Figure 1. The IFN-γ/IL-12, IL-23, IL-17 axis and NADPH complex in host defense against pathogens.

Mycobacteria are recognized and phagocytosed, leading to IL-12 (p40/p35) secretion by macrophages. Binding of IL-12 to its receptor on the surface of T _H1 (or NK) cells activates the downstream JAK2 and TYK2 signaling cascade, resulting in STAT4 phosphorylation and dimerization. STAT4 homodimers translocate to the nucleus and induce the transcription of IFN-γ. Phosphorylated STAT1 homodimers translocate to the nucleus, resulting in the transcription of host defense genes. Similarly, IL-23 comprising the p40 and p19 subunits binds to the IL-23 receptor, leading to JAK2/TYK2 activation and STAT3 phosphorylation, dimerization, and nuclear translocation, where it associates with IRF4 and RORγt in the transcription of IL17- , IL21- , and IL22-related genes. The membrane-bound gp91 ^phox and p22 ^phox heterodimer (cytochrome b558) is stabilized by the transmembrane chaperone protein EROS. The remaining cytosolic components, p67 ^phox, p47 ^phox, and p40 ^phox, along with RAC2-GTP, associate to form the activated NADPH complex. Secondary signal from CD40/CD40L signaling activates the NF-κB pathway. GATA2, GATA binding factor 2; gp, glycoprotein; IFN, interferon; IFNG, interferon gamma; IFNGR, interferon gamma receptor; IL, interleukin; IL-12RB, IL-12 receptor subunit beta; IRF4, interferon regulatory factor 4; JAK2, Janus kinase 2; NAPDH, nicotinamide adenine dinucleotide; NEMO, nuclear factor-κB essential modulator; NF-κB, nuclear factor-κB; NK, natural killer; RAC2, Rac family small GTPase 2;RORγt, RAR-related orphan receptor γt; STAT, signal transducer and activator of transcription; T _H1, T helper type 1; TYK2, tyrosine kinase 2. This figure is adapted and amended with permissions, from Figure 3 in Abers, A, Lionakis, M. Chronic mucocutaneous candidiasis and invasive fungal infection susceptibility. In: Sullivan, K.E, Stiehm, E.R Stiehm's Immune Deficiencies-Inborn Errors of Immunit. p1–44. 2nd ed. Copyright Elsevier Science & Technology. 2020 ³⁷.

This figure is adapted and amended with permissions, from Figure 3 in Abers, A, Lionakis, M. Chronic mucocutaneous candidiasis and invasive fungal infection susceptibility. In: Sullivan, K.E, Stiehm, E.R Stiehm's Immune Deficiencies-Inborn Errors of Immunit. p1–44. 2nd ed. © Academic Press