In addition to more efficiently focusing activating signals on infected macrophages, the antigen-specific induction of macrophage activation may play an important role in limiting tissue injury. By targeting only infected macrophages through MHC:peptide recognition, TH1 cells minimize ‘collateral damage’ that might otherwise result to normal components of the inflamed tissue: oxygen radicals, NO, and proteases that are toxic to host cells as well as to the pathogen that is targeted for destruction. Thus, antigen-specific macrophage activation by TH1 cells is a means of deploying this powerful defensive mechanism to maximum effect while minimizing local tissue damage. In this regard, it is notable that although ILC1s are also producers of IFN-γ, they lack antigen receptors that can focus the cytokine on infected macrophages for more efficient activation. It is not yet known whether ILC1 cells have other mechanisms with which to direct IFN-γ onto macrophages, or whether they play a more limited role in macrophage activation, but the IFN-γ they produce is important in indirectly enhancing the local inflammatory response.
11-7 Chronic activation of macrophages by TH1 cells mediates the formation of granulomas to contain intracellular pathogens that cannot be cleared.
Some intracellular pathogens, most notably Mycobacterium tuberculosis, are sufficiently resistant to the microbicidal effects of activated macrophages that they are incompletely eliminated by a type 1 response. This gives rise to chronic, low-level infection that requires an ongoing TH1 response to prevent pathogen proliferation and spread. In this circumstance, chronic coordination between TH1 cells and macrophages underlies the formation of the immunological reaction called the granuloma, in which microbes are held in check within a central area of macrophages surrounded by activated lymphocytes (Fig. 11.13). A characteristic feature of granulomas is the fusion of several macrophages to form multinucleated giant cells, which can be found at the border of the central focus of activated macrophages and the lymphocytes that surround them and which appear to have heightened antimicrobial activity. A granuloma serves to ‘wall off’ pathogens that resist destruction. In tuberculosis, the centers of large granulomas can become isolated and the cells there die, probably from a combination of lack of oxygen and the cytotoxic effects of activated macrophages. As the dead tissue in the center resembles cheese, this process is called ‘caseous’ necrosis. Thus, the chronic activation of TH1 cells can cause significant pathology. The absence of the TH1 response, however, leads to the more serious consequence of death from disseminated infection, which is now seen frequently in patients with AIDS and concomitant mycobacterial infection.
11-8 Defects in type 1 immunity reveal its important role in the elimination of intracellular pathogens.
In mice whose gene for IFN-γor CD40 ligand has been deleted by gene targeting, classical macrophage activation is impaired; consequently, the animals succumb to sublethal doses of Mycobacterium, Salmonella, and Leishmania species. Classical (M1) macrophage activation is also crucial in controlling vaccinia virus. However, although IFN-γ and CD40 ligand are probably the most important effector molecules synthesized by TH1 cells, the immune response to pathogens that proliferate in macrophage vesicles is complex, and other cytokines secreted by TH1 cells may also be crucial (see Fig. 11.12).