A Introduction

Review Article
Mannose Binding Lectin (MBL) in Autoimmunity and its
Role in Systemic Lupus Erythematosus (SLE)
Vandana Pradhan, Prathamesh Surve, Kanjaksha Ghosh
Mannose Binding Lectin (MBL) is an important element of the innate immune system. MBL binding leads to
activation and cleavage of C3 and C4 suggesting the role of MBL pathway for opsonization and/ phagocytosis.
The role of adaptive immune response in development of pathogenic autoantibodies in various autoimmune
diseases is well understood. The link between innate and acquired immunity is helpful for understanding the
immunopathogenesis of autoimmune diseases. Evidence that innate immune system could lead to autoimmunity
is growing with the major recent concept of autoimmune disease pathogenesis is related to impaired apoptotic
cell clearance. MBL have been demonstrated to facilitate clearance of apoptotic cells in vivo and in vitro. Low
MBL serum levels resulting in impaired apoptotic clearance have shown to enhance the risk for infection and
high MBL serum levels and high MBL activity have been associated with inflammatory autoimmune diseases
like Systemic Lupus Erythematosus (SLE) that in turn results in to tissue damage and finally leads to organ
damage. Serum MBL levels fluctuate during the course of SLE disease activity and MBL genotypes have been
found to be useful in assessing the risk of infection during immunosuppressive treatment the majority of the
SLE patients receive. This review focuses on the genetic and molecular characteristics of MBL and discusses
MBL disease association in autoimmunity with special emphasis on SLE.
seen in lupus are related to respiratory tract and urinary tract.3
utoimmunity is the failure of an organism to recognize its
own constituents parts as its self, which result in an immune
response against its own tissues and cells. Autoimmune diseases
are the disorders in which the body’s immune system reacts
against its own tissues and form autoantibodies which attack
its own antigens. Paul Ehrlich at the beginning of the twentieth
century had proposed the concept of “horror autotoxicus”, in
which a normal body does not recognize an immune response
against its own tissues. Inherited genes, viruses, ultraviolet light
and certain medication may play some role in etiopathogenesis
of autoimmune disorders. Genetic factors increase the
tendency of developing autoimmune diseases. Systemic Lupus
Erythematosus (SLE) is a prototype autoimmune disease
containing chronic and acute inflammation of various tissues
in the body. It is a disorder of generalized autoimmunity with
unknown etiology, characterized by autoantibody production
and immune complex (IC). Patients with SLE produce abnormal
antibodies in their blood that target tissues within their own
body rather than foreign infectious agents, these antibodies
and accompanying cells of inflammation can affect tissues
anywhere in the body, thus SLE has potential to affect a variety
of area causing disease of skin, lungs, kidney, joints and nervous
Mannose Binding Lectin (MBL)
Patients with SLE are more susceptible to infections
because they have altered immune systems, and also because
many patients are on treatment (steroids and cytotoxics) that
suppresses immune system function, leaving them more prone
to infections. Lupus patients who get infection frequently show
worse clinical signs and require longer treatment than non
lupus patients. Most of the opportunistic infections are fungal,
parasitic or protozoan. The most common bacterial infections
National Institute of Immunohaematology, Indian Council of Medical
Research, 13th floor, KEM Hospital, Parel, Mumbai 400 012, India.
