Serum sCD40L Levels Research Articles

Reduced Relapse-Free Survival in Colorectal Cancer Patients with Elevated Soluble CD40 Ligand Levels Improved by Vitamin D Supplementation.

Although elevated serum levels of soluble CD40 ligand (sCD40L) were reported in patients with cancer, the importance of high sCD40L levels in clinical oncology remains unknown. We conducted a post hoc analysis of the AMATERASU randomized clinical trial of vitamin D3 supplementation (2000 IU/day) in patients with digestive tract cancer to assess its significance. Serum sCD40L levels were measured by ELISA in 294 residual samples, and were divided into tertiles. In patients with colorectal cancer (CRC), 5-year relapse-free survival (RFS) rates in the middle and highest tertiles were 61.6% and 61.2%, respectively, which was significantly lower than 83.8% in the lowest tertile. A Cox proportional hazard analysis showed that the lowest tertile had a significantly lower risk of relapse or death than the highest tertile even with multivariate adjustment (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.11-0.80; p = 0.016). In the subgroup of CRC patients with the highest tertile of sCD40L, the 5-year RFS rate in the vitamin D group was 77.9%, which was significantly higher than 33.2% in the placebo group (HR, 0.30; 95% CI, 0.11-0.81; p = 0.018 [Pinteraction = 0.04]). In conclusion, elevated sCD40L might be a biomarker of poor prognosis in patients with CRC, but vitamin D supplementation might improve RFS in patients with high sCD40L.

Consecutive high dosing soluble CD40L injection: still ongoing pathway for constructing a murine model of autoinflammation

BackgroundAlthough Behcet’s disease (BD) etiology is not entirely known, we previously demonstrated that soluble CD40L (sCD40L)-induced neutrophil hyperactivity plays a significant role. Few unrepresentative BD animal models have been characterized so far. After serial injections of sCD40L into C57BL/6J and FVB/NJ mice, we tried to create a new mouse model. Methods4-week-old mice C57BL/6J (n = 5/group) and FVB/NJ (n = 2/ group) received serial sCD40L injections intraperitoneally. C57BL/6J received 10 ng, 100 ng, 1µg, 10µg and 40µg or saline (control group - CG) 5x/week. FVB/NJ received 40µg or saline 5x/week. Physical exam and sCD40L serum levels quantification by ELISA were performed weekly. Data extrapolated from BD patients allowed murine targeted pathogenic serum levels inference of 165 ng/mL. After 30 days, animals were euthanized for histological analyses and exsanguinated for anti-Hep-2 cell antibodies quantification and oxidative burst (OxB) assessment by dihydrorhodamine oxidation, before and after stimulation with phorbol myristate acetate (PMA) and analyzed by flow cytometry. ResultsNo phenotypic changes or animal death were detected in any group. Target sCD40L serum levels were exclusively reached by the 40µg group. Reactivity against Hep-2 cells (£1:80, homogeneous pattern) was identified in all treated groups but not in CG of C57BL/6J. C57BL/6J OxB was similar at baseline among all groups of animals (p = 0.076). PMA-stimulated OxB was significantly increased in 100 ng [mean fluorescence intensity (MFI) = 5883.5], 1 µg (7193.5) and 10 µg (MIF = 7483.5) groups compared to CG (3277; p = 0.011). Interestingly, 40 µg group PMA-stimulated OxB (15 834) was significantly higher than all other groups (p < 0.001). FVB/NJ OxB of the CG was lower than the 40µg group both on baseline (respectively, MFI = 1.15 vs 25 082; p = 0.0042) and after PMA stimulus (respectively, MFI = 5038.5 vs 41 343). Mice histological analyzes showed no damage or inflammatory infiltrates in internal organs (cerebral cortex, eye, liver, kidney, small intestine, and colon). ConclusionAlthough no BD-like phenotype observed, OxB alterations and reactivity to Hep-2 cells suggest that it is still possible to establish mouse colonies and obtain a viable experimental model. Furthermore, only serial sCD40L high doses injections (>40 µg 5×/week) exceeded the target pathogenic serum level.

