Editorial Commentary: Shall We Disregard Mannose-Binding Lectin Modification in the Future Because We Cannot Prevent Sepsis With This Molecule?

The search for a genetic basis for severe sepsis has been prompted by the demonstration of a strong association between premature sepsis death in biologic parents and their children given up for adoption. However, there was none between the adopted offspring and their adoptive parents [1]. Searching for genetic associations has been difficult given the complexity of the sepsis syndrome. Such studies have been pursued initially via candidate gene linkage and single-nucleotide polymorphisms and now have graduated to highly sophisticated techniques epitomized currently by genome-wide association studies. Deficiency states of the innate immune system that involve its cellular and humoral components’ produce identifiable phenotypes with susceptibility to recurrent bacterial infection. Chronic granulomatous disease, described in 1967, that arises from phagocytic deficiency occurs with a frequency of 1 per 250 000 births [2]. Properdin or terminal complement deficiencies lead to meningococcal meningitis, typically recurrent and mild. Overall, complement factor deficiencies are very rare in the general population but frequent in selected groups with severe or recurrent sepsis. If rare complement deficiencies of the classical and alternate pathways highlight the significance of these innate immunohumoral factors, what should we make of the high frequency of mannose-binding lectin 2 (MBL2) polymorphism that produces a very wide range of mannosebinding lectin (MBL) levels? Anciently arisen, this lectin-pathway complement activator is critical to protection from infection in human progenitors as distant as marine nonchordates. The identification of MBL came from investigation of an apparently distinctive phenotype in children with susceptibility to recurrent infections who had a deficiency of serum opsonization of Saccharomyces cerevisiae [3]. Individual infections such as meningococcal infection that were potentially associated with low or absent MBL levels were extensively examined [4]. However, no such association was ultimately confirmed [5]. Significantly, a large-scale, population-wide study failed to support a role for MBL2 deficiency encoding genotypes in sepsis mortality [6]. Who is potentially at risk from absence of MBL? Three populations spring to mind. Preterm neonates have MBL levels significantly lower than those in children and adults [7]. Overall, results suggest that these infants, highly susceptible to infection, do not get sepsis more frequently if they are MBL deficient [8]. At the other age extreme, low MBL levels are not prevalent. Indeed, and fascinatingly, centenarians have been shown to be more likely to have MBL2 genotypes encoding intermediate than either null or high MBL levels compared with the general population [9]. There are no studies specifically investigating associations between low MBL and sepsis in the elderly. Last, many studies have suggested associations between MBL deficiency and sepsis in immunocompromised patients. What possible selective advantage could there have been for the high frequency of human MBL2 polymorphism? [10] The ancient human pathogen Mycobacterium tuberculosis is promulgated as having plausibly exerted such an evolutionary pressure as high levels of MBL facilitate macrophage uptake of this organism [11]. However, the results of association Received 30 April 2015; accepted 1 May 2015; electronically published 12 May 2015. Correspondence: Damon P. Eisen, MBBS, MD, Victorian Infectious Diseases Service at the Peter Doherty Institute, 792 Elizabeth St, Melbourne, VIC 3050, Australia (damon.eisen@ mh.org.au). Clinical Infectious Diseases 2015;61(5):704–6 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/civ380