Innate immune genetic profile to predict infection risk and outcome after liver transplant

A deficiency in the plasma of an activator of complement has long been suspected as a factor that predisposes some individuals to recurrent infections. In 1968, a case of a 3-month-old girl with severe dermatitis, diarrhea, and recurrent bacterial infections was associated with a defective phagocytosis. Subsequent investigations demonstrated that the phagocytic defect was corrected in vitro by the addition of heterologous plasma, and thus, a deficiency in a plasma activator of complement was suspected. Because this was also observed in several of her relatives, a genetic origin was very likely. However, the exact nature of this plasma activator of complement was not known for 2 decades, until 1987, when this was suggested as mannose-binding lectin (MBL). Produced primarily by the liver, MBL is a major activator of the lectin pathway of complement, which serves a central role in innate immunity together with a sophisticated network of cells, barriers, and molecules that establish rapid, efficient, yet nonspecific defense against invading pathogens, while the pathogen-specific adaptive immune response is undergoing development. MBL is one of the major soluble pattern recognition molecules that recognize pathogen-associated carbohydrate moieties present in microorganisms. MBL recognizes a variety of pathogens including gram-positive and gram-negative bacteria, fungi, viruses, and parasites, thereby highlighting its broad spectrum of immunologic activity. Three related soluble pattern recognition molecules that function to recognize acetyl groups (whether presented from carbohydrates or other compounds) are the ficolins (designated as ficolin-1, ficolin-2, and ficolin-3). Recognition of pathogenderived polysaccharide and acetyl molecular patterns by MBL and ficolins, respectively, results in engagement of MBL-associated serine proteases (MASPs, primarily MASP-2), leading to complement activation (particularly the lectin pathway) and antimicrobial responses characterized by opsono-phagocytosis and formation of a membrane attack complex that causes direct lysis of the pathogen. Serum concentrations of MBL and ficolins vary widely in humans. For example, serum MBL levels vary from as low as 5 ng to >10 lg/mL, although the level for each individual is quite stable throughout life. Serum MBL and ficolin concentrations are largely under genetic control. MBL is encoded by the MBL2 gene, which is located on chromosome 10. Three missense single-nucleotide polymorphisms (SNPs) in exon 1 of MBL2 (SNP at codons 52 [referred to as allele D], 54 [allele B], and 57 [allele C], which are all collectively called the O allele, whereas wild-type is referred to as A allele) and other SNPs in the promoter and 50-untranslated region result in low serum levels of functional MBL (Table 1). The frequency of variant alleles vary in ethnic groups worldwide, and in some populations, the O allele may exceed a prevalence of 40%, and thus are relatively common in humans. Serum levels of L-ficolin, which is also produced primarily in the liver, is likewise influenced by genetic control (low levels have been associated with SNPs in the promoter region [at positions 986, 602, and 4] and in exon 8 [A258S]) of the FCN2 gene. Low levels of innate pattern recognition molecules may impair pathogen recognition, leading to an increased risk of various infectious diseases. This hypothesis has been investigated in several studies during the past decade. In this issue of HEPATOLOGY, de Rooij and colleagues investigated the hypothesis that functional SNPs within the lectin complement pathway (MBL2, ficolin-2 [FCN2], and the MASP2 gene) increases the risk of clinically-significant bacterial infections after liver transplantation. Using a sophisticated study design with principal and confirmatory cohorts, the authors observed three clinically relevant findings, namely (1) a stepwise increase in the risk of clinically significant bacterial infections with the number of SNPs in MBL2, FCN2, and MASP2; (2) an increase in the risk of infection if there was a mismatch between the donor and recipient in any of the genes (specifically when the wild-type recipient receives a liver allograft from a donor with variant genes); and Abbreviations: MASP, MBL-associated serine protease; MBL, mannosebinding lectin; SNP, single-nucleotide polymorphism. Address reprint requests to: Raymund R. Razonable, M.D., Division of Infectious Diseases, Mayo Clinic, Marian Hall 5, 200 First Street SW, Rochester, MN 55905. E-mail: Razonable.raymund@mayo.edu; fax: 507-255-7767. CopyrightVC 2010 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.23868 Potential conflict of interest: Nothing to report.