Potential Biomarkers of impulsivity in mild traumatic brain injury: A pilot study

Very few studies have investigated cognition and impulsivity following mild traumatic brain injury (mTBI) in the general population. Furthermore, the neurobiological mechanisms underlying post-TBI neurobehavioral syndromes are complex and remain to be fully clarified. Herein, we took advantage of machine learning based-modeling to investigate potential biomarkers of mTBI-associated impulsivity. Twenty-one mTBI patients were assessed within one-month post-TBI and their data were compared to 19 healthy controls on measures of impulsivity (Barratt Impulsiveness Scale – BIS), executive functioning, episodic memory, self-report cognitive failures and blood biomarkers of inflammation, vascular and neuronal damage. mTBI patients were significantly more impulsive than controls in BIS total and subscales. Serum levels of sCD40L, Cathepsin D, IL-4, Neuropilin-1, IFN-α2, and Copeptin were associated with impulsivity in mTBI patients. Besides showing that mTBI are associated with impulsivity in non-military people, we unveiled different pathophysiological pathways potentially implicated in mTBI-related impulsivity.

SCD40L Is Increased and Associated with the Risk of Gestational Diabetes Mellitus in Pregnant Women with Isolated TPOAb Positivity.

Background Autoimmune disorders are associated with gestational diabetes mellitus (GDM) in pregnant women who were positive for thyroid peroxidase antibody (TPOAb). Soluble CD40 ligand (sCD40L) and soluble interleukin-2 receptor (sCD25) are abnormally expressed in autoimmune diseases and are reliable markers of inflammation. The purpose of this study was to evaluate sCD40L and sCD25 in early pregnancy and investigate their correlation with GDM and TPOAb. Methods A total of 126 pregnant women in the first trimester were enrolled for analysis: 93 were positive for TPOAb and 33 were negative for TPOAb. Demographical and clinical data in early pregnancy were collected. A total of 123 participants underwent a 75 g oral glucose tolerance test in the second trimester. Serum sCD40L and sCD25 levels were measured by ELISA. Results The incidence of GDM was 24.4% in pregnant women with isolated TPOAb positivity in our study. Both sCD40L and sCD25 were positively correlated with TPOAb (r = 0.476, P < 0.001; r = 0.188, P < 0.05). sCD40L was highest in (P < 0.001) Ab-positive women with GDM group (P < 0.05). After adjusting for TPOAb, age, TSH, FT4, triglycerides, and low-density lipoprotein cholesterol, multivariate logistic regression analysis showed that sCD40L was an independent risk factor for GDM in pregnant women with TPOAb positivity (odds ratio = 3.235, 95% confidence interval 1.024–10.218, P < 0.05). Conclusions About a quarter of pregnant women with isolated positive TPOAb might have GDM. sCD40L was an independent risk factor for GDM in women with isolated TPOAb positivity.

Interleukin-31 and soluble CD40L: new candidate serum biomarkers that predict therapeutic response in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease that affects the central nervous system (CNS), varying from relatively benign to severely disabling. Although the roles of several cytokines and chemokines in MS are well established, their roles in MS lesions and evolution remain a matter of debate. Soluble CD40L (sCD40L) is a ligand that induces lymphocyte proinflammatory activity by stimulating the activation and maturation of B cells, promoting isotype switching and affinity hypermutation. Circulating sCD40L levels reflect activation of the CD40-CD40L complex. The interaction between CD40 and CD40L is of fundamental importance, suggesting their role in MS pathogenesis. Interleukin-31 (IL-31) is a proinflammatory cytokine that plays a role in allergies, autoimmune diseases, and is a major factor in several chronic inflammatory diseases. IL-31 triggers the JAK-STAT pathway in several different cell types, to induce proliferation and tissue remodeling in fibroblasts, epithelial cells, and endothelial cells. Some studies have described a correlation between these two cytokines and decreased serum levels of sCD40L and IL-31 after MS treatment, accompanied by a lower inflammatory response. In this review, we emphasize the possible correlation and positive feedback between IL31 and sCD40L in the MS proinflammatory response. We also describe the justification for this hypothesis and whether it is possible to investigate these cytokines as biomarkers of MS.

Increased serum levels of sCD40L were associated with rapidly progressive interstitial lung disease in idiopathic inflammatory myopathies.

