Fig. 2.

How does infection trigger persistent inflammation in XLP‐2? During infection by EBV, Listeria monocytogenes, or Candida albicans in normal healthy individuals (left), intact innate immunity generates moderate amounts of inflammatory cytokines such as TNF, IL‐6, and IFN‐γ that help control pathogen replication. Consequently, the pathogens are cleared and inflammatory cytokines subside. In contrast, XIAP‐deficient individuals cannot handle the same infections due to defective NOD2 and dectin‐1 signaling pathways (right). Accordingly, inflammatory cytokine levels are low upon immediate infection. The inability to control the pathogen results in increased pathogen load and PAMPs. Moreover, XIAP‐deficient cells are more susceptible to apoptosis, pyroptosis, and necroptosis, leading to the release of DAMPs. This buildup of PAMPs and DAMPs results in persistent release of inflammatory cytokines that further induce inflammatory cell death. The excess in inflammatory cytokines leads to severe disease and mortality.