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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 4  |  Page : 646-650
Apoptosis of peripheral blood mononuclear cells in patients with sepsis


Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

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Date of Web Publication27-Oct-2010
 

   Abstract 

Context: Recent investigations into the pathogenesis of sepsis reveal an important role for apoptosis. The present study was designed in order to assess the peripheral blood mononuclear cells' (PBMCs) apoptosis and the plasma levels of molecules associated with apoptosis belonging to tumor necrosis factor-alpha (TNF-α)/tumor necrosis factor type-1 receptor (TNFR I) pathway in patients with sepsis. Patients and Methods: Twenty-two patients with sepsis and 20 healthy subjects were included in the study. The percentage of PBMCs' apoptosis was examined using annexin-V at the time of blood draws (0 time). PBMCs were incubated for 24 hour at 37°C in medium (spontaneous apoptosis) and in the presence of TNF-α. After incubation, the percentage of apoptotic cells was counted. Plasma levels of TNF-α and soluble TNFR I (sTNFR I) were also measured by enzyme linked immunosorbent assay (ELISA). Results: PBMCs of patients showed a higher proportion of apoptotic cells than PBMCs of controls at 0 time. After 24 hour incubation, spontaneous apoptosis of PBMCs was nearly as high as that of TNF induced apoptosis. Compared with healthy volunteers, patients with sepsis had elevated levels of TNF-α and sTNFR I. Conclusions: The data indicate that a higher fraction of PBMCs was undergoing apoptosis in vivo in patients than controls. Enhanced in vitro apoptosis has also been observed in patients with sepsis, suggesting that a greater number of mononuclear cells in the peripheral circulation of patients are preprogrammed in vivo to undergo apoptosis. The circulating levels of both TNF-α and sTNFR I from patients were significantly higher (P < 0.001) than controls. The increase in levels of TNF-α is proportional to that of sTNFR I (r = 0.908), indicating that sTNFR I may have a protective effect in the early stage of sepsis.

Keywords: Apoptosis, monocytes, sepsis, soluble tumor necrosis factor type-1, tumor necrosis factor

How to cite this article:
Jadali Z, Amiri MM, Ravanbakhsh M. Apoptosis of peripheral blood mononuclear cells in patients with sepsis. Indian J Pathol Microbiol 2010;53:646-50

How to cite this URL:
Jadali Z, Amiri MM, Ravanbakhsh M. Apoptosis of peripheral blood mononuclear cells in patients with sepsis. Indian J Pathol Microbiol [serial online] 2010 [cited 2019 Dec 11];53:646-50. Available from: http://www.ijpmonline.org/text.asp?2010/53/4/646/72013



   Introduction Top


Sepsis, a systemic inflammatory response to infection, is a major health problem and a leading cause of death worldwide. [1],[2] Current mortality rates ascribable to sepsis are in the 30-40% range and rise to ~70% in specific patient groups like the elderly and those with chronic underlying disorders. [2] Although there is a common view that this reflects contributions from both the host and the pathogen with regard to an improper inflammatory response, there is a lack of agreement as to the key immune mechanisms. [3]

Apoptotic cell death in patients with sepsis holds great significance because it influences immune cells, which are essential during the course of infection. [2] Regulation of cell death is a particular aspect of the host response to infectious stress and is therefore retained under strong control. [2] In recent years, studies have proposed that dysregulated apoptotic immune cell death may contribute to immune dysfunction and multiple organ failure observed during sepsis. [4] The immune cells most affected by this dysregulated apoptotic cell death appear to be lymphocytes. [4],[5] Lymphocytes are essential for immune response to sepsis and their apoptosis was observed both in animal models and in autopsies of patients who had died from sepsis. [6]

There are different pathways for induction of apoptotic cell death and one of them is mediated by death receptors. [2] These receptors are activated upon binding to their corresponding ligands. Ligands include proteins such as Fas and TNF-α. The best studied death receptors are CD95 (Fas or ApoI) and TNFR I (p55 or CD120a). [7] Signaling through some death receptors, such as TNFR I, also mediates various biological activities like inflammation, depending on the cell type, environmental and genetic factors. [8]

In the classical view of sepsis, TNF-α constitutes an essential mediator of sepsis [6] and is an important component of the host immune response to infection. Both inflammation and apoptosis are elicited by TNF-α and its improper production seems to play an essential role in the pathogenesis of a variety of human diseases, including sepsis. [9],[10],[11]

Earlier studies have indicated that sepsis induces extensive lymphocyte apoptosis in different organs such as spleen and intestine. [4],[12],[13] While most studies concentrated on lymphocyte apoptosis in tissues, a few studies have examined the effects of sepsis on circulating lymphocytes. [14] Therefore, in this study, PBMCs of patients with sepsis were examined for apoptosis susceptibility. In addition, we evaluated levels of circulating TNF-α and sTNFR I in the plasma of septic patients before initiation of treatment and compared the results with those in healthy volunteers.


