Pediatric tuberculosis (TB) remains one of the most important communicable diseases and represents a major health problem in the developing world. Globally, approximately 1 million new cases and approximately 500,000 deaths due to pediatric TB are reported every year [1, 2].
In Italy, similar to many other industrialized nations, TB is a relatively rare disease. In the last few years, the incidence of TB has been less than 10 cases/100,000 population (in 2009 the rate was 7/100,000 population, corresponding to just over 4,200 cases) while according to WHO estimates, the prevalence of latent infections is 12% (corresponding to just over 7,200,000 latent infections) .
While 90% of immunocompetent adult patients infected by the tubercle bacillus will not develop the disease during their lifetime, children have shown various clinical forms of infection and progressive disease [2, 3]. Although pulmonary TB tends to be the most common form of TB, TB of the central nervous system (CNS) carries the highest mortality and morbidity rates and develops in 4% of infected children, especially during infancy [4–6].
It is well known that the immune system of a child is too immature to stimulate a host protective response against intracellular pathogen growth. Some progress towards understanding the mechanism involved in immune responses to Mycobacterium tuberculosis infection has been made by studying adult patients. However, other aspects need to be assessed through research in pediatric populations. The relevant role of apoptosis (programmed cell death) in the development of the immune system in children has recently been highlighted in studies on the efficacy of the TB vaccine [7, 8].
Recent studies have demonstrated that M. tuberculosis actively interferes with the apoptosis of infected cells in vitro as a means of virulence, and that dysregulation of the host's lipid metabolism is a major pathway for generating pathology and promoting necrosis over apoptosis [9, 10]. However, the importance of apoptosis as a virulence mechanism in vivo and interaction of apoptotic mechanisms with the host cytokine response have been largely unexplored until recently, with this area of research slowly being understood [10–12].
A number of alternative mechanisms of peripheral T cell apoptosis have been defined. The distinction has been made between active apoptosis, which follows stimulation and activation of the T cells, and passive apoptosis, which occurs as a result of withdrawal of the sustaining cytokines following activation [13–16]. Activation of death receptors by their ligands can initiate apoptosis. Fas and Tumor Necrosis Factor (TNF) receptors are more clearly understood than others, and their important role in peripheral T cell apoptosis has been demonstrated. The Fas/Fas ligand (FasL) interaction is particularly important in initiating activation induced cell death of CD4+ T cells [17–20].
Understanding the specific mechanisms by which children's T cells fail to contain Mycobacterium TB infection could offer potential new targets for appropriate vaccines. In addition, studying the defects in infant immune responses that explain poor bacterial control may contribute more broadly to our understanding of severe forms of TB such as CNS TB.
In this study, we analyzed spontaneous T lymphocyte (PBT) apoptosis and the subsets CD3+, CD4+ and CD8+, including the analysis of apoptotic CD8+/CD28+ T cells, in the peripheral blood of children with CNS TB, before and after starting anti tubercular treatment and compared them with healthy control children.