Mannose-Binding Lectin: Clinical
Implications for Infection, Transplantation,
Lee H. Bouwman, Bart O. Roep, and Anja Roos
ABSTRACT: Mannose-binding lectin (MBL) is a recog-
nition molecule of the lectin pathway of complement and
a key component of innate immunity. MBL variant alleles
have been described in the coding region of the MBL
gene, which are associated with low MBL serum concen-
tration and impaired MBL structure and function. Both
high and low serum levels of functional MBL have been
associated with a variety of diseases and disease compli-
cations. Functioning as double-edged sword, low MBL
serum levels have been shown to enhance the risk for
infections. On the other hand, high MBL serum levels and
high MBL activity have been associated with inflamma-
tory diseases, transplant rejection, and diabetic nephrop-
athy. Underscoring the Jekyll-and-Hyde character of
MBL, both high and low serum MBL levels are associated
with several aspects of autoimmune diseases. This review
provides a general outline of the genetic and molecular
characteristics of MBL and discusses MBL–disease associ-
ation and its consequence in infection, transplantation,
Human Immunology 67, 247–256
(2006). © American Society for Histocompatibility and
Immunogenetics, 2006. Published by Elsevier Inc.
CRD carbohydrate-recognition domain
MASP MBL-associated serine protease
SNP single nucleotide polymorphism
human immunodeficiency virus
systemic lupus erythematosus
Mannose Binding Lectin
The ability to vastly counteract a great variety of patho-
genic microorganisms is of eminent importance for im-
munological homeostasis. As the most rudimentary part
of immunity, the innate immune system is composed of
molecules that can recognize a restricted array of struc-
tures in a broad range of microorganisms, the so-called
pathogen-associated molecular patterns. Mannose-bind-
ing lectin, also referred to as mannan-binding lectin or
mannan-binding protein, is a recognition molecule of the
lectin pathway of complement. The subsequent comple-
ment activation following the binding of MBL to its
ligands is an important component of innate immunity
and is proposed to be particularly important during the
phase following the decay of maternal antibodies in
infants . However, as we will argue in this review,
MBL plays an important immunological role not only
during early infancy but also for the duration of life.
The first case of an association of MBL deficiency and
disease dates back to 1968. A small girl suffering from
severe dermatitis, diarrhea, and recurrent bacterial infec-
tions indifferent to antibiotic and steroid therapy was
reported. Hematological examination revealed a defect in
the phagocytosis of yeast particles from Saccharomyces
cerevisiae, rice starch, and Staphylococcus aureus by poly-
morphonuclear leukocytes. This defect was serum depen-
dent. Infusion of fresh plasma corrected the phagocytic
deficiency. Because the same phagocytic defect was ob-
served in several direct relatives of the patient, it was
concluded that this condition had a genetic origin .
This genetic defect was later identified as a polymor-
phism in the MBL gene .
To fully appreciate the implication of MBL in clinical
settings, biological characteristics of MBL will be dis-
cussed prior to focusing on the association of MBL with
From the Departments of Surgery (L.H.B.), Immunohaematology and
Blood Transfusion (B.O.R.), and Nephrology (A.R.), Leiden University
Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Address reprint requests to: L.H. Bouwman, MD, Department of Sur-
gery, K6-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC
Leiden, The Netherlands; Tel: ?31-71-5264005; Fax: ?31-71-
5266750; E-mail: email@example.com.
Human Immunology 67, 247–256 (2006)
© American Society for Histocompatibility and Immunogenetics, 2006
Published by Elsevier Inc.
0198-8859/06/$–see front matter
Mannose-binding lectin is a C-type serum lectin and is
primarily produced by the liver . MBL is made up of
96-kDa structural units, which in turn are composed of
three identical 32-kDa primary subunits. The subunits
consist of an N-terminal cross-linking region, a collagen-
like domain, and a C-terminal carbohydrate-recognition
domain (CRD) . Circulating MBL is composed of
dimers, trimers, tetramers, pentamers, and hexamers of
the structural homotrimeric unit. The oligomeric con-
figuration of the structural units allows the MBL mole-
cule to have multiple CRDs, facilitating multivalent
ligand binding (Figure 1). Each CRD of MBL is struc-
turally identical and is able to bind a range of oligosac-
charides including N-acetylglucosamine D-mannose, N-
L-fucose . Although the
various sugars are bound with different affinities, the
cluster-like array of multiple binding sites allows acti-
vation of complement to be most effective. MBL is
considered to play a major role in innate defense against
pathogens, involving recognition of arrays of MBL-
binding carbohydrates on microbial surfaces. However,
more recent studies have shown that MBL is also in-
volved in the recognition of self-targets, such as apopto-
tic and necrotic cells .
In plasma, MBL is associated with MBL-associated
serine proteases (MASPs). Currently, three MASPs have
been identified, MASP-1, MASP-2, and MASP-3 [7–9].
Although the functions of MASP-1 and MASP-3 remain
subject to debate, there is a general consensus that the
role of MASP-2 includes being responsible for cleavage of
C4 and C2, generation of the C3 convertase C4b2a, and
subsequent complement activation [10–12].
MBL Polymorphisms and Serum MBL
Exon 1 of the mbl-2 gene, which is located on chromo-
some 10, contains three functional single nucleotide
polymorphisms (SNPs) at codon 52 (CGT to TGT;
Arg ¡ Cys, referred to as allele “D”), codon 54 (GGC to
GAC: Gly ¡ Asp, allele “B”), and codon 57 (GGA to
GAA; Gly ¡ Glu, allele “C”) (Figure 1) . These
SNPs of exon 1 result in altered collagenous regions and,
as a consequence, interfere with the formation of high-
order oligomers. This impairment of polymerization
causes low serum levels of high molecular weight MBL
and impaired MBL function . Dependent on ethnic-
ity, the allele frequency of variant alleles B, C, and D,
commonly referred to as O alleles, may be above 40%
(wildtype ? A/A) . In addition to the three SNPs in
exon 1, there are several other polymorphic sites located
in the MBL promoter region, including SNPs located at
positions ?550 (H/L variant) and ?221 (X/Y variant),
both G to C nucleotide substitutions. Furthermore, a
polymorphic site is located at position ?4 of the 5=-
untranslated portion of the mbl-2 gene (P/Q variant, C ¡
T) [16–18] (Figure 1). The common allele A of exon 1 is
associated with the following haplotypes: HYPA, LYPA,
LYQA, and LXPA with high, high-intermediate, inter-
mediate, and low promoter activity . Although there
is great variety of MBL levels in the different haplotypes,
to ease interpretation it has been advocated to depict only
the most significant promoter allele in position ?221
(X/Y), which is found only in normal A haplotype back-
ground (YA or XA) exhibiting high and low promoter
activity and serum MBL levels . The structural al-
leles carry the following haplotypes: LYPB, LYQC, and
HYPD (Table 1).
Serum level ranges of high, intermediate, and low
MBL-producing genotypes have not been defined within
the current literature. Major problems in developing an
(32 kDa)(32 kDa)
MBL structural unit
MBL oligomers MBL oligomers
MBL structural unit
Aberrant MBL subunit
Aberrant MBL subunit
Exon 1 Exon 1
57 57-221-221-550 -550
CCBBDDXX//YY L /H L /H
MBL structural unit MBL structural unit
of the mbl-2 gene contains three known single nucleotide
polymorphisms (SNPs) at codons 52, 54, and 57, referred to as
alleles D, B, and C, respectively. All SNPs of exon 1 result in
altered collagenous regions and, as a consequence, interfere
with the formation of high-order oligomers. This impairment
of polymerization causes low serum levels of high molecular
weight MBL and impaired MBL function. Furthermore, H/L,
Y/X, and P/Q promoter polymorphisms affect gene expression.
Genetic and functional buildup of MBL. Exon 1
L.H. Bouwman et al.
MBL serum classification system are the various different
MBL serum concentration assays that detect different
molecular forms of MBL. It could be advocated that the
correct way to evaluate MBL in serum is to functionally
assess MBL activity by standardized assays [19, 20].
Correctly quantifying MBL by means of complement
activation via the lectin pathway in future studies will
enable us to develop new standard ranges for functional
serum MBL .
A great variety of allele frequencies in various ethnic
groups worldwide has been described. B allele frequen-
cies have been reported as high as 0.80 in certain South
American Indian groups with C allele frequencies as high
as 0.32 in West Africans. In contrast, no variant alleles
were found in the Aboriginal Australian population and
C or D alleles were absent in Eskimos and in certain
South American populations (reviewed in ). The
high frequency of MBL variant alleles in different ethnic
groups and demographic areas suggests that the obvious
immunological disadvantages of low MBL serum levels
somehow have a beneficial counterweight.
Currently, there are two main hypotheses suggesting
positive pressure for variant MBL alleles. One hypothesis
suggests that low MBL levels are beneficial in children
because MBL-mediated complement activation could fa-
cilitate mitigation of harmful tissue damage by priming
or promoting aggressive immune responses. The other
prevailing hypothesis suggests that MBL enhances the
uptake of intracellular microorganisms; thus low MBL
levels would be protective.
