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Summary: Tuberculosis (TB) kills more people than any other single infectious disease globally. Despite decades of research, there is no vaccine to prevent TB transmission. Bacille Calmette–Guérin (BCG) vaccine, developed a century ago, is effective against childhood (disseminated and miliary) TB. However, its protective efficacy against pulmonary TB varies from 0 to 80% in different populations. One of the main reasons for the lack of an effective vaccine against TB is the lack of complete understanding about correlates of protective immunity on which to base vaccine design and development. However, some household contacts who are extensively exposed to Mtb infection remain persistently negative to tuberculin skin test and interferon‐gamma assay. These individuals, called 'resisters', clear Mtb infection early before the development of acquired immunity. The immunological basis of early Mtb clearance is yet to be established; however, innate lymphocytes such as monocytes/macrophages, dendritic cells, neutrophils and natural killer cells, and innate‐like T cells such as mucosal‐associated invariant T cells, invariant natural killer (NK) T cells and gamma‐delta (γδ) T cells, have been implicated in this early protection. In recent years, NK cells have attracted increasing attention because of their role in controlling Mtb infection. Emerging data from animal and epidemiological studies indicate that NK cells play a significant role in the fight against Mtb. NK cells express various surface markers to recognize and kill both Mtb and Mtb‐infected cells. This review presents recent advances in our understanding of NK cells in the fight against Mtb early during infection, with emphasis on cohort studies. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) early secreted protein antigen 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are among candidate vaccines against tuberculosis (TB). Results of experimental animal models show that these antigens are associated with induction of strong T cell immunity [interferon (IFN)-γ production], while others report that these proteins as virulent factors involved in pathogenicity of Mtb infection. However, the role of ESAT-6/CFP-10 during natural Mtb infections in humans has not been established. In this paper we present results of a longitudinal study from an Mtb-infected human population from an endemic setting. Whole blood assay was used to determine levels of IFN-γ, tumour necrosis factor (TNF)-α and interleukin (IL)-10 against rESAT-6/CFP-10 in TB patients, household contacts and community controls. The levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 at baseline were significantly higher in patients and community controls than in household contacts. In patients, no significant difference was observed in the level of these cytokines before and after chemotherapy whereas, in contacts, the level of these cytokines increased significantly and progressively over time. The study shows that the levels of IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are depressed during Mtb infection or exposure but are elevated during clinical TB. Our findings from a study of naturally infected human population suggest that IFN-γ, TNF-α and IL-10 against rESAT-6/CFP-10 are markers for clinical TB but not for protective immunity. [ABSTRACT FROM AUTHOR]

Bacille Calmette-Guérin (BCG), developed a century ago, is the only licensed tuberculosis (TB) vaccine in use to date. The protective efficacy of BCG against TB varies with no apparent protection in some population, and mechanisms of its immune protection is poorly known, and yet BCG is the most widely used vaccine, with more than 4 billion BCG-vaccinated children globally. BCG is probably the only licensed vaccine currently in use believed to mediate immune protection through the production of interferon (IFN)-γ by CD4 T cells, which in turn activates macrophages to kill Mycobacterium tuberculosis ( Mtb). Currently, a number of new TB candidate vaccines are in different phases of clinical trial. The majority of these new vaccines are either recombinant forms of BCG or prime boosters of BCG (rBCG) and their immunogenicity is tested using BCG as a benchmark by measuring specific IFN-γ produced by CD4+ T cells as a protective immune marker. However, some recent studies that examined mechanisms of immune protection of BCG in animals and humans have reported a lack of correlation between IFN-γ production by CD4 cells and BCG-induced immune protection. These studies point to the fact that there is a missing link in our understanding of TB immunology. Conversely, there is emerging evidence that other T cell subsets (gammadelta, γδ), CD8+ T cells and natural killer (NK) cells may play a vital role in immune protection against Mtb infection and BCG-induced immune protection. γδ T cells and NK cells, which were considered to be part of the innate immunity in the past, have been shown to develop immunological memory upon re-encounter with the same pathogen. In this paper, the controversy over the role of IFN-γ as a marker for protective immunity against TB, and emerging data on the role of γδ T cells, CD8+ and NK cells in TB immunology, will be presented. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis ( Mtb) is one of the most important infectious diseases globally. Immune effector mechanisms that lead to protection or development of clinical disease are not fully known. It is generally accepted that cell-mediated immunity (CMI) plays a pivotal role in controlling Mtb infection, whereas antibody responses are believed to have no protective role. This generalization is based mainly on early classical experiments that lacked standard protocols, and the T helper type 1 (Th1)/Th2 paradigm. According to the Th1/Th2 paradigm Th1 cells protect the host from intracellular pathogens, whereas Th2 cells protect form extracellular pathogens. During the last two decades, the Th1/Th2 paradigm has dominated not only our understanding of immunity to infectious pathogens but also our approach to vaccine design. However, the last few years have seen major discrepancies in this model. Convincing evidence for the protective role of antibodies against several intracellular pathogens has been established. Studies of B cell-deficient mice, severe combined immunodeficiency (SCID) mice, passive immunization using monoclonal (mAb) and polyclonal antibodies and immune responses against specific mycobacterial antigens in experimental animals reveal that, in addition to a significant immunomodulatory effect on CMI, antibodies play an essential protective role against mycobacterial infections. In this review, our current understanding of the essential role of antibodies during Mtb infections, limitations of the Th1/Th2 model and the unfolding interdependence and mutual regulatory relationships between the humoral and CMI will be presented and discussed. [ABSTRACT FROM AUTHOR]

