In the standard-setting:

  1. Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells eliminate infected or tumour cells via apoptosis
  2. When the cells are cleared, the CTLs will inhibit further antigen presentation by removing antigen‐presenting Dendritic Cells (DCs)
  3. T-Regulatory Cells (Tregs) compete with and limit the proliferation of CTLs. They may also directly eliminate activated CTLs
  4. NK cells likewise control the size of the activated CTL pool via induction of apoptosis
  5. This limits the amount of CTL‐derived IFN‐γ. This is required for macrophage activation and additional cytokine production, and so this becomes limited.

In the setting of HLH:


  1. Dysregulated immune system unable to restrict the stimulatory effect of various triggers (due to single or combined defects):
    • CTLs and NK cells fail to eliminate tumour cells or infected cells, which continue to replicate, resulting in persistent antigenemia
    • CTLs no longer remove the antigen-presenting DCs, leading to prolonged and heightened antigen presentation
    • T Regulatory Cells are unable to regulate CTLs due to imbalanced cytokines. T regulatory cell numbers drop, and CTLs continue to proliferate.
    • NK fail to control the size of the activated CTL pool due to loss of cytotoxic activity
  2. The activated CTLs produce massive amounts of IFN‐γ:
    • Induces excessive macrophage activation
    • Directly provokes haem phagocytosis.
  3. Activated macrophages release vast amounts of pro-inflammatory cytokines (a ‘cytokine storm’):
    • Interleukins: (IL)-1, IL-6, IL-10, IL-12, IL-16, IL-18
    • Tumour necrosis factor (TNF)
  4. Results in ongoing cycles of inflammation and cytokine release:
    • Exacerbated by failure to clear cells via apoptosis resulting in necrosis and further inflammation