Immunity and Immunotherapy on Tuberculosis

Tuberculosis is caused by infection with Mycobacterium tuberculosis, a bacillus bacterium. It is spread by aerosol droplets and causes tissue damage in lungs and other organs including bones, joints, liver, spleen, gastrointestinal tract and brain. About 10-15% of people infected develop disease. Poverty and malnutrition contribute to the perseverance of tuberculosis.

Mycobacterium tuberculosis is an intracellular pathogen which replicates within alveolar cells. M. tuberculosis enters the human host through inhalation of small sputum particles. M. tuberculosis initially infects macrophages. M. tuberculosis is surrounded by a lipid rich outer capsule which protects it from the toxic radicals and hydrolytic enzymes produced by macrophages. Activated macrophages possess potent bactericidal activity which can kill bacilli and arrest TB infection, but generally cannot eliminate infection entirely. In fact, pathogens can replicate in macrophages. Other essential mechanisms of antimycobacterial immunity include the destruction of infected cells by cytolytic T lymphocytes.

Initial growth of M. tuberculosis results in a delayed type hypersensitivity (DTH) response which is characterized by the formation of small necrotic lesions with solid caseous centers. M. tuberculosis multiplication is probably restricted while encapsulated in these granulomatus lesions. Granulomas comprising T lymphocytes and mononuclear phagocytes of different levels of maturation and activation can form. After initiation of delayed-type hypersensitivity and tubercle formation, activation of macrophages by CD4+ T cells enables the macrophages to destroy bacilli within the tubercle. Macrophage activation appears to be a central step of acquired resistance against M. tuberculosis. CD4+ mediated DTH and cell immunity are thus closely related.

CD4+ T cells are primarily helper T cells which secrete interleukins involved in the activation of macrophages. Helper T cells are required to recruit and activate new monocytes and macrophages to the tubercle. CD4+ T cells are divided into TH1 and TH2 subsets depending on the type of cytokines produced. For example, IFN-gamma produced by TH1 cells specifically activates macrophages and stimulates them to ingest and kill mycobacteria more effectively. On the other hand, the cytokine interleukin-10 (IL-10), which is generally secreted by TH2 cells, downregulates TH1 cell activity and proliferation and enhances the survival of M. tuberculosis within macrophages. As a result, stimulation of IL-10 should be avoided for any possible immunotherapy including vaccines against TB.

The presence of an MHC Class I-restricted response to mycobacterial infection has been shown in several T lymphocytes. CD8+ cytotoxic T lymphocytes (CTLs) are able to recognize mycobacterial antigens presented by MHC Class I molecules on the surface of infected macrophages, and appear to be required for the release of intracellular M. tuberculosis residing in infected macrophages.

Gamma/delta T cells are a minor population of T lymphocytes whose role in immune protection against M. tuberculosis remains unclear. They might have a role in the initial, innate immune response to M. tuberculosis as their population is expanded by mycobacteria and mycobacterial products in tissues. These T cells also secrete IFN-gamma.

Natural killer (NK) cells may also play an important part of the host response against M. tuberculosis. NK cells are capable of lysing host cells infected with mycobacterial pathogens, similar to specific cytolytic T lymphocytes.

It is currently believed that both cytolytic T lymphocytes and IFN-g activated macrophages are necessary for conferring protective immunity against M. tuberculosis. However, massive activation of macrophages within tubercles accompanied by gush of lytic enzymes could result in necrotic tissue lesions.

How to eradicate Mycobacteria from an infected host has become a problem owing to the chronic and latent nature of the disease. Immunotherapy for tuberculosis holds a key to this issue. Vaccines, cytokines, and immunity-enhancing drugs or herbs have been actively explored in recent years. Effective solutions will be discovered as our understanding of the basic immunological mechanism progresses.