Whether coagulopathy exists in development of idiopathic inflammatory myopathies associated rapidly progressive interstitial lung disease (IIMs-RPILD) is unclear. In this study, we aimed to investigate soluble CD40 ligand and D-dimer levels in RPILD patients. Patients with IIMs-ILD were enrolled and classified as RPILD and stable-ILD group. Clinical data, laboratory examinations including coagulation-associated parameters and the myositis antibodies status, chest high-resolution computed tomography (HRCT) findings and treatment regimens were collected and serum levels of sCD40L were detected by ELISA. Univariable and adjusted multivariable cox regression were performed to identify risk factors for 6-month mortality, and further to select predictors for establishing predictive model for RPILD. Eighty patients with IIMs-ILD were enrolled and 34 of them were diagnosed as RPILD while 46 as stable-ILD. Multivariable cox regression showed that albumin<32.4 g/L and sCD40L<1658.55 pg/ml were independent risk factors of short-term mortality in RPILD. A SMAD model consisting of serum sCD40L>1054 pg/ml, anti-MDA5 positivity, albumin<32.4 g/L and D-dimer>0.865 mg/L were generated. The odds for RPILD with SMAD score of 0, 1, 2, 3 and 4 were 0, 26.9%, 66.7%, 91.7% and 100%. The 6-month survival stratified by mild (SMAD score 0), moderate (SMAD score 1 and 2) and severe group (SMAD score 3 and 4) were 100%, 79.5% and 20%, respectively. We established a predictive model for IIMs-RPILD, which provided a clue that coagulopathy might exist in IIMs-RPILD and could help to better treat patients with RPILD. This model awaits further validations.

Evaluation of Pre-miRNA-146a rs2910164 Variations and sCD40 Ligand in Egyptian Patients with Rheumatoid Arthritis

Abstract Background: Patients with Rheumatoid Arthritis (RA) are at greater risk of developing Cardiovascular (CV) events with higher rate of subsequent mortality. MicroRNAs (miR-NAs) such as MiR-146a are thought to have an important role in the pathogenesis of RA. CD40-CD40L interaction is poten-tially involved in atherogenesis and plaque rupture in RA, it can be a risk factor in development of accelerated vascular complications in RA patients. Aim of Work: Our aim is to evaluate the level of sCD40L, investigate the genetic variations (polymorphisms) in pre-miRNA-146a rs2910164 in a cohort of Egyptian RA patients and detect their possible relation to CV risk in RA. Methods: 108 RA patients were enrolled in our study and were divided into 2 groups according to presence and absence of CV risk along with 49 controls. Genotyping of pre-microRNA-146a rs2910164 polymorphism was done by Taq-Man real-time PCR and serum sCD40L levels were measured using human soluble CD40L ELISA assay. Results: sCD40L concentration was significantly lower in RA patients without CV risk and RA patients with CV risk when compared to control group (p < 0.001), but there was no statistically significant difference when comparing both patients' groups (p=0.5). The genotype and allele frequencies of pre-microRNA-146a rs2910164 did not show a statistically significant difference between the studied groups. When comparing RA group without CV risk, RA group with CV risk and control group, GG genotype was 41.8%, 39.6% and 32.7%, GC was 40%, 49.1% and 51% and CC was 18.2%, 11.3% and 16.3%, respectively. G allele frequency in RA without CV risk group, RA with CV risk group and control group was 35.2%, 35.2% and 29.5% and C allele frequency was 34.7%, 31.4% and 33.9%, respectively. Conclusion: Pre-miRNA-146a rs2910164 gene variations were not associated with RA and does not increase the sus-ceptibility to cardiovascular disease. Low serum levels of sCD40L were detected in RA patients irrespective of the presence of cardiovascular risk. Evaluating sCD40L in patients not receiving any treatment and comparing them with post-treatment levels is recommended.

Persistently higher serum sCD40L levels are associated with outcome in septic patients

BackgroundSoluble CD40 ligand (sCD40L) exhibits proinflammatory and procoagulant effects. Recent data indicated that sCD40L plays a significant role in septic patients. The aim of the present study was to determine sCD40L changes in surgical patients without sepsis (SWS) and surgical sepsis patients (SS) during the first 3 days after intensive care unit (ICU) admission and to observe the association between sCD40L and mortality.MethodsTime changes in sCD40L levels were assessed for 3 days after ICU admission in 49 patients with SS and compared with those in 19 SWS patients. Serum sCD40L concentration was detected by ELISA. Survival at 28 days served as the endpoint.ResultsSS had significantly higher sCD40L levels than SWS and control patients. We observed an association between sCD40L levels ≥1028.75 pg/mL at day 2 and 28-day mortality (odds ratio = 7.888; 95% confidence interval = 1.758 to 35.395; P = 0.007). We could not discover any significant differences in sex, presence of septic shock, site of infection, length of stay in the ICU, PaO2/FiO2 ratio, incidence of AKI, ARDS, or type of surgery between nonsurvivors and survivors.ConclusionsSeptic patients show persistently higher circulating sCD40L levels in the first 3 days after ICU admission, and serum sCD40L levels are associated with the mortality of patients with sepsis. Thus, serum sCD40L may be used as a reliable biomarker and therapeutic target in sepsis.

