrawal. After 3 months’ statin therapy, levels of sCD40L (1.93 ± 1.13 vs. 1.30 ± 0.97 ng/mL), total cholesterol and low-density lipoprotein cholesterol (LDL-C) were all reduced significantly (p < 0.05). However, sCD40L level tended to increase towards baseline on the first and second days after statin withdrawal, but was not significantly elevated until the third day after withdrawal (1.89 ± 1.28 vs. 1.30 ± 0.97 ng/mL, p < 0.05).Total cholesterol and LDL-C levels did not increase during the 3 days of statin withdrawal. No significant changes of adiponectin and resistin levels were shown after statin therapy.Conclusions — These results indicate that the effect of statin on sCD40L level was abrogated after therapy withdrawal, and was independent of serum cholesterol level. Statin therapy did not significantly alter levels of adiponectin and resistin.

Association of soluble CD40 ligand with carotid atherosclerosis in Japanese type 1 diabetic patients

It has recently been shown that the soluble form of CD40 ligand (sCD40L) interacts with CD40 on vascular cells, leading to a variety of proinflammatory responses, and that serum sCD40L levels can be a predictive marker of cardiovascular events. The aim of this study was to estimate sCD40L levels in type 1 diabetic patients to examine a possible association with carotid atherosclerosis. Human sCD40L levels in serum and intima-media thickness (IMT) of carotid artery were examined in 80 Japanese type 1 diabetic patients (27 men and 53 women, age 22.8+/-3.4 years (mean+/-SD), duration of diabetes 13.2+/-6.1 years) and 20 healthy age-matched non-diabetic individuals. Serum sCD40L levels were significantly (p=0.0185) higher in subjects with type 1 diabetes (2.10+/-1.33 ng/ml) compared with non-diabetic subjects (1.35+/-0.88 ng/ml). The greatest IMT (Max-IMT) and averaged IMT (Mean-IMT) were also significantly greater in patients with type 1 diabetes than in control subjects (0.73+/-0.14 vs 0.64+/-0.07 mm, p=0.0041, 0.63+/-0.09 vs 0.57+/-0.06 mm, p=0.0066, respectively). Levels of sCD40L were statistically significantly associated with Max-IMT (r=0.383, p<0.001) and Mean-IMT (r=0.275, p=0.0058). Furthermore, stepwise multivariate regression analyses demonstrated that sCD40L is a determinant of both Max- and Mean-IMT, independently of conventional risk factors. It is suggested that increased levels of serum sCD40L are associated with accelerated atherosclerotic change observed in young patients with type 1 diabetes.

Serum Levels of Platelet Released CD40 Ligand Are Increased in Early Onset Occlusive Carotid Artery Disease

Objective: Soluble CD40 ligand (sCD40L) has been suggested as a key mediator between inflammation and atherosclerosis, and the CD40-CD40L interaction has a role in atherosclerotic lesion progression. We evaluated if platelet released serum sCD40L and sCD40 levels differ between patients with early onset occlusive carotid artery disease and age-matched controls. Methods: sCD40L and sCD40 levels were measured in serum samples of 60 patients with occlusive carotid artery disease and 30 age-matched controls using ELISA. Degree of stenosis of the internal carotid artery (ICA), and intima-media thickness (IMT) in the common carotid artery were measured by high resolution ultrasound. Values are given as mean ± SD. Results: Mean age was 50.9 ± 3.5 and 50.1 ± 3.5 years in the patient and control groups. IMT was significantly thicker in patients than in controls (0.89 ± 0.14 vs. 0.78 ±0.12 mm, p = 0.0003). Serum levels of sCD40L were significantly higher (6.9 ± 5 vs. 4.5 ± 3.0 ng/mL, p = 0.038) in patients, whereas sCD40 did not differ significantly between patients and controls (85 ± 56.9 vs. 79.3 ± 18.7 pg/mL, p = 0.34). IMT did not correlate with sCD40L or sCD40 levels (R = −0.03, p = 0.77; and R = 0.109, p = 0.308, respectively). Conclusions: sCD40L but not sCD40 levels are significantly higher in patients with occlusive carotid artery disease. Platelet derived sCD40L may be a key mediator among inflammation, thrombosis and atherosclerosis.