MBL and Associated Diseases
MBL has been studied in a great diversity of diseases.
Both decreased and elevated serum levels of MBL and
different SNPs of the mbl2 gene and its promoter have
been associated with a variety of diseases, reflecting the
Jekyll-and-Hyde character of MBL. To structure the
discussion of this double-edged sword phenomenon, in-
volvement of MBL in different diseases will be discussed
according to the etiology.
MBL and Infection
When the adaptive immune response is either immature
or compromised, the innate immune system constitutes
the principle defense against infection. A logical conse-
quence of impaired MBL function would be an enlarged
susceptibility to infectious disease. The phenomenon of
an increased incidence of infectious disease in MBL-
deficient patients has been shown in pediatric patients
and in immune-compromised patients. However, it also
has been shown that adult patients with recurrent infec-
tious disease are more likely to have insufficient serum
MBL levels [22–24].
MBL and bacterial infections. The adaptive immune sys-
tem of children is in the developmental stage and relies
to a great extent on the innate immune system to coun-
teract infectious pathogens. In support of the theory that
MBL has an important protective role in early childhood
is a British study of 266 pediatric patients (mean age 3.5
years) suffering from meningococcal disease .
Damonstrating a clinical association between MBL vari-
ant alleles and meningococcal disease, the authors sug-
gested that genetic variants of the MBL gene might
account for one third of all meningococcal disease pa-
tients. Patients undergoing myeloablative bone marrow
transplantation or cytotoxic chemotherapy are severely
immune compromised. MBL deficiency has been shown
to be associated with severe bacterial infections after
chemotherapy and major infections following allogeneic
hemopoietic stem cell transplantation [26, 27].
The presence of MBL variant alleles in patients with
cystic fibrosis is associated with poor prognosis and a
reduction of 8 years in the estimated predicted age of
survival . It has been demonstrated that the short-
ened life span in carriers of variant alleles results primar-
ily from the more aggressive course of lung disease
caused by chronic Pseudomonas aeruginosa infection and an
increased risk of acquiring B. cepacia infection which in
turn is often associated with an even greater mortality
than chronic P. aeruginosa colonization. Although MBL
can bind only weakly to whole P. aeruginosa bacteria in
vitro, it is suggested that the protective role of MBL is a
result of clearance or neutralization of P. aeruginosa. Al-
MBL genotypes and haplotypes
Haplotype Common referencePhenotype (MBL production)
GenotypeCommon reference Phenotype (MBL production)
A: Ranking according to MBL production of the different MBL haplotypes.
Variant alleles D, B, and C are commonly referred to as O alleles.
B: Ranking according to MBL production of the different MBL genotypes.
ternatively, it is suggested that MBL may have a protec-
tive role against the viral infections suggested to precede
P. aeruginosa colonization and exacerbation, which in
turn may slow the progression of the disease.
In Caucasians, it has been suggested that individuals
homozygous for MBL exon 1 codon variants could have
an increased risk of invasive pneumococcal disease [29–
31]. However, a concomitant illness is an independent
risk factor for acquiring invasive pneumococcal infection.
Patients and controls have not been matched according
to these concomitant illnesses in these studies.
Patients with low serum MBL levels undergoing elec-
tive gastrointestinal resections for malignant disease of
the gastrointestinal tract show significantly more post-
operative infections [32, 33]. As postoperative infections
are a major cause of morbidity and mortality, identifica-
tion of patients prone to them would be of great clinical
In marked contrast to the protective properties of
MBL against extracellular bacterial infections is the ob-
servation that mycobacterial infections (Mycobacterium
tuberculosis and M. leprae) occur more frequently in pa-
tients with increased serum MBL levels. Complement-
mediated enhanced phagocytosis as a result of opsoniza-
tion has been suggested to facilitate these intracellular
MBL and virus infections. MBL has been studied in rela-
tion to various viruses. Persistent hepatitis B virus in-
fection has been reported to be associated with the vari-
ant alleles located at codons 52 and 54 of the MBL gene,
responsible for low MBL serum levels [35, 36]. Further-
more it has been suggested that high MBL serum levels
are associated with increased survival rates among Japa-
nese patients with hepatitis B .
In contrast to hepatitis B, the association of MBL and
hepatitis C appears less conclusive. Several studies have
suggested that low-MBL producing genotypes are asso-
ciated with a poor response to interferon treatment in
Japanese chronic hepatitis patients [31, 38–40]. How-
ever, these results could not be confirmed in European
The role of MBL in HIV infection has been studied to
a great extent in recent years and has recently been
extensively reviewed Several clinical studies have shown
that MBL serum levels increase during HIV infection,
indicating a role for MBL in the pathogenesis of HIV
infection and progression [42, 43]. It has been suggested
that MBL is involved in the recognition of HIV. The
envelope protein gp120 of the HIV-1 virus is highly
glycosylated with N-linked carbohydrates, enabling
MBL to bind, opsonize, and neutralize the HIV-1 virus
[44–47]. The finding that the variant MBL B allele is
more frequent among HIV patients with high viral loads
underscores the involvement of MBL in HIV progression
This antiviral quality of MBL could enrich the current
therapeutic arsenal in HIV treatment by MBL infusion.
Although infections with common pediatric viruses, in-
cluding respiratory syncytial virus and Epstein–Barr vi-
rus, lack association with MBL [48–50], it has been
shown that MBL is able to neutralize and inhibit the
spread of the influenza A virus [51, 52]. This inhibitory
quality of MBL was independent from complement, sug-
gesting that human MBL can affect innate immunity by
direct viral neutralization and inhibition of viral spread
and by indirect opsonization and complement activation.
MBL AND TRANSPLANTATION
Tissue damage and impaired organ function resulting
from ischemia/reperfusion (I/R) injury still remain enor-
mous predicaments in solid-organ transplantation. The
hypoxic state to which an organ is subjected during
organ harvesting, transport, and implantation activates
various immunological events [53–57]. The complement
system plays an important role in mediating tissue injury
after oxidative stress. Activation and deposition of com-
plement on the vascular endothelium following oxidative
stress have been demonstrated [58–60] and, more inter-
estingly, tissue injury after I/R is significantly reduced
by complement inhibition [58, 61–63]. Complement
activation via the lectin pathway following oxidative
stress has been demonstrated, indicating that inhibition
of MBL could be a novel approach in reducing ischemia/
reperfusion damage [64, 65]. Indeed, recent experiments
in MBL-knockout mice support a role for MBL in the
pathogenesis of I/R injury in vivo [66, 67].
In support of the involvement of MBL in transplant-
related I/R injury is the fact that MBL depositions were
observed early after transplantation of ischemically in-
jured kidneys . Moreover, high MBL levels are asso-
ciated with significantly decreased renal allograft sur-
vival, linked to therapy-resistant rejection . Apart
from I/R damage, MBL may also be involved in graft
failure by other MBL-mediated mechanisms. Damage
caused by acute rejection may be enhanced in the pres-
ence of high levels of circulating MBL by interaction of
MBL with damaged tissue. MBL can bind to necrotic and
late apoptotic cells, resulting in enhanced phagocytosis
of these cells by macrophages and dendritic cells. Phago-
cytosis of necrotic cells in turn may induce dendritic cell
maturation and macrophage activation. It is conceivable
that high MBL levels may increase immune reactivity
and cell damage via binding to damaged tissue and
enhancing activation of antigen-presenting cells.
Studying MBL activity and MBL serum levels in liver
transplantation, we recently demonstrated that trans-
plantation of a liver genetically mismatched for MBL
L.H. Bouwman et al.
genotype results in MBL serum conversion. This finding
corroborates the notion that the liver is the pivotal site of
MBL production. Furthermore, patients receiving donor
liver with an MBL-variant genotype have an approx-
imately fourfold increased risk of acquiring a life-
threatening infection within the first year after trans-
plantation . As infection is the primary cause of
death at all time points after liver transplantation, it is of
great clinical value to identify high-risk patients.
MBL and Autoimmunity
The role of the adaptive immune system in autoimmu-
nity is well established and interest in the role of the
innate immune system in the immunopathogenesis of
autoimmune diseases is mounting. Evidence that the
innate immune system could lead to autoimmunity,
either by priming or by promoting aggressive immune
responses, is growing [71, 72]. A major current patho-
physiological concept of autoimmunity is impaired apo-
ptotic cell clearance. MBL has been demonstrated to
facilitate the clearance of apoptotic cells in vitro [73–75]
and in vivo . A result of cells going into apoptosis is
alteration of membrane carbohydrates leading to in-
creased expression of fucose and N-acetyl-glucosamine
[77, 78]. Redistribution or clustering of glycoproteins
has been suggested to enable MBL to bind to these
carbohydrates expressed on apoptotic cells, thereby facil-
itating clearance [6, 75]. Alternatively, it can be argued
that an increased serum MBL concentration could facil-
itate and propagate a cellular immune response by lectin
pathway complement activation, after initial tissue dam-
age (Figure 2).
