Monocyte Anergy in Septic Shock Is Associated with a Predilection to Apoptosis and Is Reversed by Granulocyte‐Macrophage Colony‐Stimulating Factor Ex Vivo

Williams, Marc A.; Withington, Stuart; Newland, Adrian C.; Kelsey, Stephen M.

doi:10.1086/314447

Cited by 87 publications

(55 citation statements)

References 54 publications

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“…Given the link between severity of acute hepatic dysfunction and monocyte HLA-DR expression in AALF, the question arises as to whether the reduced surface expression of this molecule is of pathogenic significance. Functional analyses of monocyte function in ALF 11,14 and conditions characterized by reduced monocyte HLA-DR surface expression clearly demonstrate that these cells with reduced HLA-DR expression are "dysfunctional" as a consequence of their impaired ability at presenting antigen and at producing TNF-␣ following lipopolysaccharide stimulation, 21,32,33 the latter defect being directly linked to the development of recurrent bacterial and opportunistic infections. 21 Because cytokines are known to directly influence the expression of monocyte HLA-DR, we measured both proinflammatory (TNF-␣, IL-6) and anti-inflammatory (IL-10) cytokines in the circulation of our AALF patients and found elevated serum levels of both.…”

Section: Discussionmentioning

confidence: 99%

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

et al. 2006

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Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non-acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n ‫؍‬ 26) and spontaneous survivors (AALF-S, n ‫؍‬ 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-␣ and interferon (IFN)-␥ were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%, P < .001) and NAALF (22 %, P < .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%, P < .001) and higher levels of IL-4, IL-6, IL-10 and TNF-␣ (P < .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r ‫؍‬ ؊0.8 to ؊0.5, P < .01), IL-10 (r ‫؍‬ ؊0.8, P < .0001), TNF-␣ (r ‫؍‬ ؊0.4, P ‫؍‬ .02). HLA-DR percentage level <15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis. In conclusion, the strong relationship of monocyte HLA-DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis. (HEPATOLOGY 2006;44:34-43.)

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Section: Discussionmentioning

confidence: 99%

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

et al. 2006

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“…While the pro-inflammatory response is characterized by a release of cytokines such as interleukine-1β (IL-1β), IL-6 and tumor-necrosis factor α (TNF-α) as well as the activation of endothelial cells and components of the coagulation system, compensatory anti-inflammatory mechanisms are associated with an increased expression of anti-inflammatory mediators, i.e., IL-1 receptor antagonist (IL-1RA), IL-4 and IL-10 (7). The failure of the cellular immune response i.e., due to an increased apoptosis of lymphocytes (8) or the dysfunction of antigen-presenting cells like monocytes (9) indicates the resulting net sepsis-induced immune suppression (7).…”

Section: Introductionmentioning

confidence: 99%

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

et al. 2016

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Sepsis and septic shock are associated with high mortality rates and remain a serious menace for the critically ill patient. Concurrent activation of pro-and anti-inflammatory pathways and an excessive cytokine release represent initial key features in the deregulation of the humoral and cellular antimicrobial defense. Research of the last decades addressed both the ebullient inflammation as well as the resulting longterm failure of the host immunity. While the reestablishment of an adequate immune-competence is still under investigation, many promising experimental trials to limit the inflammatory response during sepsis were challenged by missing beneficial effects in clinical studies. Nevertheless, due to advanced knowledge about the complex regulation of inflammatory mediators and their overlapping involvement in other potentially life-threatening diseases, further evaluation of these approaches in relevant subgroups could help to identify critically ill patients with potential benefit from anti-inflammatory therapies.

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“…These abnormalities include a shift from a proinflammatory TH1 to an antiinflammatory TH2 lymphocyte profile, a loss in cellular MHC II expression, and a profound apoptosisinduced depletion of CD4 T and B cells (5,(11)(12)(13)(14)(15). The sepsis-induced apoptosis of lymphocytes may be particularly important not only because of the extensive lymphocyte loss but also because of a potential immunosuppressive effect of apoptotic cells on the immune system.…”

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confidence: 99%

Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

Hotchkiss

Chang

Grayson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

171

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In sepsis, both necrotic and apoptotic cell death can occur. Apoptotic cells induce anergy that could impair the host response, whereas necrotic cells cause immune activation that might result in enhanced antimicrobial defenses. We determined whether adoptive transfer of apoptotic or necrotic cells impacted survival in a clinically relevant sepsis model. We also evaluated the effects of adoptive transfer of apoptotic or necrotic cells on the prototypical TH1 and TH2 cytokines IFN-␥ and IL-4, respectively. C57BL6͞J mice had adoptive transfer of apoptotic (irradiated) or necrotic (freeze thaw) splenocytes. Controls received saline. Apoptotic cells greatly increased mortality, whereas necrotic splenocytes markedly improved survival, P < 0.05. The contrasting effects that apoptotic or necrotic cells exerted on survival were mirrored by opposite effects on splenocyte IFN-␥ production with greatly decreased and increased production, respectively. Importantly, either administration of anti-IFN-␥ antibodies or use of IFN-␥ knockout mice prevented the survival benefit occurring with necrotic cells. This study demonstrates that the type of cell death impacts survival in a clinically relevant model and identifies a mechanism for the immune suppression that is a hallmark of sepsis. Necrotic cells (and likely apoptotic cells) exert their effects via modulation of IFN-␥. Sepsis is the leading cause of death in many intensive-care units and currently ranks as the 12th most common cause of death in America (1). Septic patients are severely immune suppressed as typified by their loss of delayed type hypersensitivity, inability to eradicate their primary infection, and a predisposition to develop secondary nosocomial infections (2-6). A feature illustrative of the immune suppression in septic patients is their failure to respond to skin testing with antigens derived from microbes to which previous exposure occurred (positive controls) (2, 7). Animal studies indicate that the immune defect in sepsis may be critical to the pathogenesis and resultant mortality (8-10). Evidence to support this contention is also provided by a recent clinical trial using IFN-␥. Administration of this cytokine, which is a potent macrophage activator and an inducer of the TH1 response, improved survival in patients with sepsis (11).A number of defects in the immune system have been reported in sepsis. These abnormalities include a shift from a proinflammatory TH1 to an antiinflammatory TH2 lymphocyte profile, a loss in cellular MHC II expression, and a profound apoptosisinduced depletion of CD4 T and B cells (5,(11)(12)(13)(14)(15). The sepsis-induced apoptosis of lymphocytes may be particularly important not only because of the extensive lymphocyte loss but also because of a potential immunosuppressive effect of apoptotic cells on the immune system. Recent work has demonstrated that uptake of apoptotic cells by phagocytic cells stimulates immune tolerance by the release of antiinflammatory cytokines and suppression of release of proinflammatory cytokin...

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Monocyte Anergy in Septic Shock Is Associated with a Predilection to Apoptosis and Is Reversed by Granulocyte‐Macrophage Colony‐Stimulating Factor Ex Vivo

Cited by 87 publications

References 54 publications

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis

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