Figure 2.

Mechanisms of CRS in HLH, CAR-T cell therapy, and COVID-19. (a) In familial HLH, defects of granule-mediated cytotoxicity (e.g. perforin) in natural killers (NK) cells or cytotoxic lymphocytes (CTLs) lead to impaired killing of diseased human cells. When a trigger, such as a viral infection or genetic mutation occurs, the heightened antigen exposure results in activation of dendritic cells (DCs), whose elimination is further impaired due to defective NK/CTLs. DCs subsequently activate more NK/CTLs, leading to secretion of IFN-γ and activation of macrophages. In turn, macrophages secrete more pro-inflammatory cytokines, leading to a vicious cycle. (b) In CAR T-cell therapy, the CRS is the result of the interplay between CAR T-cells and bystander immune cells. When CAR T-cell and tumor cells are engaged, CAR T-cells are activated and start secreting IFN-γ, which can attract and activate the monocytes. Activated monocytes can secrete key CRS cytokines IL-1 and IL-6, which forms a vicious cycle by activating more monocytes. (c) The pathogenesis of CRS in COVID-19 is unclear. However, it could be secondary to direct infection and activation of immune cells through ACE-2 receptors by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Another possibility is that the complement system can be activated by SARS-CoV-2 infection, which triggers formation of C5a anaphylatoxin. The latter can directly activate neutrophils and monocytes, causing CRS. ACE, angiotensin-converting enzyme.