The Proinflammatory Soluble CD40 Ligand Is Associated with the Systemic Extent of Stable Atherosclerosis.

Background and objectives: Polyvascular atherosclerosis is frequent and associated with a high cardiovascular risk, although the mechanisms regulating the atherosclerosis extent to single or multiple arterial territories are still poorly understood. Inflammation regulates atherogenesis and soluble CD40 ligand (sCD40L) is an inflammatory mediator associated with the presence of single-territorial atherosclerosis. We assessed whether the sCD40L expression is associated with the atherosclerosis extent to single or multiple arterial territories and with the atherosclerosis severity in different territories. Materials and Methods: We prospectively enrolled 94 participants with no atherosclerosis (controls, n = 26); isolated coronary atherosclerosis (group 1, n = 20); coronary and lower extremity (LE) atherosclerosis (group 2, n = 18); coronary and carotid atherosclerosis (group 3, n = 12); and coronary, LE, and carotid atherosclerosis (group 4, n = 18). Serum sCD40L levels were quantified. Results: The sCD40L levels (ng/mL, mean (standard deviation)) were 4.0 (1.5), 5.6 (2.6), 7.2 (4.2), 5.9 (3.7), and 5.1 (2.4) in controls and groups 1 to 4, respectively (ANOVA p = 0.012). In nonrevascularized patients, the sCD40L levels were significantly higher in group 2 than in group 1 and were correlated with the number of LE diseased segments. Prior LE bypass surgery was associated with lower sCD40L levels. Coexistence of coronary and LE atherosclerosis was independently associated with the sCD40L levels. Conclusions: The sCD40L levels were increased in stable atherosclerosis, particularly in polyvascular coronary and LE atherosclerosis. The number of LE diseased segments and prior LE revascularization were associated with sCD40L expression. To our knowledge, these are novel data, which provide insights into the mechanisms underlying multi-territorial atherosclerosis expression. sCD40L may be a promising noninvasive tool for refining the stratification of the systemic atherosclerotic burden.

A preliminary study of MMP-9 and sCD40L in patients with coronary slow flow.

To explore the relationship between coronary slow flow (CSF) and both matrix metalloproteinase-9 (MMP-9) and soluble cluster of differentiation 40 ligand (sCD40L). Between July 2016 and September 2019, 80 patients suspected of having coronary heart disease due to chest tightness or other symptoms of chest pain and discomfort were admitted to Nanjing Jiangbei People's Hospital and, following a coronary angiography, were diagnosed as having CSF. These patients were assigned to the coronary slow flow phenomenon (CSFP) group. The control group, or normal coronary flow (NCF) group, consisted of 80 patients with normal coronary angiography results. Following group assignment, enzyme-linked immunosorbent assays (ELISAs) were used to measure and compare the serum levels of sCD40L and MMP-9 between the two groups. Serum levels of sCD40L and MMP-9 in the CSFP group were significantly higher than those in the NCF group (PP<0.05). Additionally, serum levels of adhesion molecules and C-reactive protein (CRP) in the CSFP group were significantly higher than those in NCF group (P<0.05). There was a positive correlation observed between sCD40L levels and adhesion molecule levels in the CSFP group, however, there was no such correlation observed in the NCF group. The CSFP group also had a significantly higher corrected TIMI frame count (CTFC) compared with the NCF group (PP<0.05). Serum MMP-9 levels were higher in patients with CSF, and MMP-9 levels were positively correlated with CTFC. This suggests that chronic inflammation may play a role in CSF pathogenesis and that atherosclerotic plaques may be present in the coronary arteries of CSF patients. Additionally, serum levels of sCD40L, adhesion molecules, and CRP were higher in CSF patients, and CRP levels were positively correlated with CTFC. Adhesion molecule expression is promoted by sCD40L. Increased levels of sCD40L may therefore promote the development of CSF.