Inverse correlation between soluble CD40 ligand and soluble CD40 is absent in patients with unstable angina

The CD40/CD40 ligand (CD40L) system mediates inflammatory processes important in atherogenesis and plaque instability. The expression of CD40L on activated T cells was suppressed by soluble CD40 (sCD40) in vitro. However, the relationship between soluble CD40L (sCD40L) and sCD40 in unstable angina (UA) is still unknown. Thirty-seven consecutive patients with recent chest pain or discomfort were recruited. Patients with both Braunwald's class IB-IIIB and with coronary stenosis (or stenoses) of >75% were assigned to the UA group (n = 19, aged 67.2 +/- 8.2 years), and the rest to the control group (n = 18, aged 63.4 +/- 8.7 years). The serum levels of sCD40L and sCD40, and the plasma levels of matrix metalloproteinase (MMP)-9, were measured by enzyme-linked immunosorbent assays. A significantly inverse correlation between sCD40L and sCD40 was shown in the controls (r = -0.72, P = 0.0007), but was absent in the UA group (r = -0.16, P not significant), although there was no statistical significance between these groups in terms of serum levels of sCD40L or sCD40. The difference of the regression slopes of these regression lines was statistically significant (P < 0.01). Additionally, there was a significant correlation between sCD40 and plasma levels of MMP-9 in the patients with and without UA (r = 0.58, P = 0.0096), but no significant correlation between sCD40L and MMP-9 levels (r = 0.00, P not significant). The balance between CD40 and CD40L may be lost in patients with UA. Soluble CD40 expression may also be related to MMP-9 expression in atherosclerotic tissues.

Plasma, Serum, and Platelet Expression of CD40 Ligand in Adults With Cardiovascular Disease

The application of soluble CD40 ligand (sCD40L) as a biomarker has garnered great scientific and clinical interest. However, there are many uncertainties with regard to the biology of sCD40L. Although presumed to be a marker of platelet activation, relative levels in plasma, serum, and platelet expression are unknown, as is the optimal method for its measurement. We measured CD40L from serum, platelet-poor plasma, and platelet surface in adults who had stable cardiovascular disease (CVD) and those who had unstable CVD (n = 40). Plasma sCD40L did not differ significantly between groups. Serum sCD40L was significantly lower (1.4 +/- 1.3 vs 5.2 +/- 3.7 ng/ml, p <0.001) and platelet membrane CD40L expression was higher (1.4 +/- 0.7% vs 0.9 +/- 0.6%, p = 0.03) in unstable compared with stable CVD. When the 2 groups were considered together, there was a significant correlation between plasma and serum sCD40L levels (rho = 0.4, p = 0.02) and negative correlations between plasma (rho = -0.3, p = 0.04) and serum (rho = -0.4, p = 0.01) sCD40L levels with platelet membrane CD40L expression. In unstable CVD, the correlation between sCD40L measurements was poor. Consistent with enhanced platelet activation, there was a positive correlation between platelet aggregation and surface CD40L expression (rho = 0.5, p = 0.02) and between platelet expression of CD40L and P-selectin (rho = 0.4, p = 0.05) in unstable CVD. There was no correlation between CD40L and platelet count or C-reactive protein. Only surface expression of CD40L compared with platelet-derived (plasma) or total (serum) CD40L level proved a reliable marker of platelet function in patients who had stable CVD and those who had unstable CVD. In conclusion, our data demonstrate the complex nature of CD40L and highlight the distinct processes of expression, shedding, and clearance of this ligand in patient populations.

Characterization and application of two novel monoclonal antibodies against CD40L: epitope and functional studies on cell membrane CD40L and studies on the origin of soluble serum CD40L.

CD40 ligand, a 33-kDa cell membrane molecule, a member of the tumor necrosis factor superfamily, is an important costimulatory molecule during immune response. Here, we report on two functional mouse anti-human CD40L monoclonal antibodies 1B1 and 4F1 characterized by flow cytometry, Western blotting, and competition assay. The antibodies bound to distinct CD40L epitopes and therefore resulted in different bioactivity. Both antibodies could induce CD4+ T-cell alloantigenic hyporesponsiveness ex vivo. The antibodies were matched to develop a two-site enzyme-linked immunosorbent assay (ELISA) for soluble CD40L (sCD40L). Using this ELISA assay, we found major differences between plasma and serum sCD40L levels. Because the count of platelet sharply decreased in aplastic anemia (AA) and idiopathic thrombocytopenic purpura (ITP), we further analyzed the sCD40L concentration in the plasma of AA and ITP patients. The results showed that the sCD40L in serum was much lower than that of healthy subjects. These data demonstrate that platelets seem to be a major contributor to sCD40L, though not the only source of sCD40L in serum.

