Mannan-Binding Lectin (MBL) Deficient Individuals with the O/O Genotype are Highly Susceptible to Gastrointestinal Diseases

Abstract

Background: Mannan-binding lectin (MBL) and ficolin-3 are initiators of the lectin pathway that is important for clearance of pathogens and apoptotic cells through complement activation. MBL deficiency (MBLD) has been associated with infectious complications but its clinical relevance in adults is unclear. Definition of MBLD is commonly linked to its low serum levels, but is mainly due to functional polymorphisms in the MBL2 gene leading to dysfunctional MBL forms. Homozygotes for dysfunctional alleles (O/O) have the lowest serum levels (<50 ng/ml) with a defect in opsonisation and complement activation. Ficolin-3 deficiency due to homozygosity of a frameshift mutation (1637delC) in the FCN3 gene was recently shown to be associated with pyogenic infections mainly in the lungs.Objective: The aim of the study was to thoroughly evaluate the clinical findings of previously defined MBL deficient cohort in relation to their MBL2 and FCN3 genotypes. Methods:A total of 120 adult individuals previously defined as MBL deficient (≤500 ng/ml) were genotyped for variants in the MBL2 gene and for the 1637delC allele in the FCN3 gene. They answered detailed questionnaire focused on pulmonary and gastrointestinal infections. For comparison, 63 adult individuals were randomly selected from the general population and served as control subjects. Results:In the MBLD cohort the prevalence of genotypes A/A, A/O and O/O was 14.2%, 71.2%, and 14.2%, respectively. Thus, 85% carried the dysfunctional allele O. The MBLD cohort was significantly more prone to a variety of recurrent and severe infections than the control cohort. O/O individuals were more susceptible to oesophagitis and gastritis and had undergone gastroscopy significantly more often than A/A an A/O. Prevalence of heterozygosity (C/-) for the 1637delC allele was 4.2%. Conclusion IntroductionComplement activation is a first-line innate defence against invading pathogens. Activation of complements via the lectin pathway (LP) is mediated by five separate soluble serum pattern recognition proteins (PRP). These are mannan-binding lectin (MBL), collectin-11 (CL-11), ficolin-1 (M-ficolin), ficolin-2 (L-ficolin) and ficolin-3 (H-ficolin) [1][2][3][4][5]. The LP-PRPs circulate in serum complexed with specific proteases named MASPs (MBL associated serine proteases; MASP-1, MASP-2 and MASP-3), and upon binding to pathogen associated sugar patterns the MASPs become activated and initiate the complement cascade leading to membranolytic attack and opsonophagocytosis [6].The physiological role of MBL has been well studied whereas the role of ficolins and CL-11 is less well investigated. MBL has a significant role in a number of pathogenetic and homeostatic processes. It binds and eliminates (through complement activation) various microorganisms and altered self-components, including dying host cells (apoptotic/ necrotic), circulating immune complexes (CICs) and immunoglobulins (agactosylated IgG and certain forms of IgM and IgA) [7][8][9][10]. The MBL molecule itself can act as a...