   Patients and Methods Top


Blood samples were collected from 22 patients (9 men and 13 women; mean age 47.6 ± 18.8 years) with sepsis and admitted to intensive care unit of hospital. Sepsis was considered to be present when patients had at least three of the following clinical findings: body temperature of >38ºC or <36ºC, heart rate > 90/min, hyperventilation evidenced by a respiratory rate of >20/min or a PaCO 2 of <4.25 kPa, a white blood cell count of >12 Χ10 9 cells/l or <4 Χ 10 9 cells/l or the presence of >10% immature neutrophils. [15] Patients with history of taking any antimicrobial agent in the 1-month period prior to presentation were excluded. Twenty healthy individuals (11 men and 9 women; mean age 45.2 ± 12.5 years) were used as controls. None of them had shown any sign of infection, and none had taken any previous medication. The study procedure was approved by the hospital ethics committee on human research.

Blood Sampling and Processing

Venous blood was taken from patients and controls (6 mL) and collected in heparinized tubes. All the blood samples were transferred to the laboratory and were used for counting of lymphocytes and measuring the proportion of apoptotic PBMCs. Plasma was separated by centrifugation at 4ºC, aliquoted, and stored at -70ºC, until assayed. The stored plasma was used later for quantifying TNF-α and sTNFR I concentrations. PBMCs were isolated from the whole blood by standard density gradient centrifugation using Histopaque (Pharmacia, Uppsala, Sweden) gradient. PBMCs were harvested from the gradient interface, washed in phosphate buffered saline (PBS), counted in trypan blue, and promptly used for experiments. To determine the proportion of apoptotic PBMCs, flow cytometry analysis was performed in an aliquot (2 Χ 10 6 cells) from the patients or control cells, immediately after their isolation (i.e., at time 0). The remaining PBMCs were divided into aliquots (2 Χ 10 6 cells), and each aliquot was incubated for 24 hour at 37ºC under the following conditions: (a) medium alone; (b) medium plus recombinant TNF-α (Abcam, Cambridge, MA, USA) used at a concentration of 50 ng/mL. After 24 hour incubation, the proportions of PBMCs that underwent spontaneous apoptosis (medium alone) or induced apoptosis (medium plus TNF-α) were analyzed by flow cytometry. The medium used for all experiments was RPMI 1640 (Sigma, Missouri, USA); it was supplemented with 10% fetal calf serum (GIBCO, Orsay, France), 100 μg/mL penicillin, and 100 μg/mL streptomycin, under standard conditions (37ºC, 5% CO 2 , saturated humidity).

Flow Cytometry Analysis

Fluorescein isothiocyanate (FITC) conjugate of annexin-V (Annexin V-FLOUS staining kit, Roche, Penzberg, Germany) recognizing phosphatidylserine (PS) was used in combination with the non-vital dye propidium iodide (PI) to discriminate among three subpopulations: (a) FITC-negative and PI-negative viable cells (FITC-, PI-) that maintain the typical asymmetry of plasma membrane lipids; (b) PI-negative and FITC-positive early apoptotic cells (FITC+, PI-) expressing PS but capable of transporting PI outside the cell; and (c) PI-positive and FITC-positive late apoptotic or necrotic cells (FITC+, PI+) with a loss of plasma membrane integrity. Cells were stained according to the instruction of manufacturer. The analysis was performed by a PA flow cytometer (Partec, Mόnster, Germany). The data were analyzed using FloMax instrument software. Results were represented as percentage of apoptotic to necrotic cells.

Enzyme Linked Immunosorbent Assay

The serum concentrations of TNF-α (Bender Med System) and sTNFR I (Hycult Biotechnology b.v., Uden, The Netherlands) were quantified by enzyme linked immunosorbent assay (ELISA) using commercial kits according to manufacturer's guidelines. Assay sensitivities were 25 pg/mL for human sTNFR I and 6.26 pg/mL for TNF-α.

