What these models may predict for human disease

The above observations appear to support the working hypothesis that certain strains of mice react to low dose aerosol infection by relying more heavily on innate mechanisms of immunity than other strains in which a prominent lymphocyte influx ensues. In both strain types we have observed an initial spike of mRNA for IFN-y in the lungs at this time (which rapidly decays in reactivating strains), suggesting that something (possibly yd or natural killer cells) is doing this, and that this is enough initially to control the infection. However, such a response scenario would not generate antigen-specific T cells, and (perhaps more importantly) memory T cells. In the absence of these effector cells the infection at some point reactivates, killing the mouse.

This may suggest that reactivation disease in humans has a genetic basis (excluding secondary infections, pulmonary vascular diseases, immuno-senescence, etc. as extraneous causes of reactivation). If correct, the above hypothesis implies that early decisions made in the lungs in terms of the triggering of innate versus acquired immunity subsequently influence/drive events leading to whether or not the individual has a memory T cell immuno-surveillance mechanism in place (Orme & McMurray 1996) and can hence prevent reactivation disease from occurring. Thus, the more the individual depends on innate mechanisms early during the infection, the more likely reactivation may occur at a later date.

I would also propose that this predisposition is not because Bcgr macrophages slow the infection down so less antigen is available; after all, the infection grows at an identical rate over this initial period. On the other hand, antigen presentation may be the key; macrophages from reactivation-prone individuals may be more catabolic or they may express co-stimulatory molecules differently (either failing to sensitize T cells or even inducing apoptosis in them). The mechanism does not seem to apply at higher bacterial loads when reactivation has begun; under these conditions some lymphocyte accumulation can be seen in the Beg1 mouse strains.

A cknowledgements

This work was supported by National Institutes of Health grants AI-40488 and AG-06946. I thank Tony Frank, Beth Rhoades, Joanne Turner and Bernie Saunders for helpful discussions.

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