What is it about?
Human tuberculosis (TB) is a heterogeneous disease whose complexity mostly originates from the host genetic susceptibility, which facilitates the progression into disease from the primary infection; moreover, the immunological memory being compounded by infection of other mycobacteria beyond M. tuberculosis, and the immunological background being altered by helminths and/or HIV infection. M. tuberculosis generally in aerosol particles are acquired via the respiratory route and deposited in the lung alveoli; thereafter, are taken up by alveolar macrophages, interstitial lung macrophages, dendritic cells, neutrophils, and natural killer (NK) cells. If these innate immunity effector cells fail to control the infection locally, dendritic cells and macrophages migrate to the regional lymph nodes and present M. tuberculosis antigens to T cells. This triggers an acquired immune response by which antigen-specific T cells migrate backward to the lung primary infection site and secrete cytokines, such as IFN-γ, that enhance macrophage, mostly NO-mediated microbicidal activity; or, being directly cytotoxic toward heavily infected macrophages by secreting granulysin and perforin. This can result in effective killing of all tubercle bacilli, the formation of infectious granulomas that wall off the bacilli and prevent further dissemination of the infection or can prove ineffective, giving rise after the development of primary TB disease to the spreading of bacilli from the lung to other organs (extra-pulmonary, disseminated TB). Meanwhile, humoral immunity is at work but until recently the role of antibodies –particularly, IgG and IgA- production by B cells in the defense against M. tuberculosis infection was quite enigmatic.
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Why is it important?
After accomplishment of the Millennium Development Goal (halting and reversing TB incidence by 2015), the 2015 Stop TB Partnership aims for a 95% reduction in TB mortality and a 90% reduction in TB incidence by 2035. Since bacillus Calmette Guerin (BCG) vaccination of newborns does not reliably protect them in adolescence or adulthood against pulmonary TB responsible for bacillary transmission, and the continuous emergence of multidrug-resistant strains of M. tuberculosis jeopardizes anti-TB chemotherapeutics effectiveness, to meet this goal the introduction of new and more efficacious interventions, such as novel vaccines, is necessary.
Perspectives
Although almost all current TB vaccine candidates are consistent with a single paradigm, i.e. the containment of M. tuberculosis infection by host immunity mediated by conventional T cells, as the first and only new candidate so far evaluated in a clinical end point trial recently failed, they all share an inherent risk of failure. However, nowadays the role of humoral immunity seems to be increasing in importance. Here and in the following review articles of the same group of Authors, relevant findings that depict the host immune system responses and susceptibility to M. tuberculosis infection, as well as mycobacterial antigens that are able to elicit effective immune responses in experimental animal models of TB, are under review with aim of unveiling novel drug targets.
professor giampietro g sgaragli
university of siena
Read the Original
This page is a summary of: Human Tuberculosis I. Epidemiology, Diagnosis and Pathogenetic Mechanisms, Current Medicinal Chemistry, September 2016, Bentham Science Publishers,
DOI: 10.2174/0929867323666160607222854.
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