Inflammation and Cytokine Storm

SCENARIO 4 Inflammation and cytokine storm SCENARIO Pathogenic infectious diseases can cause fever, pain, and other symptoms as the body's immune response. Excessive activation of the immune system can cause the release of pro-inflammatory mediators which, if continued, can cause a cytokine storm. 1. What are the risk factors for cytokine storms? One of the challenging clinical questions about cytokine storms is why some individuals appear highly susceptible but others appear relatively resistant, and there is much research to identify the underlying genetic mechanisms. Recent studies have demonstrated a large amount of variability in the innate immune response of healthy humans, as reflected by intermediate phenotypes of blood cytokine responses to bacterially produced products or substances. Hyper- and hyporesponders to bacterial products can be identified in healthy populations, partly explained by genetically determined differences in the structure and function of TLR receptors, especially TLR1. In a large population of sepsis patients, patients with single nucleotide polymorphisms (SNPs) tagging TLR1 hyperfunctioning variants have increased organ dysfunction and morbidity from Gram-positive bacteremia. Other genetic polymorphisms also contribute to the severity of the host response to sepsis and cytokine storm, but TLR1 polymorphisms have a particularly strong association with Gram-positive infections. Variants of TLR4, the major receptor for lipopolysaccharide (LPS), may predispose individuals to sepsis, as evidenced by increases in systemic inflammatory markers, including C-reactive protein (CRP), LPS-binding protein, and peripheral leukocytes in healthy humans exposed to endotoxin. Genome-wide association studies (GWAS) have linked TLR4 polymorphisms to increased susceptibility to pathogens and disease severity. For example, TLR4 Asp299Gly occurs with high frequency in Ghanaian children with severe malaria, and the polymorphism is also associated with malaria manifestations during pregnancy in Ghanaian women. GWAS recently identified several polymorphisms in the cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a member of the SOCS family that controls IL-2 signaling, that is associated with increased susceptibility to bacteremia, tuberculosis, and malaria in people in Gambia, Hong Kong, Kenya, Malawi and Vietnam. Several GWAS have also identified IFN--3 variants that are associated with spontaneous resolution and successful treatment of hepatitis C virus (HCV) infection. Potential of polyethylene glycol (PEG)-IFN--1 as a new therapy in the treatment of HCV is currently under investigation, though will likely become less reliant on PEG-IFN therapy with the development of new HCV drugs such as the protease inhibitor telaprevir.Because genetics has an important role in differential disease phenotypes, new mouse resources such as Collaborative Cross are being used to further investigate host genetics and the biological pathways involved in controlling microbes. Studies investigating host responses to influenza among genetically different recombinant inbred mice, such as the BXD RI line derived from a cross between DBA/2J and C57BL/6J mice, have demonstrated increased transcriptional responses associated with inflammation and antiviral immunity in mice. who are more susceptible to infection. Future investigations will likely reveal underlying genetic variants influencing host responses that contribute to the cytokine storm during infection Innate and adaptive immune cells are involved in the genesis of the cytokine storm, as well as macrophages, for example, in the following conditions: MAS, CART-cell therapy -associated cytokine release syndrome, ever acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Activated macrophages can produce several pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, IL6, and IL-18, which can trigger an inflammatory cascade, resulting in a cytokine storm. Hemophagocyte macrophages are frequently observed in the bone marrow and other tissues of patients exposed to cytokine storm, possibly contributing to the cytopenias commonly observed in this condition.