Gender Differences in Inflammatory Processes Could Explain Poorer Prognosis for Males

In their recent paper on the resurgence in mumps virus infections in Ireland (2), Carr et al. observed a strong (P < 10⁻³²) bias for acute mumps virus infection in males compared to females that was independent of vaccination status. The authors extrapolated to natural infections the gender differences in immune function observed in in vitro studies of human lymphoid cells and gender-based differences in humoral immunity with several vaccines, including those for influenza, hepatitis A, and measles virus. In another work on predicting sequelae and death after bacterial meningitis in childhood that was recently published (6), de Jonge et al. suggested that male gender is an important prognostic factor, a finding for which they do not have an explanation.

It is known that, even in animals (7), male gender predisposes to the development of shock in the form of, e.g., endotoxic shock in rats or in prepubertal acute respiratory distress syndrome (ARDS) patients with sepsis (1), a population in which an increased frequency (comparable to that of adults) of male patients is found. In contrast, the prognosis for females suffering from many inflammatory conditions (including those caused by infections but also those resulting from surgical procedures) has been shown to be better throughout life, whereas the prognosis for females is poorer when they suffer from chronic inflammatory diseases, such as cystic fibrosis (CF), severe asthma, or chronic pulmonary obstructive disease. In many infectious disease cases, C-reactive protein levels, erythrocyte sedimentation rate values, and neutrophil counts reached threshold levels above which values for girls were systematically higher than those observed with boys. With respect to the surgical stress of cardiac operations, females recover better than males (8), suggesting a more efficient inflammatory (and perhaps secondary anti-inflammatory) response in the face of similar levels of external insults that are limited in time and extent (e.g., those resulting from surgical trauma and extracorporeal circulation). In situations of greater complexity, such as those involving CF and autoimmunity, prognoses for females are poorer. We recently published three papers showing that the production of inflammatory markers (3) and the inflammatory process (4, 5) are clearly different for females and males. These observations could explain the male predominance in the results of the studies of Carr and de Jonge. In fact, inflammation is a double-edged sword. When patients are in good health, inflammation remains a very efficient process for avoiding important exogenous aggression of systemic life-threatening (as in the case of major thermal burns) or major local infections. In contrast, when inflammation persists, collateral deleterious effects of tissue destruction outweigh the initial advantage (as seen in cases of cystic fibrosis and lupus).

One possible explanation for these findings is that inflammatory reactions are driven by hormonal status. However, clinical data obtained before puberty imply the significance of potential differences in gene expression that depend on sexual chromosomes rather than on hormonal status, as members of prepubertal populations are largely immature and sexual hormones are far less abundant. Attention has recently been drawn to some rare genes on the X chromosome that are involved in the inflammatory cascade. As the silencing process for one of the X chromosomes is incomplete in females, some inflammation-related genes could therefore be overexpressed compared to the expression levels seen with males.