The effect of elevated serum soluble CD40 ligand on the prognostic value in patients with acute coronary syndromes

Background: Increasing evidence shows that high expression of CD40L plays an important role in the pathogenesis of atherosclerosis and coronary artery disease. We evaluated the clinical predictive value of increased serum soluble CD40 ligand (CD40L) in patients with acute coronary syndromes (ACS) and acute chest pain. Methods: Serum levels of soluble CD40 ligand were measured by ELISA in 128 patients with ACS and in 68 patients with acute chest pain. Platelet activation was assessed by flow cytometry. Results: The levels of soluble CD40 ligand were increased in 57.8% patients with ACS (>8.0 ng/ml) and in 35 patients with acute chest pain (>8.0 ng/ml), respectively. The level of soluble CD40 ligand was slightly correlated with measured levels of troponin T ( r=0.21, p<0.05), and the increased soluble CD40L levels (>8.0 ng/ml) were associated with higher risk for AMI, sudden death and recurrent angina. Patients with elevated serum levels of sCD40L and cTnT showed a significantly increased risk of major adverse cardiovascular events (including AMI, sudden death and recurrent angina) in the two groups during 30 days and 6 months of follow-up. Conclusion: In patients with unstable coronary artery disease, elevation of serum soluble CD40L levels indicated an independent increased risk of major adverse cardiovascular events.

Fetal bradycardia following intrauterine platelet transfusion: might elevated levels of donor soluble CD40 ligand play a role?

Fetal bradycardia following intrauterine platelet transfusion: might elevated levels of donor soluble CD40 ligand play a role?

Elevated circulating soluble CD40 ligand in patients with mixed connective tissue disease.

Abnormalities of CD40 ligand have been demonstrated in various kinds of diseases. Our objective was to determine serum soluble CD40 ligand (sCD40L) levels in patients with mixed connective tissue disease (MCTD). Serum sCD40L levels of 23 patients with MCTD and 21 healthy individuals were measured with specific enzyme-linked immunosorbent assays. Serum levels of sCD40L were significantly higher in patients with MCTD than in healthy individuals (median 0.179 ng/ml vs 0.99 ng/ml, 25th-75th percentile; 0.117-0.296 ng/ml vs 0.82-1.70 ng/ml, P<0.005), whereas there were no significant correlation between elevated serum sCD40L levels and clinical or serological features in patients with MCTD. These results suggest that sCD40L plays a role in the pathogenesis of MCTD. Further studies are needed to clarify this.

Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy

ObjectivesIn the present study, we investigated the effects of statins on serum levels of soluble CD40 ligand (sCD40L) in patients with familial hypercholesterolemia (FH). BackgroundAtherosclerotic disease seems to involve inflammatory and immunologic mechanisms, and sCD40L has recently been identified as one of the key players in the atherosclerotic process. HMG-Co A reductase inhibitors, statins, have been recognized as immunomodulators and reduce cardiovascular events and mortality, but the effects of statins on sCD40L has not been clarified. MethodsIn a randomized, double-blind, clinical trial, as part of the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial, 110 patients with FH were given atorvastatin 80 mg/daily (n = 57) or simvastatin 40 mg/daily (n = 53) for two years. ResultsOur main findings were: 1) at baseline patients with FH had significantly higher (approximately 27-fold) serum levels of sCD40L than healthy controls; 2) statin therapy markedly decreased serum levels of sCD40L (approximately 40% reduction); 3) this decrease in sCD40L was found during both “aggressive” (i.e., atorvastatin) and “conventional” (i.e., simvastatin) statin therapy and was not correlated with the degree of reduction in cholesterol levels. ConclusionsOur findings may suggest enhanced CD40L-CD40 interaction in FH and that this inflammatory response may be downregulated by statins.

Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and correlate with CD4(+) T-cell counts.

CD40 ligand (CD40L or CD154) is a costimulatory molecule expressed mainly on activated CD4(+) T cells. Concentrations of the soluble form of CD40L (sCD40L) in serum were determined for a cohort of 77 human immunodeficiency virus type 1 (HIV-1)-infected patients before and after initiation of highly active antiretroviral treatment (HAART) by a quantitative enzyme-linked immunosorbent assay. Circulating sCD40L levels were higher by twofold in untreated patients than in healthy controls (means +/- standard deviations [SD]: 1.41 +/- 1.48 versus 0.69 +/- 0.59 ng/ml; P < 0.001). HIV-1-infected patients classified as CD4 T-cell category 1 had significantly higher sCD40L levels than patients classified as CD4 categories 2 and 3 (mean +/- SD: 2.08 +/- 1.46 ng/ml versus 1.57 +/- 1.58 [category 2] and 0.94 +/- 1.25 ng/ml [category 3]; P = 0.046), while no correlation with clinical categories A, B, and C was found. Individual serum sCD40L levels correlated with CD4(+) T-cell counts (P = 0.039) but not with viral load, gamma globulin levels, or acute-inflammatory-response markers. After 8 to 12 months of HAART, a further threefold increase of serum sCD40L levels, which paralleled the increase of CD4(+) T-cell counts, was observed. These novel findings suggest that sCD40L measurement in HIV-1-infected patients could serve as a new surrogate marker useful in the assessment of treatment efficacy, especially in settings where well-equipped laboratories and funding required for CD4(+) T-cell count and viral load measurements are not available.

Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes.

The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma. To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow. (1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor-agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis. This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes.