HLA-DR, human leukocyte antigen-D related IgM/G, immunoglobulin M/G IL, interleukin IFN-y, Interferon y PAMPs, pathogen-associated molecular patterns TNF-α, tumor necrosis factor alpha TLR, toll-like receptor.Īs part of the innate immune system, neutrophils form a significant part of the first line of defense against pathogens. hyper-responsiveness) remains highly individualized and causes considerable diagnostic difficulties.Ĭhanges in pro- and anti-inflammatory response of the immune system during the course of sepsis and septic shock. The net effect on the immunological phenotype (hypo- vs. These processes can be observed during the early stages of the septic disease by an increase in both pro-inflammatory and anti-inflammatory cytokines ( 8, 10, 11). These subsequently cause the activation of further cytokines (e.g., IFN-y, IL-6, IL-8), complement and coagulation pathways, and, by negative feedback, downregulation of components of the adaptive immune system ( 9). This leads to the expression of “early activation genes,” including various pro-inflammatory interleukins (IL), e.g., IL-1, IL-12, IL-18, tumor necrosis factor alpha (TNF-α), and interferons (IFNs). Binding of PAMPs and DAMPs to TLRs on APCs and monocytes results in signal transduction, causing translocation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) into the cell nucleus. In many patients the concomitant immunosuppression, which is caused by downregulation of activating cell surface molecules, increased apoptosis of immune cells, and T cell exhaustion, leads to “immunoparalysis” in the later stages of the disease course and makes affected patients susceptible to nosocomial infections, opportunistic pathogens, and viral reactivation ( Figure 1) ( 7, 8). While both pro-inflammatory and anti-inflammatory pathways are upregulated, the resulting inflammation leads to progressive tissue damage, finally causing multi-organ dysfunction. These molecules activate specific receptors (toll-like receptors, TLR) on the surface of antigen-presenting cells (APCs) and monocytes, thereby initiating the clinical syndrome of sepsis via transcription of genes involved in inflammation, cell metabolism, and adaptive immunity ( 6). Recognition of pathogen-derived molecular patterns (PAMPs, e.g., endo- and exotoxins, lipids, or DNA sequences) or endogenous host-derived danger signals (damage-associated molecular patterns DAMPs) is the starting signal. The upregulation of pro- and anti-inflammatory pathways leads to a system-wide release of cytokines, mediators, and pathogen-related molecules, resulting in activation of coagulation, and complement cascades ( 5).
In contrast to an uncomplicated and localized infection, sepsis is a multifaceted disruption of the finely tuned immunological balance of inflammation and anti-inflammation. This implies that increasing awareness of sepsis and the promotion of quality improvement initiatives in the field of sepsis effectively improve patient survival, together with the development of novel diagnostics and interventions ( 4). A decisive factor is the time of correct diagnosis and the initiation of causal, supportive, and adjunctive measures. Only timely fluid resuscitation and early administration of broad-spectrum antibiotics have been shown to reduce mortality. Although our understanding of origin, pathophysiology, and immunological mechanisms of sepsis has made progress during the last three decades, our options of successful and specific therapeutic interventions remain restricted to non-existent. In septic shock, a subgroup of sepsis characterized by profound circulatory, cellular and metabolic abnormalities, the hospital mortality rate approaches 60% ( 3).Ĭomprehensively defining “sepsis” has been subject of constant development and refinement over the last decades. Globally, mortality rates seem to be declining on average, however, up to 25% of patients still succumb to sepsis. Approximately 49 million people are affected by sepsis every year and it is estimated that 11 million deaths are caused by the syndrome, accounting for up to 19.7% of all deaths worldwide ( 2). The Third International Consensus (Sepsis-3) currently defines sepsis as “organ dysfunction caused by a dysregulated host response to infection”, emphasizing for the first time the crucial role of the innate and adaptive immune response in the development of the clinical syndrome ( 1). Sepsis is a life-threatening clinical condition with extensive physiological and biochemical abnormalities.
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