In systemic lupus erythematosus (SLE), MBL alleles
were demonstrated in several studies to predispose to
disease development . This association has been un-
derscored by a recent meta-analysis which incorporated
all available published results of MBL genotyping in SLE
and demonstrated that MBL variant alleles such as MBL
exon 1 codon 54 B, promoter ?550 L, and promoter
?221 ? are SLE risk factors. Interestingly, SLE patients
with MBL deficiency manifest more frequent renal in-
volvement, increased infection rate, and strongly in-
creased risk for arterial thrombosis [79, 80]. Further-
more, MBL-deficient SLE patients manifest increased
levels of autoantibodies against molecules associated with
apoptotic cells, such as C1q and cardiolipin .
Studies of the association between MBL and rheuma-
toid arthritis have demonstrated that MBL is able to bind
to rheumatoid factor (RF) complexes and as a conse-
quence could assist RF clearance by the reticuloendothe-
lial system [82, 83]. The observations that MBL insuf-
ficiency is associated with elevated IgM RF, increased
joint erosions, inflammation, and early disease onset sup-
port the MBL RF clearance theory [84–88].
We recently demonstrated that both MBL serum con-
centration and MBL complex activity were significantly
higher in new-onset diabetic patients than in healthy
controls . We hypothesize that MBL is involved in
the pathogenesis of diabetes by assisting the autoimmune
process of insulitis, pathognomonic for early stages of
type 1 diabetes .
The above-mentioned association of MBL and auto-
immunity again underscores the Jekyl-and-Hyde charac-
ter of MBL, as both high and low serum MBL levels are
associated with several aspects of autoimmune diseases.
A major source of mortality and morbidity in diabetes
is caused by microvascular complications, as a substantial
portion of diabetic patients develop diabetic nephropathy
and retinopathy. MBL has been demonstrated to be
associated with diabetic microvascular complications.
Several studies have now characterized the association
between the increased risk of developing renal compli-
cations and the presence of high-MBL producing geno-
types in diabetic patients [90–92]. The involvement of
MBL in the pathogenesis of diabetic nephropathy now
appears to be appreciated; however, the exact immuno-
logical process involved remains to be studied. In con-
trast to microvascular diabetic complications, low MBL
has been reported to be associated with macrovascular
pathology. High MBL serum levels predict a decreased
likelihood of myocardial infarction in diabetic patients,
possibly indicating a role for MBL in the clearance of
atherogenic agents . However, it can be hypothesized
that, in a patient with high serum MBL, once a myocar-
Autoimmunity and tissue injury
munity. Low serum MBL levels could result in impaired
clearance of apoptotic cells, facilitating an aggressive immune
response leading to autoimmunity. High serum MBL levels
could cause excessive complement activation via the lectin
pathway following tissue damage. This in turn could prime
and promote an immune response resulting in autoimmunity
and tissue damage.
MBL acting as double-edged sword in autoim-
dial infarction has occurred, the sustained injury could be
greater due to the I/R damage facilitated by MBL.
Since the first report of the clinical implications of MBL
deficiency almost four decades ago , our knowledge of
the lectin pathway has expanded tremendously. At
present, MBL replacement therapy is being studied in
phase I, II, and III studies [94–96]. Infusing serum MBL
in MBL-deficient subjects could potentially induce neg-
ative effects, for example autoimmune processes. How-
ever, no adverse clinical or laboratory changes have been
reported upon repetitive MBL infusion. Furthermore, no
antibodies directed against MBL were found. Unfortu-
nately, the half-life of infused MBL is short, varying from
18 to 115 hours. Thus, to maintain sufficient MBL
serum levels, MBL should be administered twice or three
times weekly, rendering MBL substitution therapy costly
and arduous. Several other therapeutic interventions can
be put forward to compensate for MBL deficiency in
immunocompromised patients, including intensified
clinical follow-up and preemptive antimicrobial therapy.
Intravenous and subcutaneous immunoglobulin admin-
istration might also be alternative therapies to counteract
a malfunctioning lectin pathway [14, 97, 98].
Assessment of high MBL serum levels by evaluating
the risk for graft loss prior to transplantation may be
beneficial to patients with renal failure. Furthermore, as
MBL appears to be associated with I/R damage, pre-
operative assessment of serum MBL levels could be ad-
vocated prior to surgical procedures as abdominal aortic
aneurysm repair or iliaco-femoro-popliteal bypass. It can
be hypothesized that, in these cases, blockage of MBL
could be beneficial. To the best of the authors knowl-
edge, however, this has never been studied.
Nonetheless, swift clinical implementation of the cur-
rent MBL knowledge may have a vast impact on patient
care, especially in patients struggling to uphold their
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