Mannose-Binding Lectin Deficiency

A number sign (#) is used with this entry because mannose-binding lectin deficiency (MBLD) is caused by heterozygous polymorphic variation in the gene encoding MBL (MBL2; 154545) on chromosome 10q21.

Individuals who are homozygous or compound heterozygous for polymorphisms that lead to MBL deficiency may have lower serum MBL levels and more severe phenotypic manifestations.

Description

Mannose-binding lectin (MBL) deficiency, defined as MBL protein level of less than 100 ng/ml, is present in about 5% of people of European descent and in about 10% of sub-Saharan Africans. Most MBL-deficient adults appear healthy, but low levels of MBL are associated with increased risk of infection in toddlers, in cancer patients undergoing chemotherapy, and in organ-transplant patients receiving immunosuppressive drugs, particularly recipients of liver transplants (review by Degn et al., 2011). MBL is a soluble molecule that can activate the lectin pathway of the complement system; deficiency may thus lead to defects in the complement system (summary by Garcia-Laorden et al., 2008).

Genetic Heterogeneity of Lectin Complement Activation Pathway Defects

See also LCAPD2 (613791), caused by variation in the MASP2 gene (605102) on chromosome 1p36, and LCAPD3 (613860), caused by variation in the FCN3 gene (604973) on chromosome 1p36.

Clinical Features

Soothill and Harvey (1976) described a group of children between the ages of 6 months and 2 years who had recurrent pyogenic infections and failure to thrive. Serum from these children failed to opsonize the yeast S. cerevisiae with complement component-3 (C3; 120700). A similar opsonic defect was present in approximately 5% of an adult population with no obvious immunodeficiency. Super et al. (1989) identified an association between low levels of MBL and a defect of opsonization that resulted in susceptibility to frequent and chronic infections. The frequency of this deficiency in the general population has been estimated to be between 5 and 10% (Turner, 1991). The deficiency has been reported to be particularly common in infants with recurrent respiratory tract infection, otitis media, and chronic diarrhea.

Summerfield et al. (1995) challenged the view that although MBL deficiency causes recurrent infections in infants between 6 and 18 months of age, it does not predispose to adult infections. They described 4 patients with severe and unusual infections in which MBL gene mutations were the only identified cause of immunodeficiency, and 1 patient with combined MBL and IgA deficiency. Infections seen were recurrent skin abscesses, chronic cryptosporidial diarrhea, meningococcal meningitis with recurrent herpes simplex, and fatal klebsiella lobar pneumonia. Both sexes were affected, and the ages of the patients ranged from 15 to 56 years.

Bax et al. (1999) reported the case of an 18-year-old man with meningococcal meningitis and low serum concentrations of MBL. His mother and grandfather, who had also had meningitis in early adulthood, likewise had low concentrations of MBL in their serum.

The low levels of mannose-binding lectin in young children with recurrent infections (Summerfield et al., 1997) suggest that the mannose-binding lectin pathway is important during the interval between the loss of passively acquired maternal antibody and the acquisition of a mature immunologic repertoire. There is a high frequency of dominantly expressed alleles of the gene for mannose-binding lectin that result in low levels of the protein in several ethnic groups. Walport (2001), among others, suggested that this deficiency during early childhood is counterbalanced by an advantage later in life. It is possible that the opsonization of intracellular organisms such as mycobacteria by mannose-binding lectin enhances the entry of such pathogens into cells. Low levels of mannose-binding lectin, by reducing opsonization, may confer resistance against mycobacteria.

In a prospective study of 848 patients with community-acquired pneumonia, 1,447 healthy control individuals, and a control group of 519 patients without relevant infectious diseases, Garcia-Laorden et al. (2008) found that MBL deficiency, as defined by MBL2 genotype and serum levels, did not contribute to susceptibility to community acquired pneumonia. However, among the 848 patients with pneumonia, MBL deficiency was associated with more severe forms of sepsis and fatal outcome, irrespective of the causal microorganisms.

Pathogenesis

Dean et al. (2010) used whole-blood cultures stimulated with zymosan (Zy) or MBL-opsonized zymosan (MBL-Zy) of MBL-deficient or -sufficient individuals and measured intracellular cytokine expression. They found that MBL-deficient individuals produced significantly more IL6 (147620) and TNF (191160) in response to Zy, whereas these individuals produced significantly less IL6 in response to MBL-Zy. Both MLBL-sufficient and -deficient individuals upregulated CD83 (604534) expression and downregulated CXCR4 (162643), CD62L (SELL; 153240), CD49D (ITGA4; 192975), CD40 (109535), and CD86 (601020) expression in response to Zy and MBL-Zy. Allogeneic proliferative, but not effector, responses were identical between the 2 groups. Dean et al. (2010) concluded that MBL deficiency is associated with unique functional characteristics of pathogen-stimulated blood myeloid dendritic cells, particularly increased IL6 production.

Molecular Genetics

MBL Deficiency and Susceptibility to and Recovery from Infection

Summerfield et al. (1995) described 4 adult patients with severe and unusual infections in which MBL2 gene mutations (G54D, 154545.0001 and G57E, 154545.0002) were the only identified cause of immunodeficiency, and 1 patient with combined MBL and IgA deficiency. Two patients were homozygous for codon 54 mutations, 1 patient was compound heterozygous for both mutations, and 2 patients were heterozygous for codon 54 mutations.

Garred et al. (1995) investigated the frequency of 3 abnormal MBL2 alleles (154545.0001-154545.0003), each of which has a dominant effect on MBL concentration, in 228 unrelated patients referred to their laboratory over a 3-year period for immunologic investigation of various non-HIV-related immunodeficiencies. Frequency of heterozygotes for the abnormal alleles was not different from that in the background population (36% and 37.4%, respectively). By contrast, the frequency of homozygotes for the abnormal alleles was significantly increased (8.3% and 0.8%, respectively; p = 0.0017). Garred et al. (1995) suggested that homozygotes for abnormal MBL2 alleles are predisposed to recurrent infections.

Garred et al. (1997) found that a significantly higher number of HIV-infected homosexual males were homozygous for variant MBL2 alleles than were high-risk homosexual controls or healthy controls. Although no significant association was found in progression from infection to clinical AIDS, there was a significantly shorter mean survival time after AIDS diagnosis in men carrying variant MBL2 alleles and those with low serum MBL. The authors suggested that the increased risks may be associated with increased susceptibility to coinfections.

Hibberd et al. (1999) studied the association of variants at codons 52, 54, and 57 of exon 1 of the MBL2 gene in relation to susceptibility to meningococcal disease. They found homozygosity or compound heterozygosity for these 3 alleles in 1.5 to 2.7% of controls and in 7.7 to 8.3% of subjects with meningococcal disease.

Soborg et al. (2003) examined MBL2 genotypes and serum MBL levels in 109 patients with clinical tuberculosis (see 607948) and 250 controls. Heterozygotes with a variant MBL2 structural allele associated with low functional serum MBL on one chromosome and a normal MBL structural allele with a low-expression promoter polymorphism on the other chromosome appeared to be relatively protected against clinical tuberculosis, whereas genotypes associated with high MBL expression and genotypes conferring MBL deficiency were not. Soborg et al. (2003) proposed that low serum MBL may be protective against tuberculosis by limiting complement activation and uptake of bacilli by complement receptors. In the absence of MBL, bacilli may be taken up directly by mannose receptors (e.g., MRC1; 153618).

Thio et al. (2005) genotyped 2 promoter SNPs and 3 exon 1 SNPs in the MBL2 gene in a large cohort of individuals with either hepatitis B virus (HBV; see 610424) persistence or recovery. They found that a promoter SNP, -221G-C, which leads to deficient MBL production, was more common in subjects with HBV persistence. Individuals homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had highly increased odds of recovery from infection. In contrast, those homozygous for the combination of promoter and exon 1 genotypes associated with the lowest amount of functional MBL were more likely to have viral persistence.

MBL Deficiency and Cystic Fibrosis

Because MBL is a key factor in innate immunity, and lung infections are a leading cause of morbidity and mortality in cystic fibrosis (CF; 219700), Garred et al. (1999) investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, Garred et al. (1999) estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes.

MBL Deficiency and Vascular Disease

Among 76 Norwegian patients with severe atherosclerotic disease, Madsen et al. (1998) found that 13.2% of the patients were homozygous for the MBL O/O genotype, O being the common designation for the variant alleles B (154545.0001), C (154545.0002), and D (154545.0003) at codons 54, 57, and 52, respectively. Three percent of normal controls had the O/O genotype. There was a trend toward homozygous MBL-defective patients being younger than those patients carrying 1 or 2 copies of the wildtype gene, suggesting that the MBL-deficient patients may have earlier disease onset or a more progressive disease course. Madsen et al. (1998) noted that ischemic heart disease is a multifactorial disease that has been associated with Chlamydia pneumoniae infection.

MBL Deficiency and Gestational Diabetes Mellitus

To test the hypothesis that a genetic predisposition to a proinflammatory state could favor the appearance of gestational diabetes mellitus (GDM), Megia et al. (2004) studied the arg52-to-cys (R52C; 154545.0003) and G54D polymorphisms of the MBL2 gene and plasma MBL levels from 105 consecutive women with GDM and 173 healthy pregnant women. They found an association between G54D and GDM (odds ratio = 2.03 (1.18-3.49); P less than 0.01), and this association remained significant when the presence of both mutated alleles was considered (odds ratio = 1.76 (1.04-2.96); P less than 0.05). GDM patients who carried the G54D mutation required insulin therapy more frequently and had heavier infants than GDM women homozygous for the wildtype allele. An inverse correlation in GDM patients between neonatal weight and plasma MBL levels was found, remaining significant after adjustment for confounding variables.

MBL Deficiency and Preterm Delivery

Bodamer et al. (2006) genotyped 5 common polymorphisms, including the B, C, and D variants, of the MBL2 gene in 102 infants born before 36 weeks' gestation and 102 infants born at full term and found that the frequency of the D allele was significantly higher in preterm infants compared to term infants (p = 0.04).