Innate immunity is linked to the severity of stable coronary artery disease through sCD40L pathway

Abstract Introduction Soluble CD40 ligand (sCD40L) activates different cell types involved in innate immunity, including macrophages and platelets. The influence of innate immunity, particularly of sCD40L pathway, on stable coronary artery disease (SCAD) expression is not fully understood. We evaluated if sCD40L expression is related to the presence of SCAD and to its clinical and anatomical severity. Methods We prospectively recruited two groups of age- and sex-matched participants: 1) without coronary artery disease (CAD) (calcium score=0, no soft plaques on coronary angioCT scan) (controls); and 2) with stable obstructive CAD (≥50% for the left main, ≥70% for other epicardial vessels, on invasive coronary angiography). Acute atherosclerotic events or coronary artery bypass grafting (CABG) within 12 months, previous percutaneous coronary intervention, heart failure, infection, malignancy and severe renal dysfunction were exclusion criteria. Clinical, laboratorial and anatomical data were prospectively collected. Serum was stored at −80°C and measurements were performed in a blinded fashion, by ELISA (sCD40L Human Quantikine). Results Sixty-three participants were included: 14 controls and 49 patients with SCAD. In SCAD patients, classical cardiovascular risk factors were globally more prevalent and the serum levels of sCD40L (5553±3356 vs 3099±644 ng/mL, p&amp;lt;0.001), leucocytes counts (7.6±1.8 vs 6.4±1.7x109/L, p=0.010), neutrophils counts (4.4±1.5 vs 3.5±1.5x109/L, p=0.010) and neutrophils/lymphocytes ratio (2.4±1.1 vs 1.9±0.7, p=0.019) were significantly higher, while c-reactive protein (CRP) levels did not differ, compared to controls. sCD40L levels were positively correlated with leucocytes (r=0.36) and neutrophils (r=0.28) counts (all p&amp;lt;0.05), but not with CRP. Clinically, sCD40L levels were associated (ANOVA p&amp;lt;0.001) and positively correlated (Pearson r=0.54, p&amp;lt;0.001) with angina severity (Fig. 1A). Anatomically, patients with a higher number of significant coronary artery lesions presented higher sCD40L levels (Fig. 1B); sCD40L levels were positively correlated with the number of: diseased vessels (r=0.33), significant coronary artery lesions (r=0.31), and all coronary artery lesions (r=0.33) (all p&amp;lt;0.05), without correlation with the Gensini score. Linear regression analysis considering clinical and laboratorial data revealed that sCD40L was an independent predictor of CAD severity, as assessed by the number of significant lesions (model: sCD40L β 0.28, 95% CI 0.03–0.34; hypertension β 1.1, 95% CI 0.97–3.64). Among SCAD patients, those with previous CABG (n=15) had lower sCD40L levels than patients waiting for revascularization (n=34) (3317±1680 vs 6793±3631 ng/mL, p&amp;lt;0.001). Conclusions Increased expression of sCD40L was associated with the presence of SCAD, with angina severity and with CAD severity, while previous revascularization was associated with decreased sCD40L levels. Funding Acknowledgement Type of funding source: None

The Interplay Between Innate Immunity (TLR-4) and sCD40L in the Context of an Animal Model of Colitis-associated Cancer.

Several studies have found elevated soluble CD40 Ligand (sCD40L) in the serum of patients with malignancies as well as those with inflammatory bowel disease (IBD). Our goal was to determine the possible causal role of sCD40L in colitis-associated colorectal cancer (CAC) by using the well-established azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. Twelve wild type (WT) and twelve TLR4 knock out (KO) female C57BL6 mice were divided into 4 experimental groups. Six WT and six TLR4 KO mice were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three 7-day cycles of oral 2.5% DSS. The other two groups included 6 WT and 6 TLR4 KO mice that received only water and served as the control groups. The mice were sacrificed after 84 days. All mice in the AOM/DSS WT group developed CAC while all mice from the AOM/DSS TLR4 KO group were protected from CAC. We measured the serum and pathologic tissue levels of sCD40L with quantitative sandwich enzyme-linked immunoassay (ELISA) and found that serum sCD40L was significantly higher in wild-type mice that developed CAC compared to their healthy counterparts (wild-type and TLR-4 KO controls). In comparison, serum sCD40L levels were comparable between TLR-4 KO mice, which are protected from developing CAC, and their healthy counterparts (wild-type and TLR-4 KO controls). Of note, tissue levels of sCD40L were not affected by the development of CAC. Our findings point to the presence of an axis between TLR-4 and sCD40L, which may lead to decreased immunosurveillance and the subsequent development of colitis-associated cancer.

Role of inflammation in initiation and maintenance of atrial fibrillation in rheumatic mitral stenosis - An analytical cross-sectional study.

