• Granulomatous inflammation and tissue damage. In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis. Macrophages activated by IFN-γ differentiate into the “epithelioid histiocytes” that aggregate to form granulomas; some epithelioid cells may fuse to form giant cells. In many individuals, this response halts the infection before significant tissue destruction or illness occur. In other individuals with immune deficits due to age or immunosuppression, the infection progresses and the ongoing immune response results in caseation necrosis. Activated macrophages also secrete TNF and chemokines, which promote recruitment of more monocytes. The importance of TNF is underscored by the fact that patients with rheumatoid arthritis who are treated with a TNF antagonist have an increased risk for tuberculosis reactivation.
In summary, immunity to a tubercular infection is primarily mediated by TH1 cells, which stimulate macrophages to kill mycobacteria. This immune response, while largely effective, comes at the cost of hypersensitivity and the accompanying tissue destruction. Defects in any of the steps of a TH1 T cell response (including IL-12, IFN-γ, TNF, or nitric oxide production) result in poorly formed granulomas, absence of resistance, and disease progression. Individuals with inherited mutations in any component of the TH1 pathway are extremely susceptible to infections with mycobacteria. Reactivation of the infection or reexposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as hypersensitivity and resistance appear in parallel, so, too, the loss of hypersensitivity (indicated by tuberculin negativity in a M. tuberculosis-infected patient) is an ominous sign of fading resistance to the organism.
Primary tuberculosis is the form of disease that develops in a previously unexposed and therefore unsensitized patient. About 5% of those newly infected acquire significant disease.
In the large majority of otherwise healthy individuals, the only consequence of primary tuberculosis are the foci of scarring discussed earlier. However, these foci may harbor viable bacilli and thus serve as a nidus for disease reactivation at a later time if host defenses wane. Uncommonly, new infection leads to progressive primary tuberculosis. This complication occurs in patients who are overtly immunocompromised or who have more subtle defects in host defenses, as is characteristic of malnourished individuals. Certain racial groups, such as the Inuit, also are more prone to the development of progressive primary tuberculosis. The incidence of progressive primary tuberculosis is particularly high in HIV-positive patients with significant immunosuppression (i.e., CD4+ T cell counts below 200 cells/µL). Immunosuppression results in an inability to mount a CD4+ T cell–mediated response that would contain the primary focus; because hypersensitivity and resistance are most often concomitant factors, the lack of a tissue hypersensitivity reaction results in the absence of the characteristic caseating granulomas (nonreactive tuberculosis) (see
Fig. 13.35D
Fig. 13.34 Primarypulmonarytuberculosis,Ghoncomplex.Thegray-whiteparenchymalfocus(arrow) isunderthepleurainthelowerpartoftheupperlobe.Hilarlymphnodeswithcaseationareseen(left).