Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.

Background-We investigated the immunoinflammatory profile of patients successfully resuscitated after cardiac arrest, representing a model of whole-body ischemia/reperfusion syndrome. Methods and Results-Plasma cytokine, endotoxin, and ex vivo cytokine production in whole-blood assays was assessed in 61, 35, and 11 patients, respectively. On admission, high levels of plasma interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor (TNF) receptor type II could discriminate between survivors and nonsurvivors. Among nonsurvivors, the initial need for a vasopressor agent was associated with higher levels of IL-1 receptor antagonist, IL-10, and IL-6 on day 1. Plasma endotoxin was detected in 46% of the analyzed patients within the 2 first days. Endotoxin-induced TNF and IL-6 productions were dramatically impaired in these patients compared with healthy control subjects, whereas an unaltered production was observed with heat-killed Staphylococcus aureus. In contrast, IL-1 receptor antagonist productions were enhanced in these patients compared with healthy control subjects. The productions of T-cell-derived IL-10 and interferon-␥ were also impaired in these patients. Finally, using in vitro plasma exchange between healthy control subjects and patients, we demonstrated that the endotoxin-dependent hyporeactivity was an intrinsic property of patients' leukocytes and that an immunosuppressive activity was also present in their plasma. Conclusions-Altogether, the high levels of circulating cytokines, the presence of endotoxin in plasma, and the dysregulated production of cytokines found in these patients recall the immunological profile found in patients with sepsis. (Circulation. 2002;106:562-568.)

Muropeptides are degradation products of bacterial peptidoglycan (PG) sensed by nucleotide-binding oligomerization domain 1 (NOD1) and NOD2, members of a recently discovered family of pattern recognition molecules (PRM). One of these muropeptides, muramyl dipeptide (MDP) mediates cell signaling by NOD2, exerts adjuvant activity and synergizes with lipopolysaccharide (LPS) to induce proinflammatory responses in vitro and in vivo. In contrast, few and contradictory results exist about the stimulatory capacity of NOD1 agonists. Thus, the ability of NOD1 (MurNAc-L-Ala-c-D-Glu-meso-diaminopimelic acid, MtriDAP) and NOD2 (MurNAc-LAla-D-isoGln, MDP; MurNAc-L-Ala-c-D-Glu-L-Lys, MtriLYS) agonists to activate primary human myeloid cells was examined. We show that both CD14 + monocytes and CD1a + immature dendritic cells (DC) express NOD1 and NOD2 mRNA. Stimulation of primary human monocytes and DC with highly purified muropeptides (MtriDAP, MDP and MtriLYS) induces release of pro-inflammatory cytokines. We reveal here that NOD1 as well as NOD2 agonists act cooperatively with LPS to stimulate the release of both proand anti-inflammatory cytokines in these myeloid cell subsets. Finally, we report that NOD1 as well as NOD2 agonists synergize with sub-active doses of LPS to induce DC maturation, demonstrating that NOD agonists act cooperatively with molecules sensed by Toll-like receptor 4 to instruct the onset of adaptive immune responses.

SummaryThe gram-negative pathogen Shigella flexneri causes bacillary dysentery, an invasive disease of the human colonic mucosa. A major characteristic of the infectious process is the occurrence of an acute inflammatory reaction of mucosal tissues which is generally considered as a consequence of primary invasion and destruction of colonic epithelial cells by the pathogen. Confirming in vitro demonstration that S. flexneri is unable to invade the apical pole of colonic cells and that polymorphonuclear (PMN) cells may assist them in reaching the basal side of epithelial cells where they can invade, we have provided here in vivo evidence that S.flexneri enters the epithelial barrier essentially through the dome of lymphoid follicles at the early stage of infection and that subsequent invasion and destruction of the epithelium is primarily due to immigration of leukocytes, particularly PMN that destroy cohesion of the epithelial barrier. These conclusions are based on experiments carried out in infected rabbit ligated intestinal loops, with some animals treated by an anti-CD18 monoclonal antibody that blocked immigration of leukocytes into infected tissues.

