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Fig. 1 | BMC Medicine

Fig. 1

From: ‘”Why me, why now?” Using clinical immunology and epidemiology to explain who gets nontuberculous mycobacterial infection

Fig. 1

The immune response to mycobacterial infection and known sites of dysfunction. Human genetic syndromes which affect the immune response to mycobacterial infection are known to result from disorders in the following genes: ISG15, IL-12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IRF8, ISG-15, GATA2 and NADPH oxidase complex subunit genes such as CYBB. Nontuberculous mycobacteria (A) are phagocytosed (B), triggering release of IL-12 (C), a heterodimeric cytokine formed from the gene products of IL12A and IL12B, which binds a receptor heterodimer (D) of IL-12RB1 and IL-12RB2 on T cells and NK cells. Signalling to the nucleus mediated by TYK2 (E) then results in IFNγ production. IFN gamma binds its receptor (F), a heterodimer of IFNGR1 and IFNGR2, triggering phosphorylation of JAK2, JAK1, and STAT1 (G). The resultant phosphorylated STAT1 molecule homodimerises to form the pSTAT1 complex which translocates to the nucleus and binds the IFN gamma activating sequence. This triggers transcription of interferon stimulated genes (ISG) via IRF8 (H), and increases IL12, TNFα, ISG15 (I), and potentiation of macrophage activation. Activated macrophages demonstrate enhanced phagosome maturation and increased killing of intracellular pathogens, and upregulated antigen presentation, thereby activating Th1-phenotype T cells to proliferate and release further IFNγ. TNFα drives development of granulomas. IRF8 aids differentiation of myeloid progenitors into monocytes, and controls transcriptional responses of mature myeloid cells to interferons (IFNs) and Toll-like receptor (TLR) agonists. NFκB is a rapid-acting transcription factor modulated by NEMO (J) and activated by stimuli including signalling through CD40 (K), TLR (L), reactive oxygen species and TNFα. Activation allows a host of inflammatory and immune responses, including IL12 release. Effective intraphagosomal killing through reactive oxygen species requires an intact NADPH oxidase complex (M). Intact haematopoiesis of monocyte lineages is also required via GATA2 (N)

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