Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach.
Hotchkiss Richard S,Monneret Guillaume,Payen Didier
The Lancet. Infectious diseases
Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion-a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis.
10.1016/S1473-3099(13)70001-X
The interplay between inflammasome activation and antifungal host defense.
van de Veerdonk Frank L,Joosten Leo A B,Netea Mihai G
Immunological reviews
Fungal infections cause significant morbidity and mortality in humans, and they are a growing problem due to the increased usage of broad-spectrum antibiotics and immunosuppressive therapies. The equilibrium between the commensal microbial flora and the immune system that protects the host against invasive fungal infection is disturbed during disease, and understanding this disturbed balance is important to develop new therapeutic interventions for the treatment of fungal infection. In the context of tolerating fungi during colonization and eliciting a vigorous immune response to eliminate invading fungal pathogens when needed, the inflammasome has been identified as an integral component of antifungal host defense. It contributes to mucosal host defense by regulating T-helper 17 (Th17) cell responses, and contributes to protective responses such as neutrophil influx during fungal sepsis. Several aspects are important for understanding the role of the inflammasome for antifungal host defense, such as the role of fungal cell wall morphology and its components in triggering the inflammasome, the pattern recognition pathways and downstream signaling cascades involved in the activation of the inflammasome, and the effects of inflammasome activation during fungal infection. The future perspectives of inflammasome research in fungal immunology, with emphasis on targeting the inflammasome for the design of future immunotherapies, is also discussed.
10.1111/imr.12280
Phagocyte subsets and lymphocyte clonal deletion behind ineffective immune response to Staphylococcus aureus.
Pozzi Clarissa,Lofano Giuseppe,Mancini Francesca,Soldaini Elisabetta,Speziale Pietro,De Gregorio Ennio,Rappuoli Rino,Bertholet Sylvie,Grandi Guido,Bagnoli Fabio
FEMS microbiology reviews
Lack of known mechanisms of protection against Staphylococcus aureus in humans is hindering development of efficacious vaccines. Preclinical as well as clinical data suggest that antibodies play an important role against S. aureus. For instance, certain hypogammaglobulinaemic patients are at increased risk of staphylococcal infections. However, development of effective humoral response may be dampened by converging immune-evasion mechanisms of S. aureus. We hypothesize that B-cell proliferation induced by staphylococcal protein A (SpA) and continuous antigen exposure, without the proper T-cell help and cytokine stimuli, leads to antigen-activated B-cell deletion and anergy. Recent findings suggest an important role of type I neutrophils (PMN-I) and conventionally activated macrophages (M1) against S. aureus, while alternatively activated macrophages (M2) favour biofilm persistence and sepsis. In addition, neutrophil-macrophage cooperation promotes extravasation and activation of neutrophils as well as clearance of bacteria ensnared in neutrophil extracellular traps. Activation of these processes is modulated by cytokines and T cells. Indeed, low CD4(+) T-cell counts represent an important risk factor for skin infections and bacteraemia in patients. Altogether, these observations could lead to the identification of predictive correlates of protection and ways for shifting the balance of the response to the benefit of the host through vaccination.
10.1093/femsre/fuv024
Involvement of receptor-interacting protein 2 in innate and adaptive immune responses.
Chin Arnold I,Dempsey Paul W,Bruhn Kevin,Miller Jeff F,Xu Yang,Cheng Genhong
Nature
Host defences to microorganisms rely on a coordinated interplay between the innate and adaptive responses of immunity. Infection with intracellular bacteria triggers an immediate innate response requiring macrophages, neutrophils and natural killer cells, whereas subsequent activation of an adaptive response through development of T-helper subtype 1 cells (TH1) proceeds during persistent infection. To understand the physiological role of receptor-interacting protein 2 (Rip2), also known as RICK and CARDIAK, we generated mice with a targeted disruption of the gene coding for Rip2. Here we show that Rip2-deficient mice exhibit a profoundly decreased ability to defend against infection by the intracellular pathogen Listeria monocytogenes. Rip2-deficient macrophages infected with L. monocytogenes or treated with lipopolysaccharide (LPS) have decreased activation of NF-kappaB, whereas dominant negative Rip2 inhibited NF-kappaB activation mediated by Toll-like receptor 4 and Nod1. In vivo, Rip2-deficient mice were resistant to the lethal effects of LPS-induced endotoxic shock. Furthermore, Rip2 deficiency results in impaired interferon-gamma production in both TH1 and natural killer cells, attributed in part to defective interleukin-12-induced Stat4 activation. Our data reflect requirements for Rip2 in multiple pathways regulating immune and inflammatory responses.
10.1038/416190a
Role of C5a in inflammatory responses.
Guo Ren-Feng,Ward Peter A
Annual review of immunology
The complement system not only represents an effective innate immune mechanism of host defense to eradicate microbial pathogens, but it is also widely involved in many forms of acute and chronic inflammatory diseases including sepsis, acute lung injury, ischemia-reperfusion injury, and asthma, to give just a few examples. The complement-activated product, C5a, displays powerful biological activities that lead to inflammatory sequelae. C5a is a strong chemoattractant and is involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, in activation of phagocytic cells and release of granule-based enzymes and generation of oxidants, all of which may contribute to innate immune functions or tissue damage. Accumulating data suggest that C5a provides a vital bridge between innate and adaptive immune functions, extending the roles of C5a in inflammation. Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma.
