Sepsis is a common disease in western society. With an annual incidence of 2–3 per 1,000 population, sepsis may account for as many deaths as acute myocardial infarction (1). Sepsis affects all age groups but is more prevalent at the extremes of age, and particularly with increasing age. With an increasing proportion of older age groups in the developed world, sepsis is becoming increasingly prevalent in western society. While the case fatality rate of sepsis in western society is decreasing, as the incidence of sepsis increases, the overall mortality is increasing (2). However, despite recent advances in supportive care, sepsis mortality rates remain disturbingly high at nearly 30% (3). With improved support of failing organ systems for patients with septic shock, patients with severe sepsis and septic shock endure a prolonged illness, often characterised by recurring health care associated infections (4,5). Thus while patients with septic shock commonly recover from the infection that precipitated their initial illness, they frequently succumb to subsequent health care associated infections. Why does this happen?
Surprisingly the pathophysiology of sepsis in humans remains a conundrum. Early sepsis research focused intensively on the concept that septic shock, and sepsis-related organ dysfunction, were induced by an exuberant pro-inflammatory response to systemic bacterial products, notably the bacterial cell wall molecule lipopolysaccharide (LPS). Evidence supporting this idea accrued from experiments involving blockade of molecular mediators of inflammation that improved outcome in experimental animal and bench models of sepsis (6,7). The results of these experiments formed the rationale for human trials investigating cytokine antagonism in sepsis. Subsequently clinical trials have failed to show a consistent benefit from this therapeutic approach, with some even demonstrating worse outcome in patients (8,9).
These failures have given rise to increasing concerns regarding the broader applicability of various animal sepsis models to humans (10,11). The complex interplay between circulating bacteria and the innate immune response was further elucidated in studies examining human cytokine responses following exposure to live bacteria. Apparently the initial inflammatory response to pathogens may be beneficial, as it appears crucial in the priming of immune responses required to eventually clear infection (12). Furthermore an anti-inflammatory cytokine response to infection may not be beneficial, as for example the archetypic anti-inflammatory cytokine IL10, which is an important factor contributing to impairment of bacterial clearance in pulmonary sepsis (13).
Gene arrays provide a useful platform to study genome-wide transcription patterns in lymphocytes of patients with sepsis. A systematic review of array-based transcription profiling in human sepsis, published in 2010, reviewed 12 microarray based studies including 784 patients, and performed between 1987 and 2010 (14). An immediate activation of both pathogen recognition receptors and associated signalling pathways is apparent from these studies. Yet there was no evidence supporting distinctive pro or anti-inflammatory phases of gene transcription in these studies of septic patients. It was also notable that in many of these genes array studies unequivocal evidence of immune suppression was observed, with non-survivors down-regulating genes linked to antigen presentation and those characterising T cell activation.
Pathogen or host
The relative importance of the pathogenic attributes of infecting microorganisms in the pathophysiology of sepsis may have been overstated, particularly in comparison to the significance of the human immune response to infection. Evidence for this is provided by results of gene expression profiling, again using microarrays, in patients with staphylococcal infection (15). In this study the clinical characteristics of infection were associated with host gene transcription patterns, rather than any bacteriologic virulence factor. This hypothesis, that the human host response is of pivotal importance in the pathophysiology of sepsis in patients, and of equal or greater importance than the type of infection, is supported by other studies demonstrating similar gene expression patterns in patients with gram positive and gram negative infections (16,17). Lastly a recent study comparing cytokine gene expression in an enriched pool of monocytes and T lymphocytes reported a highly significant link between pattern of cytokine gene expression and clinical disease severity, regardless of the nature of the infectious pathogen (18).
As an appreciation of the importance of immune compromise in the pathophysiology of human sepsis and health care associated infection is gaining more widespread acceptance, at this juncture it is worthwhile reviewing the evidence for specific aspects of immune deficiency in septic patients (19).