BackgroundInflammation has been implicated in the initiation and perpetuation of non‐valvular atrial fibrillation (AF). However, there is a lack of similar data on AF in rheumatic heart disease (RHD). The objective of this study was to analyze the association of inflammation as measured by serum inflammatory biomarkers with AF in rheumatic mitral stenosis (Rh‐MS).MethodsA comparative cross‐sectional analytical study was conducted on 181 Rh‐MS patients in normal sinus rhythm (NSR; n = 69), subclinical transient AF (SCAF; detected by 24‐hours Holter monitoring; n = 30) and chronic AF (n = 82). Serum hs‐CRP, IL‐6, and sCD‐40L were assessed using ELISA immunoassay and compared in all groups of Rh‐MS with or without AF.ResultsWe found significantly higher serum hs‐CRP and sCD‐40L levels in the overall AF (Chronic AF + SCAF) group (hs‐CRP: 4.5 ± 3.4 vs 2.3 ± 2.9 mg/L, P < .01; sCD‐40L: 6.4 ± 4.8 vs 3.1 ± 3.4 ng/mL, P < .01) and chronic AF subgroup (hs‐CRP: 4.9 ± 3.4 vs 2.3 ± 2.9 mg/L, P < .01; sCD‐40L: 6.9 ± 5.1 vs 3.1 ± 3.4 ng/mL, P < .01) compared to patients with sinus rhythm. There was a statistically significant graded increase of serum IL‐6 level from the NSR to the SCAF (vs NSR: 6.8 ± 3.9 vs 4.0 ± 2.2 pg/mL, P = .03), and chronic AF subgroups (vs NSR: 9.3 ± 6.5 vs 4.0 ± 2.2 pg/mL, P < .01; vs SCAF: 9.3 ± 6.5 vs 6.8 ± 3.9, P = .05) of atrial fibrillation.ConclusionsElevated levels of serum hs‐CRP, IL‐6, and sCD‐40L were strongly associated with overall AF and also with SCAF and chronic AF in Rh‐MS patients indicating a potential role of inflammation in the pathophysiology of rheumatic AF.

Serum sCD40L levels are increased in patients with psoriatic arthritis and are associated with clinical response to apremilast.

The pathogenesis of psoriatic arthritis (PsA) involves several pathways, including the CD40/CD40L signaling which promotes the release of multiple cytokines. Transmembrane CD40L is also released in soluble form (sCD40L) and phosphodiesterase 4 (PDE4) seems to be involved in its cleavage. We aimed to investigate whether apremilast, a PDE4 inhibitor, could modify circulating levels of sCD40L in PsA patients, and the possible associations of these changes with clinical response. Consecutive PsA patients starting apremilast in routine clinical practice were prospectively observed. Disease Activity of Psoriatic Arthritis (DAPSA), Psoriasis Area Severity Index (PASI), Leeds Enthesitis Score (LEI) and serum samples were collected at baseline and at 6months. Samples were run in a Bio-Plex ProTM plate for sCD40L. To investigate the association of sCD40L level with DAPSA based minor response, low disease activity (LDA) and/or remission at 6months of treatment, multivariate logistic regression models with backward selection (P<0·05) were built. We studied 27patients (16 of 27 women, 59·6%) with PsA and mean age [±standard deviation (s.d.)] of 58·4±10years. A significant reduction of the mean values of DAPSA, LEI and PASI was detected at 6months. Mean serum levels of sCD40L decreased from baseline 5364±2025pg/ml to 4412±2629 at 6months (P=0·01). Baseline DAPSA [odds ratio (OR)=0·80, 95% confidence interval (CI)=0·65-0·98] and sCD40L (OR=1·001, 95% CI=1·0001-1·0027) were independently associated with DAPSA LDA/remission at 6months. In PsA patients, sCD40L levels decrease upon apremilast treatment and might predict short-term clinical response to apremilast.

