Hemophagocytic lymphohistiocytosis caused by STAT1 gain-of-function mutation is not driven by interferon-γ: A case report

Figure 1 Clinical manifestation and results of gene sequencing. A: Bacille Calmette-Guerin vaccination scar was flushed and swollen; B: Sanger sequencing result of STAT1 of the patient (B1), father (B2) and mother (B3) indicated spontaneous mutation of STAT1(c.1154C>T); C: Cavitary lesion in the lung before and after antifungal therapy.

Figure 2 Pathophysiology of STAT1 gain-of-function mutation causing hemophagocytic lymphohistiocytosis and infection. In Mycobacterium bovis infection, Toll-like receptor 9 is activated by the pathogen, which then induces persistent phosphorylation of STAT1 due to its gain-of-function mutation, together with interferon-γ, leading to the overwhelming activation of phagocytic cells, resulting in hemophagocytic lymphohistiocytosis. In addition, increased STAT1 phosphorylation inhibits interleukin (IL) 12R/IL-23R signaling, leading to diminished T helper (Th) 1/Th17 and IL-12 responses, which then increase susceptibility to various infections. HLH: Hemophagocytic lymphohistiocytosis; TLR9: Toll-like receptor 9; IL-12: interleukin-12; Th1: T helper 1.