In human immunity monocytes are the principle lymphocytes of innate immunity, and act as antigen presenting cells (APC), to activate T lymphocytes of the adaptive immune system. It is crucially important to understand that regulation of T lymphocyte activation is mediated by monocyte surface human leukocyte antigen DR (HLA-Dr) expression, and by monocyte costimulatory ligands and cytokines. Activation of adaptive immune T lymphocytes is required to clear bacterial infection in humans.
Monocyte, macrophages and dendritic cells are classed as professional APCs, by nature of their ability to present antigens bound by surface HLA molecules, thereby activating T cells of the adaptive immune system. Co-stimulatory molecules that are present on the monocyte surface are essential co-factors for T cell activation. Human circulating monocyte populations may be broadly characterised on the basis of the expression of the antigens CD14 and CD16 (20,21). Although the CD14+/CD16+ monocyte subset are responsible for production of cytokines important in sepsis immune responses (22-24), monocytes contribute little to the overall levels of increased cytokines that are found in the blood of septic patients, despite their known function as cytokine secreting cells (25).
Monocytes of patients with sepsis express surface receptors that typify an overall activation state. These receptors include the immunoglobulin receptor CD64, in addition to CD163 (a scavenger receptor for the haemoglobin/haptoglobin complex) and CD206 (a mannose receptor) (26). Both surface expression of Toll receptors, and expression of Toll receptor genes TLR-2 and TLR-4, are increased on monocytes of patients with sepsis (27). Collectively these receptors characterise an appropriate activation state that is to be expected as a normal response in a patient with an infection (26,28).
Monocytes of patients with sepsis are however less responsive than those from healthy controls (29). LPS-induced monocyte tumor necrosis factor α (TNF-α) production is decreased in patients with sepsis, and has been used as an index of immune responsiveness in patients with sepsis, identifying patients likely to benefit from an immune adjuvant, such as granulocyte monocyte-colony stimulating factor (GM-CSF) (30). Furthermore, increased gene expression of inhibitory Toll receptor signalling molecules that have been reported in monocytes in patients with sepsis may predict subsequent mortality (31), and may be predictive of both subsequent staphylococcal bacterial co-infection and mortality in children with influenza (32).
Cytokine production by monocytes is inhibited by IL10, and archetypic anti-inflammatory cytokine that is over expressed in patients with sepsis. Thus IL6, TNFα and IL12p40 gene expression in human monocytes are inhibited by IL10, and this effect is mediated in part by miRNA-187 (33).
Thus while some cell surface receptor expression suggest monocyte activation in sepsis, monocyte responsiveness in patients with sepsis appears to be very abnormal.
Monocyte-T cell interactions
The interaction between the monocyte co-stimulatory protein CD40 and CD40 ligand (CD40L) on CD4+ T lymphocytes is an important step in T lymphocyte activation. This interaction also enhances surface expression by monocytes of other co-stimulatory molecules, namely CD80 and CD86. Expression of surface CD40 on monocytes in patients with sepsis is decreased (34). Surface expression of CD80 is markedly lower on monocytes from septic patients (35), and fails to increase in response to CD40/CD40L ligation. Gene expression of yet another co-stimulatory molecule CD86 is also down-regulated in patients with sepsis (36). Collectively these studies demonstrate that, despite evidence for monocyte activation in sepsis, downstream monocyte signalling is nonetheless impaired in septic patients.
Programmed cell death-1 (PD-1) and programmed death-1ligand (PD-L1)
The programmed cell death receptor PD-1 and its ligand PD-L1 are important in regulating the interaction between monocytes and T cells. The PD-L1 ligand is expressed on APCs in response to stimulation, and also expressed on T and B lymphocytes upon activation. Formation of a PD-1 receptor/PD-L1 ligand complex transmits inhibitory signals, involved in reducing proliferation of T lymphocytes. In patients with sepsis, CD4+ and CD8+ T lymphocyte expression of PD-1 is increased, as is monocyte PD-L1, facilitating this immune inhibitory signalling pathway (37). Blockade of this receptor-ligand interaction reduces apoptosis in T cells, increases TNFα and IL6 production, and decreases production of IL10 by monocytes. Greater expression of monocyte PD-1 itself is reported in association with health care associated infection and mortality in patients with severe sepsis (38,39). Modulation of the PD-1/PD-L1 pathway in patients with sepsis is currently being evaluated as a potential sepsis immune therapy.
