Footprints of genetic susceptibility to pulmonary tuberculosis: Cytokine gene variants in north Indians

Tuberculosis (TB) causes significant morbidity and mortality throughout the world1. The vast majority of individuals infected with Mycobacterium tuberculosis (up to 95%) remain healthy, probably because of mounting an effective immune response against M. tuberculosis. In 1949, Haldane proposed that the maintenance of multiple genes that confer relative susceptibilities on the host to infectious diseases would be favoured by evolution. In support of this hypothesis, certain populations appear to be at risk for both increased susceptibility to infection2 and progressive clinical disease due to mycobacteria3. Several case-control studies have identified association between TB and candidate genes potentially involved in immune response to TB4,5. A growing body of evidence supports a role of host genetic components in the development of tuberculosis. The observation of familial clustering of disease with higher concordance of tuberculosis disease in monozygotic versus dizygotic twins6, the ethnic clustering of tuberculosis disease with a higher prevalence of tuberculosis in individuals of recent African descent2, as well as the demonstration of both common polymorphisms and rare mutations which confer susceptibility to mycobacterial species in humans7 point significantly in this direction. These studies suggest that unique environment and natural selective factors may be responsible for the development of ethnic-specific host genetic factors associated with TB. The first step in innate host defense is cellular uptake of M. tuberculosis, which involves different cellular receptors and humoral factors. The subsequent inflammatory response is regulated by the production of pro- and anti-inflammatory cytokines and chemokines. Interferon-gamma (IFN-γ one of the most important cytokines involved in macrophage activation, stimulating anti-tumour and anti-microbicidal activities as well as expression of MHC-II8,9. Interleukin-4 (IL-4), an anti-inflammatory cytokine has been implicated to downregulate IFN-γ, and thus has a deleterious effect on TB patients10. It also promotes the induction of Th2 cells11. IL-12, a heterodimeric pro-inflammatory cytokine produced by activated macrophages, monocytes, β-lymphocytes and dendritic cells is the principal Th1 response inducing cytokine11. This cytokine is important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to intracellular pathogen. Like tumour necrosis factor-alpha (TNF-α), IL-1β is mainly produced by monocytes, macrophages, and dendritic cells12. In tuberculosis patients, IL-1β is expressed in excess13 and at the site of disease14. Implicated mainly in tuberculosis pleurisy, a usually self-resolving type of primary tuberculosis, one may hypothesize that an increased IL-1β /IL-1Rα ratio protects against a more severe form of tuberculosis. TNF-β or lymhotoxin-alpha (LTα) is considered to be a proinflammatory cytokine and it is shown that secreted LTα is essential for the control of an intracellular bacterial infection15. Recently Allie et al16 suggested that LTα might not have a critical role in host defense to acute mycobacterial infection, independent of TNF, but certainly a contribution of LTα in the control of chronic M. tuberculosis infection is observed17. Association studies from north India probing multiple loci across the spectrum of candidate cytokine genes are scanty. The present study, therefore, was aimed to bring in focus certain unexplored polymorphisms in the context of tuberculosis susceptibility in north Indian population. The role and importance of genetic background in tuberculosis has now become univocal with ethnicity playing a crucial role. Probing new loci relating to tuberculosis susceptibility could suggest novel approach in pharmacogenomics and therapy to combat this pathogen. Also it could provide an insight into predicting individual's genetic proneness to tuberculosis and of being future diagnostic tool for preventive therapy against tuberculosis.