10.1146/annurev.immunol.23.021704.115835
Advances in the understanding and treatment of sepsis-induced immunosuppression.
Venet Fabienne,Monneret Guillaume
Nature reviews. Nephrology
Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Sepsis can induce acute kidney injury and multiple organ failures and represents the most common cause of death in the intensive care unit. Sepsis initiates a complex immune response that varies over time, with the concomitant occurrence of both pro-inflammatory and anti-inflammatory mechanisms. As a result, most patients with sepsis rapidly display signs of profound immunosuppression, which is associated with deleterious consequences. Scientific advances have highlighted the role of metabolic failure, epigenetic reprogramming, myeloid-derived suppressor cells, immature suppressive neutrophils and immune alterations in primary lymphoid organs (the thymus and bone marrow) in sepsis. An improved understanding of the mechanisms underlying this immunosuppression as well as of the similarities between sepsis-induced immunosuppression and immune defects in cancer or immunosenescence has led to novel therapeutic strategies aimed at stimulating immune function in patients with sepsis. Trials assessing the therapeutic benefit of IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF) and antibodies against programmed cell death protein 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) for the treatment of sepsis are in progress. The reappraisal of sepsis pathophysiology has also resulted in a novel approach to the design of clinical trials evaluating sepsis treatments, based on an evaluation of the immune status and biomarker-based stratification of patients.
10.1038/nrneph.2017.165
Sepsis-induced immune dysfunction: can immune therapies reduce mortality?
Delano Matthew J,Ward Peter A
The Journal of clinical investigation
Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay between inflammatory and antiinflammatory responses. With advances in intensive care management and goal-directed interventions, early sepsis mortality has diminished, only to surge later after "recovery" from acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to alter innate and adaptive immune responses for sustained periods after clinical "recovery," with immunosuppression being a prominent example of such alterations. Recent studies have centered on immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell dysfunction that is associated with mortality long after the acute events of sepsis have resolved.
10.1172/JCI82224
Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis.
Science (New York, N.Y.)
Sepsis is a frequently fatal condition characterized by an uncontrolled and harmful host reaction to microbial infection. Despite the prevalence and severity of sepsis, we lack a fundamental grasp of its pathophysiology. Here we report that the cytokine interleukin-3 (IL-3) potentiates inflammation in sepsis. Using a mouse model of abdominal sepsis, we showed that innate response activator B cells produce IL-3, which induces myelopoiesis of Ly-6C(high) monocytes and neutrophils and fuels a cytokine storm. IL-3 deficiency protects mice against sepsis. In humans with sepsis, high plasma IL-3 levels are associated with high mortality even after adjusting for prognostic indicators. This study deepens our understanding of immune activation, identifies IL-3 as an orchestrator of emergency myelopoiesis, and reveals a new therapeutic target for treating sepsis.
10.1126/science.aaa4268
A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1.
Pillay Janesh,Kamp Vera M,van Hoffen Els,Visser Tjaakje,Tak Tamar,Lammers Jan-Willem,Ulfman Laurien H,Leenen Luke P,Pickkers Peter,Koenderman Leo
The Journal of clinical investigation
Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11cbright/CD62Ldim/CD11bbright/CD16bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide from the neutrophils into the immunological synapse between the neutrophils and T cells mediated the suppression of T cell proliferation and required neutrophil expression of the integrin Mac-1 (αMβ2). Our data demonstrate that suppression of T cell function can be accomplished by a subset of human neutrophils that can be systemically induced in response to acute inflammation. Identification of the pivotal role of neutrophil Mac-1 and ROS in this process provides a potential target for modulating immune responses in humans.
10.1172/JCI57990
Immune cells in experimental acute kidney injury.
Jang Hye Ryoun,Rabb Hamid
Nature reviews. Nephrology
Acute kidney injury (AKI) prolongs hospital stay and increases mortality in various clinical settings. Ischaemia-reperfusion injury (IRI), nephrotoxic agents and infection leading to sepsis are among the major causes of AKI. Inflammatory responses substantially contribute to the overall renal damage in AKI. Both innate and adaptive immune systems are involved in the inflammatory process occurring in post-ischaemic AKI. Proinflammatory damage-associated molecular patterns, hypoxia-inducible factors, adhesion molecules, dysfunction of the renal vascular endothelium, chemokines, cytokines and Toll-like receptors are involved in the activation and recruitment of immune cells into injured kidneys. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after IRI, and some of their subpopulations also participate in the repair process. These immune cells are also involved in the pathogenesis of nephrotoxic AKI. Experimental studies of immune cells in AKI have resulted in improved understanding of the immune mechanisms underlying AKI and will be the foundation for development of novel diagnostic and therapeutic targets. This Review describes what is currently known about the function of the immune system in the pathogenesis and repair of ischaemic and nephrotoxic AKI.
10.1038/nrneph.2014.180