Monocytes, HLA-Dr and sepsis
The expression by monocytes of the MHC class II antigen presenting molecule HLA-Dr, which is crucial for T lymphocyte activation and expansion, is markedly downregulated in humans with severe sepsis, and remains so for at least 28 days after the onset of sepsis (40). After major trauma, this decrease in HLA-DR expression is related to the occurrence of subsequent sepsis and health care associated infection (41,42). However, this decrease in HLA-Dr expression does not consistently predict clinical outcome in trauma patients (43). By contrast, the decrement in monocyte HLA-Dr expression is reliably predictive of mortality and the occurrence of health care associated infection in patients with severe sepsis (44-46). Therefore, quantification of monocyte HLA-Dr expression has been advocated both as a sepsis biomarker, and as a tool to identify profoundly immune suppressed sepsis patients, who are at risk for health care associated infection, and for inclusion in clinical trials of immune adjuvant therapies, such as GM-CSF (46,47).
Stimulation by the cytokine interferon gamma (IFNγ) restores monocyte HLA-DR expression, and attenuates the reduction in LPS induced TNFα production. On this basis, IFNγ has also been proposed as an immune adjuvant for patients with sepsis (48).
Monocytes and the IL12 family cytokines
The IL12 family of cytokines regulate the interaction of innate and adaptive immune responses: IL12, IL23 and IL27 are members of this cytokine family that are produced by APCs (49). These cytokines regulate CD4+ T cell differentiation into specific phenotypes. IL12 promotes CD4+ T cell differentiation to a Th1 phenotype with production of IFNγ, which is of pivotal importance in clearing intracellular bacterial infection in humans. IL12 production by monocytes has been extensively studied in humans: IL12 is composed of two subunits, p35 and p40 (p40 is also a component of IL23). In postoperative surgical patients, production of IL12p40 subunit by monocytes is reduced (50). Pre-term neonates produce less IL12p40 than mature infants, with the decrement in production being more marked in neonates who develop sepsis (51). In trauma patients, inducible monocyte IL12 production is decreased in patients who develop health care associated infection and sepsis (52). The importance of IL12 in immunity is also reflected by a case of recurrent paediatric sepsis linked to an underlying deficiency in IL12 production, where in vitro studies of circulating lymphocytes noted near complete absence of IFNγ production (53).
IL27 appears to inhibit bactericidal potency of polymorphs in humans (54). Elevated IL27 has been observed in patients with sepsis, and indeed has been advocated as a biomarker in paediatric sepsis (55,56). However it is not clear whether IL27 is a marker of any infection, or whether it is linked with the occurrence of severe sepsis (18).
IL23, produced by monocytes, promotes CD4+ T lymphocyte differentiation to an activated Th17 phenotype, which is crucially important in the clearance of extracellular bacterial and fungal infections. Thus inherited defects in IL17 and its receptor are associated with chronic mucocutaneous candidiasis (57). Decreased IL23 gene expression has been linked with the occurrence of sepsis in patients with infection, and with health care associated respiratory infection after thoracic surgery (56,58).
Dendritic cells (DCs) differentiate into professional APCs from monocytes (59). Phenotypically, circulating DCs are commonly divided into CD11c+ myeloid dendritic cells (mDCs) and CD123+ plasmacytoid dendritic cells (pDC) based on surface expression of these antigens (60). Both mDCs and pDCs have been shown to be decreased in patients with septic shock. Furthermore, persistent depletion of mDCs was associated with both mortality and with developing health care associated infection in existing ICU patients (61,62).
Ancillary features linking monocyte activation and sepsis
Other factors such as polymorphisms in TNF promoter regions have been shown to influence susceptibility to pathogens such as meningococcus, through effects on monocyte TNFα production (63). Further, regulation of TNFα production by monocytes, at the post-transcriptional level by miRNA-125b, has been recently reported in the setting of neonatal sepsis (64). In addition molecules such as CTLA-4 (cytotoxic T lymphocyte antigen-4) and BTLA (B- and T-lymphocyte attenuator) have been shown to impair innate and adaptive immune cell responses in sepsis (65).
