Cytokine Storm-Definition, Causes, and Implications

Abstract

The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators). Usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death. Not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies. Due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce.

Keywords: CAR-T cell therapy; cytokine release syndrome; cytokine storm; immunity; invasive meningococcal disease; overwhelming post-splenectomy infection; post-cardiac arrest syndrome; sepsis.

Figure 1

Aspects of immunological dysfunction caused by sepsis with details of the entities involved. APC, antigen-presenting cell; BLC, B-lymphocyte chemoattractant; CD, cluster of differentiation; CNC, critical neutrophil concentration; IFN-y, interferon y; Ig, immunoglobulin; IL, interleukin; IP-10, IFN-gamma-inducible protein 10; MCP-1, monocyte chemoattractant protein-1; MHC II, major histocompatibility complex II; PD1, programmed death protein 1; sIL-1r, soluble interleukin-1 receptor; sTNFR, soluble tumor necrosis factor receptor; TCR, T-cell receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF-β, transforming growth factor β. Adapted from Bermejo-Martin JF with permission [151].