Downregulation of CD40 Ligand Response in Monocytes from Sepsis Patients

Sinistro, Anna; Almerighi, Cristiana; Ciaprini, Chiara; Natoli, Silvia; Sussarello, Emanuele; Fino, Sara Di; Calò-Carducci, Francesca; Rocchi, G; Bergamini, Alberto

doi:10.1128/cvi.00184-08

Cited by 42 publications

(34 citation statements)

References 54 publications

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“…The main receptor of CD40L is CD40, and it is interesting to note that a recent study demonstrated increased expression of both CD40L and CD40 on monocytes in sepsis [8]. Somewhat in contrast to that observation, Sinistro et al [9] reported that CD40-mediated stimulation of septic monocytes is attenuated in terms of cytokine production and expression of co-stimulatory molecules. CD40L (CD154) is a member of the tumour necrosis factor (TNF) family and is expressed as a transmembrane protein in activated platelets [10].…”

Section: Introductionmentioning

confidence: 51%

Soluble CD40L (CD154) is increased in patients with shock

et al. 2010

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Section: Introductionmentioning

confidence: 51%

Soluble CD40L (CD154) is increased in patients with shock

et al. 2010

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“…And secondly, sepsis induces a number of stimuli that trigger lymphocyte apoptosis (18). Further, we postulate that the persistent lymphopenia seen in non-survivors is most likely due to ongoing sepsis-induced lymphocyte apoptosis secondary to continued release of pro-apoptotic stimuli during the immunosuppressive phase of sepsis (12,32–34). These findings are especially striking because the optimal host response to infection should be to increase lymphocyte proliferation and thereby augment the number of lymphocyte effector cells.…”

Section: Discussionmentioning

confidence: 97%

“…It is well known, however, that monocytes show severe functional deficits which contribute to the immunosuppressive state in septic patients (34–36). Laboratory procedures designed to identify monocytic defects (such as measurement of monocyte human lymphocyte antigen (HLA)-DR expression or ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-_) levels) have successfully been shown to predict survival in septic patients (36–39).…”

Section: Discussionmentioning

confidence: 99%

Persistent Lymphopenia After Diagnosis of Sepsis Predicts Mortality

Drewry¹,

Samra

Skrupky

et al. 2014

Shock

368

333

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Objective To determine whether persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts mortality. Methods Single-center, retrospective cohort study of 335 adult patients with bacteremia and sepsis admitted to a large university-affiliated tertiary care hospital between January 1, 2010 and July 31, 2012. All complete blood cell count profiles during the first four days following the diagnosis of sepsis were recorded. The primary outcome was 28-day mortality. Secondary outcomes included development of secondary infections, 1-year mortality, and hospital and intensive care unit lengths of stay. Results 76 (22.7%) patients died within 28 days. Lymphopenia was present in 28-day survivors (median 0.7 cells/μl × 103 [IQR 0.4, 1.1]) and non-survivors (median 0.6 cells/μl × 103 [IQR 0.4, 1.1]) at the onset of sepsis and was not significantly different between the groups (p = .35). By Day 4, the median absolute lymphocyte count was significantly higher in survivors compared to non-survivors (1.1 cells/μl × 103 [IQR 0.7, 1.5] vs 0.7 cells/μl × 103 [IQR 0.5, 1.0], p < .0001). Using logistic regression to account for potentially confounding factors (including age, APACHEII score, comorbidities, surgical procedure during the study period, and time until appropriate antibiotic administration), day 4 absolute lymphocyte count was found to be independently associated with 28-day survival (adjusted OR 0.68 [95% CI 0.51, 0.91]) and 1-year survival (adjusted OR 0.74 [95% CI 0.59, 0.93]). Severe persistent lymphopenia (defined as an absolute lymphocyte count ≤ 0.6 cells/μL × 103 on the fourth day after sepsis diagnosis) was associated with increased development of secondary infections (p = .04). Conclusions Persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts early and late mortality and may serve as a biomarker for sepsis-induced immunosuppression.

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“…CD40L is expressed on activated CD4 lymphocytes and binds CD40 of monocytes during antigen presentation. Circulatory concentrations of sCD40L are considered a reflection of the expression of CD40L (17). As a consequence, since the levels of sCD40L did not change upon treatment with clarithromycin, whereas the expression of CD86 on monocytes was increased in parallel, it may be postulated that therapy with clarithromycin was accompanied by more efficient antigen presentation.…”

Section: Figmentioning

confidence: 99%

Effect of Clarithromycin in Inflammatory Markers of Patients with Ventilator-Associated Pneumonia and Sepsis Caused by Gram-Negative Bacteria: Results from a Randomized Clinical Study

Spyridaki

Rosario

Antonopoulou

et al. 2012

Antimicrob Agents Chemother

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dOne recent, double-blind, randomized clinical trial with 200 patients showed that clarithromycin administered intravenously for 3 days in patients with ventilator-associated pneumonia (VAP) accelerated the resolution of pneumonia and decreased the risk of death from septic shock and multiple organ dysfunctions (MODS). The present study focused on the effect of clarithromycin on markers of inflammation in these patients. Blood was drawn immediately before the administration of the allocated treatment and on six consecutive days after the start of treatment. The concentrations of circulating markers were measured. Monocytes and neutrophils were isolated for immunophenotyping analysis and for cytokine stimulation. The ratio of serum interleukin-10 (IL-10) to serum tumor necrosis factor alpha (TNF-␣) was decreased in the clarithromycin group compared with the results in the placebo group. Apoptosis of monocytes was significantly increased on day 4 in the clarithromycin group compared with the rate of apoptosis in the placebo group. On the same day, the expression of CD86 was increased and the ratio of soluble CD40 ligand (sCD40L) to CD86 in serum was unchanged. The release of TNF-␣, IL-6, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by circulating monocytes after stimulation was greater in the clarithromycin group than in the placebo group. The expression of TREM-1 on monocytes was also increased in the former group. These effects were pronounced in patients with septic shock and MODS. These results suggest that the administration of clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators in patients with sepsis; this was accompanied by more efficient antigen presentation and increased apoptosis. These effects render new perspectives for the immunotherapy of sepsis.

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Downregulation of CD40 Ligand Response in Monocytes from Sepsis Patients

Cited by 42 publications

References 54 publications

Soluble CD40L (CD154) is increased in patients with shock

Soluble CD40L (CD154) is increased in patients with shock

Persistent Lymphopenia After Diagnosis of Sepsis Predicts Mortality

Effect of Clarithromycin in Inflammatory Markers of Patients with Ventilator-Associated Pneumonia and Sepsis Caused by Gram-Negative Bacteria: Results from a Randomized Clinical Study

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