Thus mechanisms of lymphocyte activation by monocytes appear to be crucially deranged in patients with sepsis.
T lymphocytes play a pivotal role as facilitators and effectors of the adaptive immune response to infection. An effective functioning pool of T lymphocytes is essential to control and then eradicate infection. CD4+ T lymphocytes expand and are activated in response to antigen presentation by monocytes, in combination with the interaction of costimulatory ligands with their cognate receptors.
The gamma chain cytokines (IL2, IL7 and IL15) are important regulators of T lymphocyte homeostasis and expansion. Inherited defects in receptors for these cytokines account for many cases of severe combined immune deficiency (66). Septic patients and patients with health care associated infection after thoracotomy exhibit inappropriate down regulation of these gamma chain family cytokines IL2 and IL7 (67).
T lymphocytes have a capacity to differentiate into distinct phenotypes. The Th1 T lymphocyte phenotype characteristically secretes IFNγ and is essential to the clearance of intracellular bacterial infection. Interestingly in trauma patients, the CD4+ T cell phenotype is skewed toward a Th2 phenotype, in contrast to the typical Th1 responses that should be seen in the setting of bacterial infection.
CD4 Th17 lymphocytes
CD4+ T cells expressing IL17 (Th17 phenotype) are important in host defences at mucosal surfaces, but represent less that 1% of the total population of CD4+ cells in sepsis patients (28). There are few human studies of the role of IL17 expressing CD4+ cells in sepsis (68). In patients with severe thermal injury, blood levels of IL17 were increased in paediatric patients. Furthermore, IL17 levels in whole blood were detected in greater concentrations in adults than in children (69,70). However, when CD4+ cells were studied in thermally injured adults, there was a marked decrease in the number of CD4+ cells expressing IL17, with this finding mirrored by a reduction in inducible CD4+ IL17 production (71). Furthermore, thermally injured adult patients exhibited a marked decrease in expression of RORt (the signature CD4+Th17 transcription factor) in response to T cell receptor stimulation and following challenge with Candida albicans. Thus although the role of CD4+Th17 T lymphocytes in sepsis is presently unclear, there appears to be an association between down regulation of CD4+TH17 pathways and sepsis in humans.
Additional T lymphocyte subpopulations, including CD4+CD25+Foxp3+ T regulatory cells (T reg), gamma delta (γδ) T cells and NK-T cells, are increasingly recognised as of importance in immune responses in injury and sepsis (72,73). This importance may be attributed to the capacity of these rare niche lymphocytes that are not dependent upon APCs for activation, to interact with both innate and adaptive arms of the immune system.
In general absolute lymphocyte numbers are reduced in sepsis. Activated CD4+ Th1 and CD4+ Th17 cells appear to be reduced, as are the population of circulating γδ T cells, in patients with sepsis, while the population of inhibitory CD4+T reg cells is increased or unchanged (28,74,75).
Interestingly persistent T cell lymphopenia in sepsis, resulting in changes in proportions of CD4+ T cell subsets, has been recently observed in an elderly patient cohort. In this study a reduction in immunocompetent CD4+CD28+ T cells (rather than inhibitory and regulatory T cells) was linked to poor prognosis (76). Lymphopenia is also observed in patients with infection who are not septic: one study demonstrated decreased active and naïve CD4+ and CD8+ lymphocytes in patients with acute respiratory infection from Legionella species. Complete recovery of lymphocyte counts was observed following resolution of the acute infection (77). Thus while lymphopenia appears to be a feature of all infections, persistent lymphopenia as seen in sepsis is linked with adverse outcomes.
T cell function
T lymphocytes in patients with sepsis express both the lymphocyte activation marker CD69 and Ki67 as a marker of proliferation (78). Apoptotic markers were also more prominent in CD4+ but not CD8+ cells of patients with sepsis. Hence, the population of CD4+ cells of patients with sepsis includes the full gamut of proliferating T cells, activated T cells and T cells undergoing apoptosis.
