Immune Intervention in Sepsis

Abstract

Sepsis is a host immune disorder induced by infection. It can lead to multiple organ dysfunction syndrome (MODS), which has high morbidity and mortality. There has been great progress in the clinical diagnosis and treatment of sepsis, such as improvements in pathogen detection technology, innovations regarding anti-infection drugs, and the development of organ function support. Abnormal immune responses triggered by pathogens, ranging from excessive inflammation to immunosuppression, are recognized to be an important cause of the high mortality rate. However, no drugs have been approved specifically for treating sepsis. Here, we review the recent research progress on immune responses in sepsis to provide a theoretical basis for the treatment of sepsis. Constructing and optimizing a dynamic immune system treatment regimen based on anti-infection treatment, fluid replacement, organ function support, and timely use of immunomodulatory interventions may improve the prognosis of sepsis patients.

Keywords: cytokine; immune intervention; immunosuppression; inflammatory; sepsis.

FIGURE 1

Immune response following pathogen infection. Figure (A): Pathogen invasion induces local inflammatory response in tissues. The activated innate immune and adaptive immune cells migrate locally to tissues, inhibit microbe duplication and systematic dissemination, and finally clear the pathogen. Inflammation is controlled and immune balance of the body is achieved. (B): Heavy load infection accompanied by local damage activated innate and adaptive immune cells are in a hyperinflammatory state under the dual effects of pathogens and DAMPs. The cytokine storm generated by these cells inhibits the pathogens to a certain extent, but also leads to further tissue damage. Microbes migrate to the whole body through damaged blood vessels, causing a strong inflammatory response and thus leading to systemic immune dysregulation and injury.

FIGURE 2

Immunity mechanism of sepsis induced by different pathogens. The predominant pathogens that cause sepsis are bacteria, fungi and viruses. The lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria can be recognized by TLR4, while the lipoprotein in the cell wall of Gram-positive bacteria can be bound to TLR2/TLR1. They activate the downstream signaling molecule of MyD88 and ubiquitinate TRAF6. Ubiquitinized TRAF6K recruits the TAK1-TAB1/2 protein complex, while TAK1 kinase activates the transcription factor NF-kB and facilitates the production of key pro-inflammatory cytokines such as IL-1, IL-6, and TNF. Fungus β-glucan and mannose are commonly recognized by CLRs which mobilizes Syk protein kinases to coordinate the innate immune response, and eventually activate NFkB to produce pro-inflammatory factors through the CARD9/BCL10/MALT1 complex. iIfluenza viruse causing common viral infection in sepsis can be recognized by RIG-I in the cytoplasm and signal to TAK1 and TBK1 through oligomerization of MAVs molecules on mitochondria, which ultimately activates NF-kB and IRF family transcription factors and promotes the production of inflammatory factors and type 1 interferon. These changes cause damage to important viscera of airframe.

FIGURE 3

The ideal treatment for sepsis is routine treatment throughout the course of disease, continuous immunity monitoring, and moderate immunnity intervention. Patients with early sepsis are classified into two types: non-inflammatory storm and inflammatory storm according to the monitoring of immune indexes on admission: patients without inflammatory storm are given routine treatment, and appropriate anti-inflammatory storm therapy is adopted for patients with inflammatory storm. Some patients may achieve immune homeostasis after treatment improvement, and continuous immune monitoring found that the other patients may develope immunosuppression with the prolonged course of disease, so immunostimulation therapy is needed to finally restore the immune homeostasis. The goal of immunotherapy in sepsis is to maintain immune homeostasis by continuously monitoring the time of intervention, guiding the dose and course of intervention.