The world is confronted with major tuberculosis (TB) outbreaks at a time when the protection of bacillus Calmette–Guérin (BCG) vaccine has become inconsistent and controversial. Major TB outbreaks are caused by a group of genetically similar strains of Mycobacterium tuberculosis ( Mtb) strains, including the Beijing family genotypes. The Beijing family genotypes exhibit important pathogenic features such high virulence, multi-drug resistance and exogenous reinfection. These family strains have developed mechanisms that modulate/suppress immune responses by the host, such as inhibition of apoptosis of infected macrophages, diminished production of interleukin (IL)-2, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and elevated levels of IL-10 and IL-18. They demonstrate distinct expression of proteins, such as several species of α-crystallin (a known Mtb virulence factor), but decreased expression of some antigens such as heat shock protein of 65 kDa, phosphate transport subunit S and a 47-kDa protein. In addition, the Beijing family strains specifically produce a highly bioactive lipid (a polyketide synthase)-derived phenolic glycolipid. This altered expression of proteins/glycolipids may be important factors underlying the success of the Beijing family strains. The Beijing family strains are speculated to have originated from South-east Asia, where BCG vaccination has been used for more than 60 years. The hypothesis that mass BCG vaccination may have been a selective factor that favoured genotypic and phenotypic characteristic acquired by the Beijing family strains is discussed. [ABSTRACT FROM AUTHOR]

There are speculations that the puberty-related hormone dehydroepiandrosterone sulphate (DHEAS) might influence the intensity of infection and immune responses during Schistosoma infections. We studied the relationships between DHEAS, intensity of Schistosoma mansoni infection and humoral immune responses in 135 residents of Ethiopia. Serum levels of eight antibody isotypes against worm and egg antigens were determined by ELISA. DHEAS was measured with an immunoluminometric assay. There was a significant negative correlation between serum levels of DHEAS and intensity of S. mansoni infection. A significant increase in serum levels of DHEAS in the age group 15–19 years was accompanied by a progressive decline in the intensity of infection. Peak level of DHEAS coincided with the lowest intensity of infection in the age group 20–29 years. Multiple regression analysis showed that DHEAS alone had a significant (p<0.0001) negative effect when the effect of age was removed. Age also had a significant (p<0.0001) negative effect on the intensity of infection, after removing the effect of DHEAS. The two predictive variables accounted for 34.4% of the decline in the intensity of infection. Age accounted for 24.9%, whereas DHEAS accounted for 15.2% when the effect of each of the variables was removed. DHEAS had significant negative effects on AWA-specific IgG (p=0.02) and IgG1 (p=0.018) and SEA-specific IgG1 (p=0.009), after adjusting for the effect of age. [ABSTRACT FROM AUTHOR]