A study measuring cellular ATP content in CD4+ T cells from sepsis patients showed a decrease in CD4+ T cell ATP levels in non-survivors, thus linking mortality in sepsis with a failure of T lymphocyte activation (79). In patients with severe sepsis, T cell receptor diversity is markedly reduced and this reduction in T cell receptor diversity correlates with the occurrence of health care associated infection (80). This study again linked a failure of T cell activation and expansion with mortality in human sepsis.
Further evidence of a link between T lymphocyte dysfunction and sepsis was gleaned from a study of patients who developed sepsis after trauma. T lymphocytes in patients who subsequently developed sepsis, sampled at the time of splenectomy prior to the onset of infection, exhibited a decrease in inducible IFNγ (81). This study is interesting as it supports the hypothesis that an attenuated immune response is present before the onset of sepsis, and thus may be causal rather than coincidental in nature.
Thus sepsis in patients has consistently been associated with persistent lymphopenia and failure of T lymphocyte activation, which in turn have been linked with health care associated infection and excess mortality in patients.
Neutrophil function has also been shown to be impaired in sepsis. Activation of TLR2 by LPS can induce neutrophil apoptosis (82). Low neutrophil counts are associated with poorer outcomes in sepsis, and detection of phenotypically immature granulocytes has been proposed as a biomarker of severity (83,84). Despite expressing increased activation markers, neutrophil trafficking is nonetheless impaired in sepsis. This may be due to lower levels of expression of the adhesion molecule CXCR2 which is important for neutrophil chemotaxis. For example, lower levels of CXCR2 expression were observed in neutrophils of patients who died of sepsis. IL33, a recently identified member of the IL1 cytokine family, has been shown to prevent this TLR mediated reduction in CXCR2 dependent chemotaxis (85).
In conclusion, septic patients, and patients who develop health care associated infection, appear to exhibit a profound complex and long lasting immune deficiency state, involving lymphocytes of both the innate and adaptive immune responses. In time immune modulation must play a crucial role in sepsis therapies of the future.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10. [Crossref] [PubMed]
- Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007;35:1244-50. [Crossref] [PubMed]
- Rodriguez A, Lisboa T, Blot S, et al. Mortality in ICU patients with bacterial community-acquired pneumonia: when antibiotics are not enough. Intensive Care Med 2009;35:430-8. [Crossref] [PubMed]
- Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344-53. [Crossref] [PubMed]
- Vincent JL. EPIC II: sepsis around the world. Minerva Anestesiol 2008;74:293-6. [PubMed]
- Fischer E, Marano MA, Van Zee KJ, et al. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 1992;89:1551-7. [Crossref] [PubMed]
- Windsor AC, Mullen PG, Walsh CJ, et al. Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis. Arch Surg 1994;129:80-9. [Crossref] [PubMed]
- Abraham E. Why immunomodulatory therapies have not worked in sepsis. Intensive Care Medicine 1999;25:556-66. [Crossref] [PubMed]
- Zanotti S, Kumar A. Cytokine modulation in sepsis and septic shock. Expert Opin Investig Drugs 2002;11:1061-75. [Crossref] [PubMed]
- Rittirsch D, Hoesel LM, Ward PA. The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol 2007;81:137-43. [Crossref] [PubMed]
- Raven K. Rodent models of sepsis found shockingly lacking. Nat Med 2012;18:998. [Crossref] [PubMed]
- Schultz MJ. Poll Tvd. Animal and human models for sepsis. Annals of Medicine 2002;34:573-81. [Crossref] [PubMed]
