Date Published: December 22, 2009
Publisher: Public Library of Science
Author(s): Olivier Neyrolles, Lluis Quintana-Murci
Abstract: Olivier Neyrolles and Lluis Quintana-Murci review the evidence on why tuberulosis notification is twice as high in men as in women in most countries.
Partial Text: Tuberculosis (TB) claims over 1.7 million lives throughout the world each year according to the most recent World Health Organization (WHO) report . Men seem to be more affected than women, with a male/female ratio of 1.9±0.6 for the worldwide case notification rate (Box 1; Figure 1) . In some countries this ratio may reach values as high as 3 (4.7 in Armenia for instance), but ratios below 1 are extremely rare and mostly correspond to very small populations of patients . This excess of male pulmonary TB cases is seen in all regions of the world, and in almost all countries (Figure 2A), at least in non–HIV-infected patients. It is also seen in adults of all ages, but does not seem to apply to children and young adolescents (Figure 2B).
The effects of sex steroid hormones on the immune response to infection and other noninfectious immune disorders, and, more generally, the interplay between the endocrine and the immune systems, are widely documented in humans and animal models –. Simple experiments in castrated and hormone-reconstituted animals can reveal the influence of sex hormones on immune functions. For example, it has been reported that androgen deprivation due to the castration of male mice leads to an increase in the absolute number of T lymphocytes in the peripheral lymph nodes and an increase in the proliferation of these cells following antigen recognition .
It is now widely accepted that host genetic factors play a major role in determining differential susceptibility to infection and disease outcome in humans ,. Most studies in the context of TB have investigated the role of specific candidate genes, chosen on the basis of the effects of their murine orthologs on the response to experimental mycobacterial infections or the known biology of the disease. Despite the fact that the quality of these studies varies greatly, genetic variation in an increasing number of genes (e.g., NRAMP1, HLA class II, VDR, MAL/TIRAP, DC-SIGN, MCP-1, TLR8) has been found to be associated with complex susceptibility to pulmonary TB (reviewed in ,).
Sex-specific features of nutrition and metabolism may also be associated with susceptibility or resistance to M. tuberculosis. Iron, for instance, is a crucial component of several enzymes and redox systems in mycobacteria, as in all living organisms. The extrusion of iron from the microbial vacuole has long been recognized as an innate immune system mechanism, conserved throughout evolution, for host phagocyte control of various intracellular pathogens, including mycobacteria . Iron deficiency is common in women from developing and industrialized countries . It remains unclear whether anemia is correlated with greater resistance to TB in humans. However, experimental evidence from animals suggests that iron overload increases permissiveness to M. tuberculosis considerably, both in vivo  and in vitro .
Large prevalence surveys have suggested that the sex bias observed in pulmonary TB cases may result partly from genuine biological differences in male and female susceptibility to M. tuberculosis infection or the development of TB disease. This finding would not be particularly surprising, as many studies in humans and experimentally infected animals have established clear links between sex-specific factors, including steroid hormones and genetic variants, and the differential susceptibility of males and females to a number of other infectious and noninfectious diseases. In particular, gender bias among pulmonary microbial diseases is not restricted to TB, and important sex differences in the incidence and severity of a number of respiratory tract bacterial infections have been reported in the literature . As a selected example, it has been shown that men have a 4-times higher risk of developing nosocomial Legionella pneumophila infection than women .