Depletion of Dendritic Cells, But Not Macrophages, in Patients with Sepsis

Hotchkiss, Richard S.; Tinsley, Kevin W.; Swanson, Paul E.; Grayson, Mitchell H.; Osborne, Dale F.; Wagner, Tracey H.; Cobb, J. Perren; Coopersmith, Craig M.; Karl, Irene E.

doi:10.4049/jimmunol.168.5.2493

Cited by 333 publications

(273 citation statements)

References 24 publications

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“…A possible explanation of mDC loss may be the increased apoptosis rate which we found in septic PBDC with respect to controls. These observations are consistent with previous observation indicating that DC in lymph nodes and spleen undergo caspase-mediated apoptosis during experimental sepsis, (26,28) and that spleens from patients who died of sepsis exhibited extensive apoptotic DC loss (33).…”

Section: Dendritic Cells In Severe Sepsissupporting

confidence: 82%

“…The procedures followed were in accordance with the ethical standards of the institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Severe sepsis and septic shock were defined according to the 1992 Consensus Conference of the American College of Chest Physicians/Society of Critical Care Medicine (33). Patients were enrolled in the study in the presence of a documented or suspected infection and sepsis-induced failure of at least two organs or systems that lasted no longer than 48 h at the time of screening.…”

Section: Materials and Methods Patients And Study Designmentioning

confidence: 99%

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Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Riccardi¹,

Porta²,

Rovati³

et al. 2010

Cytometry

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Background: Dendritic cells (DC) play a key role in cell-mediated immunity. We aimed to analyse the number and function of peripheral blood (PB) myeloid and plasmacytoid DC (mDC/pDC) in patients with severe sepsis.Methods: Twenty-six septic patients, 20 surgical patients (abdominal aortic aneurysm) and 20 healthy controls were enrolled in this prospective study.Results: At day 1 (enrollment in the study), septic patients showed in comparison with healthy controls, decreased mDC (P < 0.001) and increased pDC (P 5 0.03), resulting in a reduction of the mDC/ pDC ratio (P < 0.001). Surgery induced a decrease in both mDCs and pDCs level, without modification of mDC/pDC ratio. Septic patients included 15 survivors and 11 nonsurvivors. At day 1 no significant difference was found in mDC between the two groups, while pDCs were significantly higher in nonsurvivors (P 5 0.03). At the outcome, mDC were selectively increased with respect to day 1 in survivors (P 5 0.001), while no significant differences were observed as far as pDC count is concerned in both groups. Sorted DC from septic patients showed in comparison with healthy controls, reduced levels of HLA DR (P < 0.001), CD11c (P < 0.001), CD83 (P 5 0.006) and of costimulatory molecule CD86 (P 5 0.003); an up-regulation of chemokine receptor CXCR4 (P 5 0.031) and increased apoptosis (P < 0.001).Conclusions: Sepsis has a profound effect on PB DC compartment. These alterations appear to be sepsisspecific. Increased apoptosis and alteration of migration and trafficking mechanism may be involved in DC compartment modification. DC alterations could contribute to sepsis-mediated immunoparalysis. V C 2010 International Clinical Cytometry Society

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Section: Dendritic Cells In Severe Sepsissupporting

confidence: 82%

Section: Materials and Methods Patients And Study Designmentioning

confidence: 99%

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Riccardi¹,

Porta²,

Rovati³

et al. 2010

Cytometry

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“…Forty to 50% losses of both total (CD11c high ) and lymphoid (CD8␣ ϩ ) DC populations were seen within 24 h. Similar results have been observed by others (11,12), and Hotchkiss et al (13) have reported an increased loss of DCs from the spleens of patients who had died from sepsis. Furthermore, the intrapulmonary installation of bone marrow-derived DCs prevented lethal Aspergillosis infection in septic animals (14), suggesting a functional role for DCs in opportunistic fungal infections in the lung during sepsis.…”

supporting

confidence: 77%

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Scumpia¹,

McAuliffe²,

O’Malley³

et al. 2005

The Journal of Immunology

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CD11c+ dendritic cells (DCs) are APCs that link innate and adaptive immunity. Although DCs are lost from spleen and lymph nodes in sepsis, their role in outcome remains unclear. Transgenic mice (B6.FVB-Tg.Itgax-DTR/EGFP.57Lan/J) expressing the diphtheria toxin (DT) receptor on the CD11c promoter (DCKO mice) received 4 ng/kg DT, which resulted in depletion of 88–95% of mature myeloid and lymphoid DCs, with less depletion (75%) of plasmacytoid DCs. Pretreatment of DCKO mice with DT resulted in reduced survival in sepsis compared with saline-pretreated DCKO mice (0 vs 54%; p < 0.05) or DT-treated wild-type littermates (0 vs 54%; p < 0.05). This increased mortality was not associated with either increased bacteremia or plasma cytokine concentrations. Intravenous injection of 107 wild-type DCs improved survival in DCKO mice (42 vs 0%; p = 0.05). These data confirm that DCs are essential in the septic response and suggest that strategies to maintain DC numbers or function may improve outcome.

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“…Concominantly, there is substantial depletion of DC along with increased levels of circulating Treg [31][32][33]. However, the mechanism of how DC apoptosis can contribute to immunosuppression in sepsis is unclear.…”

Section: Discussionmentioning

confidence: 99%

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

et al. 2010

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DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-b1, which induced differentiation of naïve T cells into Foxp3 1 Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3 1 Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.Key words: Apoptosis . Autoimmunity . DC . Tolerance Introduction DC are professional antigen-presenting cells, which are well positioned in peripheral tissues to capture foreign antigens. DC are phagocytic and can ingest apoptotic cells, and hence are affected by the death of other cells in close proximity [1][2][3]. Clearance of apoptotic cells results in their removal from tissues, and provides protection from release of pro-inflammatory contents. Necrotic cells impact the immune response by acting as ''danger signals'', whereas apoptotic cells are cleared without an immunological response [3,4]. Studies have identified necrotic cells acting as adjuvants, whereas apoptotic cells have been reported as immunogenic [5][6][7] or immunosuppressive [8,9]. DC apoptosis in itself is an important event for maintenance of tolerance. Defects in DC apoptosis have been linked to the development of autoimmunity with systemic autoimmune diseases modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. However, it is unclear how defects in DC apoptosis 1022can trigger autoimmune responses. Furthermore, spontaneous DC apoptosis has been reported in sepsis as well as breast cancer patients with its significance being unclear [14][15][16]. Most patient deaths associated with sepsis occur at later time points and are associated with prolonged immunosuppression [17]. In this later stage, there is marked apoptosis of DC, with no effects on macrophage and neutrophil apoptosis. In addition, immunostimulants such as CpG DNA inhibit DC apoptosis [18], whereas the deficiency of pro-apoptotic Bim protein in DC results in autoimmunity [19].Immature DC have the ability to acquire protein complexes or soluble antigen using many different pathways such as macropinocytosis, endocytosis and even through ingestion of entire cells. Despite the importance of DC apoptosis in the immune response, studies ...

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Depletion of Dendritic Cells, But Not Macrophages, in Patients with Sepsis

Cited by 333 publications

References 24 publications

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

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Depletion of Dendritic Cells, But Not Macrophages, in Patients with Sepsis

Cited by 333 publications

References 24 publications

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

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Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg