ArticlesDeficiency of mannose-binding lectin and burden of infection in children with malignancy: a prospective study
Introduction
In the Western world, more than one in 600 children will develop a malignancy in the first 15 years of life.1 Although there have been major advances in therapy, most children have chemotherapy-associated complications, the commonest of which is infection.2, 3 The consequences of infection in these patients are substantial, and include infection-associated mortality (65%2 and 2%3 of treatment-related deaths in patients with acute myeloid leukaemia [AML] and acute lymphoblastic leukaemia [ALL], respectively), organ dysfunction, antibiotic-associated complications, delays in chemotherapy administration, and lengthy and frequent hospital admissions. The main cause of infection is chemotherapy and disease-induced neutropenia.2 However, although all patients will have neutropenic episodes, not all will suffer equally from the associated complications. The reasons for this finding are unclear.
Mannose-binding lectin (MBL) is a collagenous lectin (collectin) found in serum. It binds to mannose and Nacetyl glucosamine residues when presented in the orientations and densities commonly found on microorganisms.4 On binding, it activates the complement system independently of antibodies via two associated serine proteases, MBL-associated serine protease 1 and 2. The latter cleaves C4 and then C2 to form the C3 convertase, C4b2a.5, 6 Cellular receptors for MBL have been proposed, and several studies have shown direct interactions of MBL with phagocytic cells, resulting in enhanced phagocytosis and modification of cellular activation.7 Deficiency of MBL was first identified in human beings in association with a common defect of opsonisation in children.8 Subsequent studies of consecutive9 and prospective10 series of children have confirmed that MBL deficiency predisposes to infectious illness.
Human deficiency of MBL is now known to be predominantly caused by point mutations within exon 1 of the MBL gene at codons 52, 54, or 57 (termed B, C, and D variants, respectively) which result in aminoacid substitutions that compromise assembly of functional oligomers.4 Individuals heterozygous for these mutations have reduced concentrations of MBL in serum, whereas the protein is almost absent from the serum of homozygotes and compound heterozygotes.11 In addition to the exon 1 mutations, there are three major polymorphisms in the promoter region of the MBL gene, and one of these variants (X/Y) also profoundly influences expression of the protein.12, 13 The MBL promoter polymorphisms are expressed as four haplotypes called HYP, LYP, LXP and LYQ. These are in linkage disequilibrium with the exon 1 polymorphic variants, so that the D variant is linked to the HYP promoter haplotype, the B variant is linked to the LYP haplotype, and the C variant is linked to LYQ. The wildtype (A) exon 1 sequence is found in association with all four promoter haplotypes. In our study, promoter and exon 1 variants for each individual were combined to give a complete MBL haplotype—ie, HYPA, LYPA, LXPA, LYQA, HYPD, LYPB, or LYQC. More than a third of the population will have haplotypes that predispose to low MBL concentrations, and very low concentrations are expected in 12%.11
MBL deficiency is thought to be clinically most apparent in the context of co-existent immune defects,8 including primary and secondary immune deficiencies. We aimed to investigate the possible part played by MBL in influencing the frequency and severity of infections in children undergoing chemotherapy for malignancy.
Section snippets
Patients
From November, 1997, to March, 1999, we enrolled all children (⩽17 years of age) diagnosed with cancer at the Haematology and Oncology Departments of Great Ormond Street Hospital for Children, London, UK. Patients admitted for a bone-marrow transplant were excluded. Approval for the study was granted by the Great Ormond Street Hospital for Children/Institute of Child Health Research Ethics Committee, and parental consent was obtained.
Procedures
We used blood surplus to clinical requirements taken at the
Results
100 children with malignancies were enrolled. The mean age at enrolment was 5·4 years (range 4 weeks–17 years; 57 boys). There was no significant difference in age distribution between the two groups studied (ie, children of A/A genotype vs children of A/O or O/O genotype). Similarly, there was no significant difference between the genotype groups with respect to sex or diagnostic group (Kruskal-Wallis tests for all comparisons). Some eligible patients were not enrolled because of
Discussion
This study shows that innate immune mechanisms are an important determinant of the infectious burden of cancer patients undergoing chemotherapy. MBL deficiency was associated with a two-fold increase in the number of febrile days experienced by children receiving chemotherapy for malignancy. This effect was apparent in patients with MBL concentrations of less than 1000 μg/L and was not restricted to patients who were homozygous for exon 1 mutations. Thus, up to 40% of patients11 could be at
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2016, International Journal of Pediatric OtorhinolaryngologyCitation Excerpt :Even among individuals with identical allotypes, the concentration of MBL level in plasma vary considerably [8]. The cut off value defining the deficency for MBL ranges from 50 ng/ml to 1 μg/ml [9,10]. Mannose -binding lectin (MBL) binds on surfaces of variety of microorganisms and activates complement system.