Statistical Analysis

Results are reported as mean ± SD. The comparison between groups was done using the Mann-Whitney U test. The relationship between two variables was analyzed using Spearman's rank correlation test. The correlation coefficient (r) and its 95% confidence interval are shown. Values were considered statistically significant at P < 0.05.


   Results Top


Spontaneous Apoptosis in Peripheral Blood Mononuclear Cells of Patients with Sepsis

When PBMCs of patients and normal subjects were analyzed at the time of blood draws (time 0) for the presence of apoptotic cells (annexin-V+), only a very small proportion of apoptotic cells was observed. However, even at time 0, a small but very significantly greater proportion of PBMCs (P < 0.001) was apoptotic in patients (1.6 ± 0.45%) than those of normal subjects (0.29 ± 0.18%).

After 24 hour incubation of patients' PBMCs in medium alone, a greater proportion of these cells (2.47 ± 0.58%) became annexin-V+. This proportion was higher (P < 0.001) than that in PBMCs obtained from normal subjects (1.04 ± 0.4%) and examined in parallel with patients' cells in the similar assays.

Induced Apoptosis in Peripheral Blood Mononuclear Cells of Patients with Sepsis

To search for the mechanism of the high apoptotic sensitivity of PBMCs from patients with sepsis, we used TNF-α to induce apoptosis ex vivo in these PBMCs. After 24 hour incubation in medium supplemented with TNF-α, the patients' PBMCs (2.54 ± 0.53%) contained a higher (P < 0.001) proportion of annexin-V+ cells than similarly treated normal control (1.08 ± 0.45%) cells [Figure 1].
Figure 1 :Box plots showing percentages of annexin V+ cells among PBMCs in 22 patients with sepsis and 20 normal controls. There are no significant differences (P=0.657) between values for spontaneous apoptosis and TNF-á-induced apoptosismeasured at 24h.

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We also assayed the percentage of apoptotic cells at two time points, 0 and 24 hours, for all groups. There were differences between 0- and 24 hour apoptosis in patients and controls (P < 0.0001). There were no significant differences (P = 0.657) between values for spontaneous apoptosis and TNF-α-induced apoptosis measured at 24 hour.

Analysis of Serum Tumor Necrosis Factor-a and Soluble Tumor Necrosis Factor Type-1 Receptor Concentrations

TNF-α and sTNFR I were assayed on all samples [Figure 2]. Statistical analysis of these molecules showed that there were significant differences among patients and controls (P < 0.001). In patients and normal controls, mean plasma concentrations of sTNFR I were 696.35 ± 192.37 and 421.63 ± 184.05 pg/mL, respectively. The mean value of TNF-α was 26.14 ± 20.64 pg/mL for the patients. TNF-α was not detec table in normal controls.
Figure 2 :Comparison levels of TNF-α and TNFR I in patient (N=22) and control group (N=20)

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   Discussion Top


The present study was designed to investigate the percentage of annexin-V+ cells within PBMCs of patients with sepsis and to find out whether PBMCs of these patients were predetermined in vivo to undergo spontaneous apoptosis. It would seem likely that such PBMCs are the first to die when incubated ex vivo in medium for 24 hours. Annexin-V binding was used in this study to be able to approximate the proportion of PBMCs in early apoptosis (thus not yet cleared from the circulation).

In the course of this investigation, we found the presence of higher proportions of annexin-V+ PBMCs in patients with sepsis than in normal subjects at the time of blood draw (time 0) and after 24 hour incubation. It means that PBMCs' apoptosis that initiated in vivo proceeded after these cells were placed in medium and incubated. PBMCs from normal controls did not show comparable numbers of apoptotic cells. Therefore, this process seems to be associated with the disease and may have biological significance.

It must be mentioned that these results also support previous studies that examined circulating lymphocyte apoptosis in human sepsis with the annexin-V method used in the present study. [14],[16] Le Tulzo et al. [14] reported that lymphocytes from patients with septic shock had an elevated apoptosis (16.5 ± 3.5%) and this was increased compared with the lymphocyte apoptosis in patients with sepsis but without shock (7.5 ± 1%) and the lymphocyte apoptosis in critically ill (7.5 ± 1.5%), nonspecific patients. In another study, the values of lymphocyte apoptosis for septic patients, patients with septic shock and critically ill, nonspecific patients were 9.4 ± 0.1, 10.6 ± 0.1, and 5.1 ± 0.2%, respectively. [16]

