Either excessive or deficiency of molecular or cellular immune elements may predispose to unprotective granuloma or defense against Mtb. The diagram illustrates that either deficiency or excessive of specific immune components (x-axis) may result in increased susceptibility and severity of TB (y-axis). Using the immune checkpoint inhibitors as an example, we posit that in conditions where the host is either severely immunocompromised, immune checkpoint inhibition would be beneficial against mycobacterial infection, as exemplified by: (i) advanced AIDS patient with severe mycobacterial infection that improved with an anti-PD-1 antibody and (ii) TIM3 antagonism or TIM3 gene knockout mice are protected against mycobacteria in the less immunocompetent BALB/c mice. In contrast, in hosts with better preserved immune function, immune checkpoint inhibition results in a hyperinflammatory state, worsening control of mycobacterial infections, as exemplified by the mice with genetic disruption for PD-1 or PD-L1 gene. Perhaps the severity of TB is not as severe in the PD-L1 knockout mice than the PD-1 knockouts because in the PD-L1 knockout mice, PD-L2 is still intact and thus the enhanced immune activation with the genetic disruption of PD-L1 is not as severe as of PD-1. We have also shown other molecular and cellular components in which deficiency or excess predispose to TB. See also text and Table 2 for further discussion. AIDS, acquired immunodeficiency syndrome; HIF-1α, hypoxia-inducible factor 1-alpha; HO-1, heme oxygenase-1; ICI, immune checkpoint inhibitor; IDO-1, indoleamine 2,3-dioxygenase; IFNγ, interferon-gamma; IL-12, interleukin-12; IL-17, interleukin-17; LTA4H, leukotriene A4 hydrolase; MAC, Mycobacterium avium complex; MP, macrophages; MMP, matrix Mtb, Mycobacterium tuberculosis; NFκB, nuclear factor-kappa B; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand-1; TB, tuberculosis; TGFβ, transforming growth factor-beta; TNF, tumor necrosis factor.
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