- Steinhauser ML, Hogaboam CM, Kunkel SL, et al. IL-10 Is a Major Mediator of Sepsis-Induced Impairment in Lung Antibacterial Host Defense. The Journal of Immunology 1999;162:392-9. [PubMed]
- Tang BM, Huang SJ, McLean AS. Genome-wide transcription profiling of human sepsis: a systematic review. Crit Care 2010;14:R237. [Crossref] [PubMed]
- Banchereau R, Jordan-Villegas A, Ardura M, et al. Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. PLoS One 2012;7:e34390. [Crossref] [PubMed]
- Yu SL, Chen HW, Yang PC, et al. Differential gene expression in gram-negative and gram-positive sepsis. Am J Respir Crit Care Med 2004;169:1135-43. [Crossref] [PubMed]
- Tang BM, McLean AS, Dawes IW, et al. Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit Care Med 2008;36:1125-8. [Crossref] [PubMed]
- Grealy R, White M, Stordeur P, et al. Characterising cytokine gene expression signatures in patients with severe sepsis. Mediators Inflamm 2013;2013:164246. [PubMed]
- Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013;13:260-8. [Crossref] [PubMed]
- Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003;19:71-82. [Crossref] [PubMed]
- Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009;27:669-92. [Crossref] [PubMed]
- Skrzeczyńska-Moncznik J, Bzowska M, Loseke S, et al. Peripheral blood CD14high CD16+ monocytes are main producers of IL-10. Scand J Immunol 2008;67:152-9. [Crossref] [PubMed]
- Belge KU, Dayyani F, Horelt A, et al. The Proinflammatory CD14+CD16+DR++ Monocytes Are a Major Source of TNF. J Immunol 2002;168:3536-42. [Crossref] [PubMed]
- Fingerle G, Pforte A, Passlick B, et al. The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. Blood 1993;82:3170-6. [PubMed]
- Gille-Johnson P, Smedman C, Gudmundsdotter L, et al. Circulating monocytes are not the major source of plasma cytokines in patients with sepsis. Shock 2012;38:577-83. [Crossref] [PubMed]
- Hirsh M, Mahamid E, Bashenko Y, et al. Overexpression of the high-affinity Fcgamma receptor (CD64) is associated with leukocyte dysfunction in sepsis. Shock 2001;16:102-8. [Crossref] [PubMed]
- Armstrong L, Medford AR, Hunter KJ, et al. Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol 2004;136:312-9. [Crossref] [PubMed]
- Brunialti MK, Santos MC, Rigato O, et al. Increased percentages of T helper cells producing IL-17 and monocytes expressing markers of alternative activation in patients with sepsis. PLoS One 2012;7:e37393. [Crossref] [PubMed]
- Tsujimoto H, Ono S, Majima T, et al. Differential toll-like receptor expression after ex vivo lipopolysaccharide exposure in patients with sepsis and following surgical stress. Clin Immunol 2006;119:180-7. [Crossref] [PubMed]
- Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med 2011;37:525-32. [Crossref] [PubMed]
- Wiersinga WJ, van't Veer C, van den Pangaart PS, et al. Immunosuppression associated with interleukin-1R-associated-kinase-M upregulation predicts mortality in Gram-negative sepsis (melioidosis). Crit Care Med 2009;37:569-76. [Crossref] [PubMed]
- Hall MW, Geyer SM, Guo CY, et al. Innate immune function and mortality in critically ill children with influenza: a multicenter study. Crit Care Med 2013;41:224-36. [Crossref] [PubMed]
- Rossato M, Curtale G, Tamassia N, et al. IL-10-induced microRNA-187 negatively regulates TNF-alpha, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci U S A 2012;109:E3101-10. [Crossref] [PubMed]
- Sugimoto K, Galle C, Preiser JC, et al. Monocyte CD40 expression in severe sepsis. Shock 2003;19:24-7. [Crossref] [PubMed]
- Sinistro A, Almerighi C, Ciaprini C, et al. Downregulation of CD40 ligand response in monocytes from sepsis patients. Clin Vaccine Immunol 2008;15:1851-8. [Crossref] [PubMed]
- Lissauer ME, Johnson SB, Bochicchio GV, et al. Differential expression of toll-like receptor genes: sepsis compared with sterile inflammation 1 day before sepsis diagnosis. Shock 2009;31:238-44. [Crossref] [PubMed]