Sepsis is associated with an exacerbated production of both pro- and anti-inflammatory cytokines, which are detectable within the bloodstream. Their 'half-angel, half-devil' properties are fully illustrated in sepsis. While they are a prerequisite to fight infection, their overzealous production is deleterious. The highest levels are found in plasma of non-surviving patients: they are markers and causative agents of poor outcome. Only the level of the chemokine RANTES is inversely associated with the APACHE II score (r = -0.7; p = 0.02) and low levels are associated with poor outcome. The link, interplay and network of cytokines taking place during sepsis are illustrated by the correlations between the levels of most pro- and anti-inflammatory cytokines. Excessive release of anti-inflammatory cytokines may be associated with the immunodysregulation observed in sepsis. However, despite the presence of huge amounts of anti-inflammatory cytokines and molecules targeting specifically interleukin-1 (IL-1) (i.e. IL-1 receptor antagonist) and tumour necrosis factor (TNF) (i.e. soluble TNF receptors), there is no indication that their levels are sufficient to counteract fully these proinflammatory cytokines. TNF was initially thought to be the 'hub of the cytokine network'. Although TNF contributes towards favouring the production of many other cytokines within a complex cascade, there are numerous examples to illustrate that its presence is not a prerequisite for these productions.

Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin. Endotoxin tolerance protects against a lethal challenge of LPS and prevents infection and ischemia-reperfusion damage. Endotoxin tolerance is paralleled by a dramatic reduction of tumor necrosis factor (TNF) production and some other cytokines in response to LPS. Endotoxin tolerance involves the participation of macrophages and mediators, such as glucocorticoids, prostaglandins, IL-10, and transforming growth factor-β. Endotoxin tolerance is accompanied by the up-regulation of inhibitory molecules that down-regulate the Toll-like receptor (TLR)4-dependent signaling pathway. Cross-tolerance between LPS and other TLR specific ligands, as well as IL-1 and TNF, has been regularly reported. A similar loss of LPS reactivity has been repeatedly reported in circulating leukocytes of septic patients and in patients with non-infectious systemic inflammation response syndrome (SIRS). Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations reminiscent of those observed in endotoxin tolerant cells. However, altered responsiveness to LPS of leukocytes from sepsis and SIRS patients is not synonymous with a global down-regulation of cellular reactivity. The term 'cellular reprogramming', which has been proposed to qualify the process of endotoxin tolerance, defines well the immune status of circulating leukocytes in septic and SIRS patients. In vivo endotoxin tolerancePaul Beeson first reported endotoxin tolerance in 1946 [1] as the abolition of the fever response of rabbits undergoing repeated daily injection of the same dose of typhoid vaccine. Later, it was shown that plasma of a tolerant rabbit could passively transfer tolerance to pyrogenicity of bacterial endotoxin to another animal [2]. In human volunteers, it was shown that inoculation of live Salmonella typhosa led to a reduced fever in response to endotoxin or killed bacteria compared to before infection [3]. Interestingly, a similar observation was reported with volunteers inoculated with Plasmodium cynomolgi by mosquito bites [4], suggesting that cross-tolerization between different stimuli could occur. In addition to human volunteers, reduced fever to endotoxin or killed bacteria was reported in different infections, such as in patients with pyelonephritis [5], in patients convalescent from typhoid and paratyphoid fever [6], and in patients recovering from malaria [7].Not only can a pretreatment with endotoxin reduce subsequent lipopolysaccharide (LPS)-induced fever in rabbits, it also prevents LPS-induced lethality [8]. In mice, even when LPS-induced lethality was dramatically enhanced by galactosamine treatment, LPS tolerization could prevent mortality [9]. By specific cell transfer from LPS-resistant to LPS-sensitive mice, Freudenberg and Galanos [9] elegantly demonstrated the role of macrophages in the induction of endotoxin tolerance in vivo. Endotoxin tolerance...

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Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.