Another interesting aspect of the process of ex vivo apoptosis was that the amount of spontaneous apoptosis at 24 hour was about as high as that induced by exogenous TNF-α. At the first glance, it may be possible to conclude that most PBMCs expressing TNFRs are undergoing apoptosis. Nonetheless, the level of TNF-α-induced apoptosis was not higher than that of spontaneous apoptosis. In other words, there are no significant differences (P = 0.657) between values for spontaneous apoptosis and TNF-a-induced apoptosis measured at 24 hour. These results suggest that PBMCs' apoptosis in sepsis is not TNF-α-dependent, even if we accept increased expression of TNFRs on apoptotic PBMCs in patients. These observations also propose that PBMCs' apoptosis may be due to mechanisms other than TNF-αit is clearly known that at least three pathways are involved in the induction of apoptosis and culminate in caspase activation: the death receptor pathway, the mitochondrial pathway, and the endoplasmic reticulum pathway. [2]

As part of the investigation, we also measured plasma levels of TNF-αand sTNFR I in patients and healthy controls for two main reasons: first, sepsis is characterized by production of the pro-inflammatory cytokines such as TNF-αat the early stage and, second, TNF-α and its receptors play an important role in the induction of apoptosis in sepsis. [6] Our results indicated that TNF-α and sTNFR I were significantly higher in patients than in control individuals. There was also significant positive correlation between TNF-αand sTNFR I [Figure 3].
Figure 3 :Correlation between TNF-α and sTNF-R I in septic patients (N=22) and in controls (N= 20). Spearman's correlation coefficient R= 0.908, P< 0.001

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In our opinion, some important points in interpretation of these data must be considered, especially the positive or negative effects of TNF-αand sTNFR I on disease progression.

Several studies have indicated that death and survival signals can be transmitted through some of the death receptors including TNFR I. [17],[18],[19]

The attachment of TNF to TNFR I triggers a series of intracellular events that eventually culminates in the activation of two essential transcription factors, nuclear factor κB (NF-κB) and c-Jun. These transcription factors are responsible for the inducible expression of genes significant for different biological processes involving cell growth and death. [20] In addition, studies on sepsis have revealed that the frequency of an exaggerated systemic inflammatory response is lower than it was initially considered to be. [21],[22],[23],[24] Although cytokines are thought to be culprits, they also have useful properties in sepsis. Studies using animal model of peritonitis indicated that blocking TNF-α worsens the survival. [25],[26] Combination immunotherapy targeting TNF-α and interleukin-1 receptors was lethal in a neutropenic model of sepsis. [27] It is well known that TNF acts as a double edge sword associated with both pathogenesis and host defense. Whether or not TNF is beneficial or detrimental in sepsis remains to be elucidated.

Analysis of sTNFR I indicated an increase in its circulating levels. In addition, a positive correlation was noted between the levels of sTNFR I and TNF-α in the patients. Therefore, it seems, at least with regard to our patients, that TNF response is maintained under tight control.

Different studies indicate that in concert with the inflammatory response, the host generates counterbalancing anti-inflammatory mediators, such as IL-10 and various soluble cytokine receptors, including sTNFR. [3] Munford and Pugin [28] believe that the body's normal stress response is activation of anti-inflammatory mechanisms and that, outside the involved tissues, the body's systemic anti-inflammatory responses overcome. In the case of TNF, soluble TNF receptors can compete for TNF with the cell surface receptors and therefore inhibit its bioavailability and activity, [29],[30],[31] acting as physiological attenuators of the TNF activity and protecting against its potential harmful effects. [32] It seems that the imbalance between TNF-α and sTNFR could be of great significance in the physiopathology of the development of shock. [32],[33] We would like to remind the fact that apoptosis itself is also anti-inflammatory and prompts the release of anti-inflammatory mediators. [34],[35],[36]

In summary, the results of this study indicated that the percentage apoptosis of PBMCs from patients with sepsis is higher than that of normal controls. Among PBMCs, the level of spontaneous ex vivo apoptosis was nearly as high as TNF-α-induced apoptosis. Moreover, increased levels of spontaneous apoptosis at time 0 in patients with sepsis revealed that a higher fraction of PBMCs was undergoing apoptosis in vivo in patients than in normal subjects. We have also shown that patients with sepsis have higher plasma levels of TNF-α and sTNFR I as compared with that of healthy individuals. Therefore, we propose that these cells are programmed in vivo to undergo apoptosis. The exact mechanism leading to this phenomenon remains to be determined.

 
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Correspondence Address:
Zohreh Jadali
Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.72013

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