Innate Response to Tetanus Toxoid

Effect of Tetanus Toxin on Macrophages
The lysozyme activity of GG2EE macrophages has been found to decrease upon exposure to tetanus toxoid.  In a study by Pitzurra et al. (1993), macrophages treated with tetanus toxoid showed a dose-dependent decrease in the upregulation of lysozyme mRNA.  However, exposing macrophages to tetanus toxin fragments or heat-inactivated toxin does not produce such inhibitory effects.  Interestingly, this reduction in lysozyme activity is only seen in macrophages that are preincubated with IFN-γ.  It is believed that IFN-γ promotes the expression of tetanus toxin receptor sites on the macrophage surface, which allow for toxin binding and ingestion of the molecule.

The pathways of secretion for both phagocytes and neurons seem to be quite similar, since both employ stimulation-secretion coupling mechanisms. Additionally, ionized intracellular calcium acts as a messenger in both secretion pathways. As a result, it is believed that the mechanism by which tetanus exerts its toxic effects is similar in both macrophages and neurons (Pitzurra et al., 1993).

The Tetanus Endotoxin
Tetanus toxoid exists as a structural component of the tetanus bacterium cell membrane, and is also known as an endotoxin, or lipopolysaccharide (LPS, Figure 1). 

Figure 1. Structure of the cell wall of a bacterium, such as C. tetani, that contains endotoxic molecules on its surface (Beutler et al., 2003).

Mice exposed to purified TNF display symptoms similar to those elicited by exposure to LPS; in addition, mice that are immunized with anti-TNF antibodies and exposed to LPS show a marked decrease in LPS toxicity.  Therefore, it seems that macrophages can act to augment the effects of the tetanus endotoxin, since these cells are responsible for the production of TNF.

The specific mechanism by which macrophages augment the effects of tetanus toxoid remains unknown.  However, LPS-binding protein (LBP) is a plasma protein produced by the liver that was found to bind LPS.  Such binding seems to increase the sensitivity of mononuclear cells to LPS, thereby increasing the toxic effects of the endotoxin (Beutler et al., 2003).

This web page was produced as an assignment for an undergraduate course at
Davidson College.

Contact: cahermes@davidson.edu