How tumour necrosis factor blockers interfere with tuberculosis immunity

Abstract

Tumour necrosis factor (TNF) is a potent inflammatory cytokine that plays an important role in immunity to numerous bacterial infections, including Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans. Infliximab, adalimumab, certolizumab pegol and etanercept are anti-TNF agents used to treat a range of inflammatory/autoimmune diseases, such as rheumatoid arthritis. The use of some of these drugs has been linked to reactivation TB. In addition to blocking TNF-mediated immune responses, some anti-TNF drugs have been found to interfere with innate immune responses, such as phagolysosomal maturation and monocyte apoptosis, as well as cell-mediated responses, including interferon-gamma secretion by memory T cells, complement-mediated lysis of Mtb-reactive CD8+ T cells and increased regulatory T cell activity. This review summarizes some of the reported effects of TNF blockers on immune cell responses in the context of the observed clinical data on TB reactivation in patients on anti-TNF therapy.

Fig. 1

Mycobacterium tuberculosis inhibits phagosome maturation. Normal phagosome maturation requires the recruitment of Rab5 to the phagosomal membrane, followed by the generation of phosphotidylinositol-3-phosphate (PI3P) by the phosphotidylinositol-3-kinase vps34. This leads to the recruitment of Rab5 effectors, including early endosome antigen 1 (EEA1) and hepatocyte growth factor-regulated tyrosine substrate (Hrs). Subsequent recruitment of Rab7 allows fusion with lysosomes, acidification of the phagosome and release of lysosomal hydrolases into the lumen of the mature phagosome. M. tuberculosis subverts this process through the release of lipoarabinomannan (LAM) and the PI3P phosphatase secreted acid phosphatase M (SapM), which prevents the generation and recruitment of PI3P to the phagosomal membrane. These phagosomes remain immature, but are still able to fuse with recycling endosomes that can transport nutrients, such as iron, thus providing a protective environment for bacterial survival and replication.

Fig. 2

Tumour necrosis factor (TNF) induces autophagy in macrophages. RAW264·7 murine macrophages or human phorbol myristate acetate (PMA)-differentiated monocyte/macrophage (THP-1) cells were treated with TNF for 2 h then fixed and stained with antibody against the autophagosome marker LC3, followed by secondary staining with Alexa 488-conjugated antibody [87]. (a) Confocal images of control and TNF-stimulated RAW264·7 cells showing TNF-induced LC3⁺ autophagosome formation (distinct punctate staining). (b) Quantitative analysis of LC3⁺ autophagosome formation in RAW264·7 cells treated with TNF (5 ng/ml). (c) TNF-induced LC3⁺ autophagosome formation is abrogated in RAW264·7 cells transfected with siRNA against beclin 1 (Atg6, white bars) or control siRNA (black bars). (d) TNF-induced LC3⁺ autophagosome formation in THP-1 cells. (e) TNF-induced LC3⁺ autophagosome formation in THP-1 cells is inhibited by the PI3K inhibitor 3-methyladenine (3-MA), a known inhibitor of autophagy.

Fig. 3

Tumour necrosis factor (TNF) blockers and immunity to tuberculosis (TB): potential points of interference. After ingestion of Mycobacterium tuberculosis, the ability of the macrophage phago-lysosomal compartment to acidify is TNF-dependent and phagosome maturation is inhibited by TNF blockers. TNF-induced autophagy may also play a role in phagosome maturation. Some TNF blockers also induce killing of T cells (and monocytes) by apoptosis, complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), while allowing expansion of immunosuppressive regulatory T cells. The net result may be reduced interferon-γ responses, coupled with increased interleukin-10 which, with other direct anti-TNF effects, may explain some of the observed increase in susceptibility to TB reactivation in patients treated with TNF blockers.