Different roles of soluble CD40 ligand in central nervous system damage

ABSTRACT Backgroud and purpose: Soluble CD40 ligand (sCD40L) plays an important role in inflammation and autoimmune disorders. There is still a controversy regarding sCD40L in neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). Herein the aims of this study were to evaluate the levels of sCD40L in patients with NMOSD, MS, and other noninflammatory neurological diseases; to investigate its potential relationship with laboratory parameters, glial fibrillary acidic protein (GFAP), thrombopoietin (TPO) and IL-6; and to address whether serum sCD40L levels in acute attacks of NMOSD patients were decreased after treatment with immunoglobulins, plasma exchange, or methylprednisolone.Materials and methods: We enrolled 13 patients with NMOSD, 9 patients with MS, and 9 patients with other noninflammatory neurological diseases. The levels of sCD40L, IL-6 were measured by cytokine multiplex assay. GFAP levels were measured by ELISA.Results: Both serum and cerebrospinal fluid (CSF) sCD40L levels were increased in NMOSD and MS. No differences were found in serum and CSF sCD40L levels between NMOSD and MS. The CSF sCD40L levels were positively correlated with the CSF cell counts in NMOSD, whereas serum sCD40L levels were positively correlated with the albumin index in MS. Furthermore, the levels of CSF sCD40L were positively correlated with CSF GFAP levels in NMOSD. Serum sCD40L levels were correlated with serum TPO levels in MS. No correlation was found between levels of sCD40L and IL-6 in NMOSD and MS. No statistically meaningful difference between NMOSD patients with or without immunotherapy. Conclusions: Our study suggests that sCD40L can contribute to the destruction of the blood-brain barrier in MS, whereas it may contribute to CNS inflammation in NMOSD. The serum sCD40L concentrations were not changed after treatment with immunoglobulins, plasma exchange, or methylprednisolone in acute attacks of NMOSD.

Risk factors associated with myasthenia gravis in thymoma patients: The potential role of thymic germinal centers

Thymomas are associated with a very high risk of developing Myasthenia Gravis (MG). Our objectives were to identify histological and biological parameters to allow early diagnosis of thymoma patients susceptible to developing MG. We conducted a detailed retrospective analysis from a patient database, searching for differences between patients with thymoma-associated MG (MGT, n = 409) and thymoma without MG (TOMA, n = 111) in comparison with nonthymomatous MG patients (MG, n = 1246). We also performed multiplex and single molecule arrays to measure the serum levels of cytokines in these groups of patients and controls (n = 14–22). We identified a set of parameters associated with MG development in thymoma patients: 1) detection of anti-acetylcholine receptor (AChR) antibodies, 2) development of B1 or B2 thymoma subtypes, 3) presence of ectopic thymic germinal centers (GCs), 4) local invasiveness of thymoma, and 5) being a woman under 50 years old. Among these parameters, 58.8% of MGT patients displayed GCs with a positive correlation between the number of GCs and anti-AChR titers. By immunohistochemistry, we found thymic GCs in the adjacent tissues of thymomas encircled by high endothelial venules (HEVs) that could favor peripheral cell recruitment. We also clearly associated MG symptoms with higher IFN-γ, IL-1β and sCD40L serum levels, specifically in MGT patients compared to TOMA patients. Altogether, these analyses allowed the clear identification of histological, in particular the presence of GCs, and biological parameters that would facilitate the evaluation of the probability of the MG outcome postoperatively in thymoma patients.

High Serum sCD40L Levels During the First Week of Malignant Middle Cerebral Artery Infarction and Mortality

Higher circulating soluble cluster of differentiation 40 ligand (sCD40L) levels at admission of an ischemic stroke have been found in nonsurvivor than in survivor patients. The objectives of this study were to determine whether serum sCD40L levels during the first week of a severe malignant middle cerebral artery infarction (MMCAI) are higher in nonsurvivor than in survivor patients and whether they could be used as biomarker of mortality prediction. This multicenter study included patients with severe MMCAI (defined as Glasgow Coma Scale score <9). We determined serum sCD40L concentrations at days 1, 4, and 8 and performed receiver operating characteristic analyses to determine their capacity for 30-day mortality prediction. Nonsurvivors (n= 34) showed higher sCD40L levels on days 1 (P < 0.001), 4 (P= 0.004), and 8 (P < 0.001) than did survivor patients (n= 34). Areas under the curve of serum sCD40L concentrations at days 1, 4, and 8 of severe MMCAI for 30-day mortality prediction were 83% (P<0.001), 89% (P < 0.001), and 87% (P < 0.001), respectively. The findings that nonsurvivors showed higher serum sCD40L levels during the first week of MMCAI than did survivors and that serum sCD40L levels during the first week of MMCAI could be used as a mortality predictor biomarker are 2 novel findings.

Association between the No-Reflow Phenomenon and Soluble CD40 Ligand Level in Patients with Acute ST-Segment Elevation Myocardial Infarction.

