Characterization of Early Peripheral Immune Responses in Patients with Sepsis and Septic Shock

Abstract

(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the immune system leading to an altered immune response and immunosuppression, the high complexity of the pathophysiology of sepsis requires further investigation to characterize the immune response in sepsis and septic shock. (2) Methods: This study analyzes the immune-related responses occurring during the early stages of sepsis by comparing the amounts of cytokines, immune modulators and other endothelial mediators of a control group and three types of severe patients: critically ill non-septic patients, septic and septic shock patients. (3) Results: We showed that in the early stages of sepsis the innate immune system attempts to counteract infection, probably via neutrophils. Conversely, the adaptive immune system is not yet fully activated, either in septic or in septic shock patients. In addition, immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. (4) Conclusions: The highest levels of IL-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found in septic shock patients, which correlated with D-dimer. Moreover, endothelial function may be affected as shown by the overexpression of adhesion molecules such as s-ICAM1 and E-Selectin during septic shock.

Validation of circulating histone detection by mass spectrometry for early diagnosis, prognosis, and management of critically ill septic patients

“…Extracellular histones are responsible for cell damage via several transduction pathways [ 15 , 20 , 28 – 31 ]. It has been demonstrated that circulating histones mediate innate immunity dysregulation, triggering inflammatory responses, endothelium injury, and coagulation [ 28 , 32 – 38 ], thus their levels are associated with sepsis severity, tissue damage and risk of death [ 17 , 17 , 21 , 21 – 23 , 39 , 40 ]. This last mortal event is influenced mainly by endothelium damage and vascular endothelial cell death, which may in turn induce barrier function impairment, decreased blood flow, vascular tone and blood pressure, and activation of the coagulation cascade.…”

Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation

“…In this regard, Gogos et al, recently found differences between the early status of the innate and adaptive immune system between sepsis and SS patients, and those differences were related to the infection source [ 59 ]. Regarding innate and adaptive immune activation, our group also showed that during the first stages of sepsis, adaptive immunity is not completely active [ 60 ]. In line with these observations, we propose that, during the first stages of sepsis, innate immunity is overexpressed in comparison with the later stages of sepsis, especially in the SS patient group.…”

Alterations in leukocyte DNA methylome are associated to immunosuppression in severe clinical phenotypes of septic patients

“…The exacerbated hyper-inflammatory response can also damage non-infected tissues and lead to dysfunction of different organs and systems linked to hypotension, vasculature damage, and coagulation events, aggravating the disease status of septic patients, and producing early deaths at the initial stages of sepsis ( 2 ). The hyperinflammatory process is an acute event occurring usually at initial stages of sepsis just after infection ( 3 – 5 ). A compensatory anti-inflammatory response syndrome (CARS) can sometimes simultaneously occur, which can induce long-term immunosuppression, leading to secondary infections and most sepsis-associated late deaths ( 6 , 7 ).…”

“…Likewise, Myeloid-derived suppressor cells (MDSCs) are also involved in sepsis-induced immunosuppression throughout the production of arginase 1 and contribute to T-cell dysfunction ( 16 ). Importantly, levels of MDSCs mediators and the expression of genes with immunosuppressive functions, such as S100A8/A9 , S100A12 , and ARG1 , are highly elevated in patients with sepsis ( 3 , 16 ). Despite accumulating scientific evidence on the pathogenetic mechanisms underlying sepsis, data explaining sepsis-induced immunosuppression is still lacking, and the molecular mechanisms occurring in the host leading to immunosuppression in human sepsis remain poorly understood ( 6 , 17 , 18 ).…”