In the standard-setting:
- Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells eliminate infected or tumour cells via apoptosis
- When the cells are cleared, the CTLs will inhibit further antigen presentation by removing antigen‐presenting Dendritic Cells (DCs)
- T-Regulatory Cells (Tregs) compete with and limit the proliferation of CTLs. They may also directly eliminate activated CTLs
- NK cells likewise control the size of the activated CTL pool via induction of apoptosis
- 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:
- 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
- The activated CTLs produce massive amounts of IFN‐γ:
- Induces excessive macrophage activation
- Directly provokes haem phagocytosis.
- 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)
- Results in ongoing cycles of inflammation and cytokine release:
- Exacerbated by failure to clear cells via apoptosis resulting in necrosis and further inflammation