Background and objectives: No-reflow (NR) phenomenon is defined as insufficient myocardial perfusion in coronary circulation in the absence of angiographic evidence of mechanical obstruction. The primary mechanisms of the NR occurrence are thought to be high platelet activity and thrombus burden. Soluble CD40 ligand (sCD40L), which is released into the plasma following platelet activation, accelerates the inflammatory process and causes further platelet activation. The aim of our study is to investigate the relationship between the NR phenomenon and sCD40L level in patients with ST-elevation myocardial infarction (STEMI). Methods: A total of 81 acute STEMI patients undergoing primary percutaneous coronary intervention and 40 healthy participants were included in this study. Acute STEMI patients were classified into two groups: 41 patients with the NR phenomenon (NR group) and 40 patients without the NR phenomenon (non-NR group). The serum sCD40L level was measured for all groups. Results: The serum sCD40L level was significantly higher in the NR group than in non-NR and control groups (379 ± 20 pg/mL, 200 ± 15 pg/mL and 108 ± 6.53 pg/mL, respectively; p < 0.001). Univariate regression analysis demonstrated that male sex, age, Gensini score and sCD40L level were the possible factors affecting the occurrence of the NR phenomenon. In multivariate regression analysis, age (odds ratio [OR], 1.091; 95% confidence interval [CI], 1.023–1.163; p < 0.008) and serum sCD40L (OR, 1.016; 95% CI, 1.008–1.024; p < 0.001) remained the independent predictor of the presence of NR. Conclusions: Our study showed that serum sCD40L level was an independent predictor of the NR phenomenon occurrence.

Nonsurviving Patients with Severe Traumatic Brain Injury Have Maintained High Serum sCD40L Levels

Soluble cluster of differentiation 40 ligand (sCD40L) is a member of the tumor necrosis factor family with proinflamatory and procoagulant effects. A previous study found higher serum sCD40L levels at day 1 of traumatic brain injury (TBI) in nonsurviving than surviving patients. Thus the objective of this study was to compare serum sCD40L levels during the first week of a severe TBI between surviving and nonsurviving patients and to determine whether it could be used as a mortality predictor biomarker. In this multicenter study severe TBI patients (with Glasgow Coma Scale score <9) with an Injury Severity Score in noncranial item <9 were included. Serum sCD40L concentrations at days 1, 4, and 8 of TBI were determined. We performed receiver operating characteristic analyses to determine the capacity of 30-day TBI mortality prediction by serum sCD40L levels at days 1, 4, and 8 of TBI. We found that nonsurviving (n= 34) patients in comparison with surviving (n= 90) patients had higher sCD40L levels on days 1 (P < 0.001), 4 (P= 0.004), and 8 (P<0.001) of TBI. We also found that the areas under curve of serum sCD40L concentrations at days 1, 4, and 8 of TBI to 30-day mortality prediction were 82% (P < 0.001), 72% (P=0.01) and 83% (P < 0.001), respectively. The existence of higher serum sCD40L levels in nonsurviving than surviving patients during the first week of TBI and fact that serum sCD40L levels during the first week of TBI can be used as a mortality predictor biomarker are the new findings of our study.

The skewed frequency of B-cell subpopulation CD19+ CD24 hi CD38 hi cells in peripheral blood mononuclear cells is correlated with the elevated serum sCD40L in patients with active systemic lupus erythematosus.

CD19+ CD24hi CD38hi cells play an essential role in maintaining immune homeostasis. CD40 signaling is involved in regulating the induction and function of CD19+ CD24hi CD38hi cells. Changes in B-cell subpopulations and CD19+ CD24hi CD38hi cells have been observed in systemic lupus erythematosus (SLE) patients. Whether changes in the B-cell subpopulation are related to the aberrant CD40 signaling in SLE patients remains unclear. In this study, we examined changes in the levels of CD19+ CD24hi CD38hi cells and CD19+ CD24hi CD38low cells in peripheral blood mononuclear cells and the serum level of soluble CD40 ligand (sCD40L) in 30 patients with SLE. Through routine biochemical assays and flow cytometry assay, we found that (1) the CD19+ CD24hi CD38hi cell subset was upregulated in SLE patients compared to that in healthy controls (HCs) (P < 0.05); (2) the CD19+ CD24hi CD38low cell subset was downregulated in SLE patients compared with that in HCs; and (3) CD38 expression was positively correlated with SLE manifestations and the serum sCD40L level (P < 0.05). In conclusion, the relative level of Bregs is significantly higher in SLE patients than in HCs and is positively correlated with disease activity and sCD40L level.