- Zhang Y, Li J, Lou J, et al. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 2011;15:R70. [Crossref] [PubMed]
- Guignant C, Lepape A, Huang X, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 2011;15:R99. [Crossref] [PubMed]
- Shao R, Fang Y, Yu H, et al. Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study. Crit Care 2016;20:124. [Crossref] [PubMed]
- Poehlmann H, Schefold JC, Zuckermann-Becker H, et al. Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care 2009;13:R119. [Crossref] [PubMed]
- Gouel-Cheron A, Allaouchiche B, Guignant C, et al. Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma. PLoS One 2012;7:e33095. [Crossref] [PubMed]
- Cheron A, Floccard B, Allaouchiche B, et al. Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma. Crit Care 2010;14:R208. [Crossref] [PubMed]
- Trimmel H, Luschin U, Kohrer K, et al. Clinical outcome of critically ill patients cannot be defined by cutoff values of monocyte human leukocyte antigen-DR expression. Shock 2012;37:140-4. [Crossref] [PubMed]
- Wu JF, Ma J, Chen J, et al. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit Care 2011;15:R220. [Crossref] [PubMed]
- Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 2010;36:1859-66. [Crossref] [PubMed]
- Lukaszewicz AC, Grienay M, Resche-Rigon M, et al. Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med 2009;37:2746-52. [PubMed]
- Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009;180:640-8. [Crossref] [PubMed]
- Turrel-Davin F, Venet F, Monnin C, et al. mRNA-based approach to monitor recombinant gamma-interferon restoration of LPS-induced endotoxin tolerance. Crit Care 2011;15:R252. [Crossref] [PubMed]
- Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007;25:221-42. [Crossref] [PubMed]
- Mokart D, Leone M, Sannini A, et al. Reduced interleukin-12 release from stimulated monocytes in patients with sepsis after major cancer surgery. Acta Anaesthesiol Scand 2010;54:643-8. [Crossref] [PubMed]
- Lavoie PM, Huang Q, Jolette E, et al. Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis. J Infect Dis 2010;202:1754-63. [Crossref] [PubMed]
- Spolarics Z, Siddiqi M, Siegel JH, et al. Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward Th2-type lymphocyte pattern in severely injured male trauma patients. Crit Care Med 2003;31:1722-9. [Crossref] [PubMed]
- Haraguchi S, Day NK, Nelson RP Jr, et al. Interleukin 12 deficiency associated with recurrent infections. Proc Natl Acad Sci U S A 1998;95:13125-9. [Crossref] [PubMed]
- Rinchai D, Khaenam P, Kewcharoenwong C, et al. Production of interleukin-27 by human neutrophils regulates their function during bacterial infection. Eur J Immunol 2012;42:3280-90. [Crossref] [PubMed]
- Wong HR, Cvijanovich NZ, Hall M, et al. Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Crit Care 2012;16:R213. [Crossref] [PubMed]
- O'Dwyer MJ, Mankan AK, White M, et al. The human response to infection is associated with distinct patterns of interleukin 23 and interleukin 27 expression. Intensive Care Med 2008;34:683-91. [Crossref] [PubMed]
- Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011;332:65-8. [Crossref] [PubMed]
- White M, Martin-Loeches I, Lawless MW, et al. Hospital-acquired pneumonia after lung resection surgery is associated with characteristic cytokine gene expression. Chest 2011;139:626-32. [Crossref] [PubMed]
- Leon B, Ardavin C. Monocyte-derived dendritic cells in innate and adaptive immunity. Immunol Cell Biol 2008;86:320-4. [Crossref] [PubMed]
- Grabbe S, Kampgen E, Schuler G. Dendritic cells: multi-lineal and multi-functional. Immunol Today 2000;21:431-3. [Crossref] [PubMed]
- Grimaldi D, Louis S, Pene F, et al. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med 2011;37:1438-46. [Crossref] [PubMed]
- Guisset O, Dilhuydy MS, Thiebaut R, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med 2007;33:148-52. [Crossref] [PubMed]
- Read RC, Teare DM, Pridmore AC, et al. The tumor necrosis factor polymorphism TNF (-308) is associated with susceptibility to meningococcal sepsis, but not with lethality. Crit Care Med 2009;37:1237-43. [Crossref] [PubMed]
- Huang HC, Yu HR, Huang LT, et al. miRNA-125b regulates TNF-alpha production in CD14+ neonatal monocytes via post-transcriptional regulation. J Leukoc Biol 2012;92:171-82. [Crossref] [PubMed]
- Shubin NJ, Chung CS, Heffernan DS, et al. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukoc Biol 2012;92:593-603. [Crossref] [PubMed]
- Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev 2004;202:67-83. [Crossref] [PubMed]
- White M, Mahon V, Grealy R, et al. Post-operative infection and sepsis in humans is associated with deficient gene expression of gammac cytokines and their apoptosis mediators. Crit Care 2011;15:R158. [Crossref] [PubMed]
- Rendon JL, Choudhry MA. Th17 cells: critical mediators of host responses to burn injury and sepsis. J Leukoc Biol 2012;92:529-38. [Crossref] [PubMed]
- Finnerty CC, Jeschke MG, Herndon DN, et al. Temporal cytokine profiles in severely burned patients: a comparison of adults and children. Mol Med 2008;14:553-60. [Crossref] [PubMed]
- Finnerty CC, Herndon DN, Przkora R, et al. Cytokine expression profile over time in severely burned pediatric patients. Shock 2006;26:13-9. [Crossref] [PubMed]
- Inatsu A, Kogiso M, Jeschke MG, et al. Lack of Th17 cell generation in patients with severe burn injuries. J Immunol 2011;187:2155-61. [Crossref] [PubMed]
- Tschop J, Martignoni A, Goetzman HS, et al. Gammadelta T cells mitigate the organ injury and mortality of sepsis. J Leukoc Biol 2008;83:581-8. [Crossref] [PubMed]
- Venet F, Chung CS, Monneret G, et al. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol 2008;83:523-35. [Crossref] [PubMed]
- Venet F, Bohe J, Debard AL, et al. Both percentage of gammadelta T lymphocytes and CD3 expression are reduced during septic shock. Crit Care Med 2005;33:2836-40. [Crossref] [PubMed]
- Venet F, Chung CS, Kherouf H, et al. Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med 2009;35:678-86. [Crossref] [PubMed]
- Inoue S, Suzuki-Utsunomiya K, Okada Y, et al. Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit Care Med 2013;41:810-9. [Crossref] [PubMed]
- de Jager CP, Gemen EF, Leuvenink J, et al. Dynamics of peripheral blood lymphocyte subpopulations in the acute and subacute phase of Legionnaires' disease. PLoS One 2013;8:e62265. [Crossref] [PubMed]
- Roger PM, Hyvernat H, Ticchioni M, et al. The early phase of human sepsis is characterized by a combination of apoptosis and proliferation of T cells. J Crit Care 2012;27:384-93. [Crossref] [PubMed]
- Lawrence KL, White PH, Morris GP, et al. CD4+ lymphocyte adenosine triphosphate determination in sepsis: a cohort study. Crit Care 2010;14:R110. [Crossref] [PubMed]
- Venet F, Filipe-Santos O, Lepape A, et al. Decreased T-cell repertoire diversity in sepsis: a preliminary study. Crit Care Med 2013;41:111-9. [Crossref] [PubMed]
- Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011;306:2594-605. [Crossref] [PubMed]
- Navarini AA, Lang KS, Verschoor A, et al. Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections. Proc Natl Acad Sci U S A 2009;106:7107-12. [Crossref] [PubMed]
- Nahm CH, Choi JW, Lee J. Delta neutrophil index in automated immature granulocyte counts for assessing disease severity of patients with sepsis. Ann Clin Lab Sci 2008;38:241-6. [PubMed]
- Seok Y, Choi JR, Kim J, et al. Delta neutrophil index: a promising diagnostic and prognostic marker for sepsis. Shock 2012;37:242-6. [Crossref] [PubMed]
- Alves-Filho JC, Sonego F, Souto FO, et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med 2010;16:708-12. [Crossref] [PubMed]