Received: 12.10.2009; Accepted: 21.01.2010
Mannose Binding Lectin (MBL) is an important element of
innate immune defense system. The protein binds to the sugars
present on many microbial surfaces and subsequently activates
the complement system through a family of specific proteases
called the MASPs (MBL Associated Serine Proteases). MBL has
an oligomeric structure (400-700 kDa), built of subunits that
contain three identical peptide chains of 32 kDa each. MBL has
a bouquet-like structure with many similarities to C1q. Each
is characterized by a lectin domain, an α-helical coiled-coil
hydrophobic neck region, a collagenous region and a cysteinerich N-terminal region. Three such chains interact to give a
collagenous triple helix, but separate at the neck region to give
three independent carbohydrates recognition domains.4
MBL belongs to the class of collectins in the C-type lectin
superfamily, whose function appears to be pattern recognition in
the first line of defense in the pre-immune host. MBL recognizes
carbohydrate patterns, found on the surface of a large number
of pathogenic micro-organisms, including bacteria, viruses,
protozoa and fungi. To activate the complement, MBL in the
blood complexes binds to another known as serine proteases
called MASPs. The MASP protein function like a convertase to
clip C3 into C3a and C3b. C3b combines with other complement
proteins to make a Membrane Attack Complex (MAC), which
causes lysis of pathogens and cells. C3b can also bind to
complement receptors on phagocytes causing opsonization
of pathogens. The MBL pathway involves the MBL proteins,
MASP-1, MASP-2, C4, and C2. MASP acts as a C3 convertase,
creating a C3b fragment from C3. C3b attaches to the pathogen
surface and binds to receptors on phagocytes leading to
opsonization. C3b can also combine with other proteins on the
pathogen surface and form a membrane attack complex.5,6
© JAPI • november 2010 • VOL. 58
Structure of MBL2 Gene
tissue damage and inflammation. Accordingly, a dysregulated
complement system has been associated both with increased
susceptibility to infections and autoimmune disease. Mannosebinding lectin (MBL), being another important part of innate
immunity, is a key component of the lectin pathway of the
complement system. Serum levels of MBL are closely correlated
to polymorphism in promoter regions as well as mutations in the
MBL gene. Children with recurrent pulmonary infection have
low MBL, but low MBL do not seem to increase mortality or the
occurrence of infectious disease in an adult population. Altered
MBL level have been associated with persistent inflammation
and tissue destruction. High serum MBL concentrations in some
cases enhance the risk of infection. As an opsonizing factor, it
favors a penetration of some intracellular pathogens such as
mycobacteria into their target cells.11-15
nt C/T P/Q A/D/B/C
-550 G>C
exon 2
exon 3
exon 4
-221 G>C
-70 C>T
+4 C>T
+223 C>T
+239 G>A
+230 G>A
Gene Localization
+223 (A/D)
+230 (A/B)
+239 (A/C)
Amino Acid
Collagen-like domain (D2)
CRD (D4)
Most subjects who are MBL-deficient appear to remain
healthy. However, low serum MBL levels and their cognate
haplotypes have been associated with a range of bacterial
infections in both children and adults. The wide variety
of pathogens involved in these infections is typical of an
immunodeficiency. However, the fact that most MBL-deficient
people do not get infections had led to speculation that a second
immune defect needs to be present for susceptibility to infection
leading in several primary and secondary immunodeficiency
Human MBL is derived from a single gene on chromosome
10 in the region 10q 21-24. There is a single functional MBL gene
comprising four exons. Exons 1 encodes the signal peptides, a
cysteine rich region and part of glycine-rich collagen like region.
The normal structural MBL alleles is named A, while the common
designation for the 3 variant structural allele B (mutation in
codon 54, Gly to Asp), C (mutation in codon 57, Gly to Glu) and
D (mutation in codon 52, Arg to Cys) are O. MBL expression
is influenced by polymorphic sites in the upstream part of the
MBL gene nucleotides substitutions at positions -550, -221 and
+4 which give rise to H/L, Y/X and P/Q respectively and causes
different haplotypes, while LX haplotypes is associated with
low MBL plasma levels. MBL enhances the opsonization and
activates complement. Dysfunctional alleles of MBL have been
associated with low plasma concentrations of MBL and increased
risk of SLE, thus case control studies of MBL polymorphism are
performed in different Ethnic groups. MBL genotyping in SLE
shows that the MBL functional variants are associated with SLE.7
Immunodeficiency and Low MannoseBinding Lectin Levels
Common Variable Immunodeficiency (CVID) is a
heterogeneous syndrome characterized by failure of B cell
differentiation and defective immunoglobulin (Ig) production
leading to recurrent bacterial infections, particularly in the
respiratory tract. Although reduced Ig secretion from B cells
is the hallmark of CVID, other immunological abnormalities
such as T cells dysfunction and monocyte/macrophages
hyperactivity are seen in a considerable proportion of patients.
These abnormalities may be importance for both the B cells
deficiency as well as for some of the clinical manifestations
in these patients such as increased frequency of autoimmune
disorders, granulomatous inflammation and malignant and
nonmalignant lymphoid hyperplasia.13,19,20
Homozygosity for MBL variant alleles leads to increased
risk of complicating infections in SLE patients. Codon 52, 54,
57 polymorphism are all on exon 1 of the MBL gene, and the
presence of any of the minority alleles significantly reduces
serum MBL concentration. The incidence rates of SLE in
individuals with C1q and C4 are reported to be around 90% and
75% respectively. Patients with C2 deficiency develop SLE with
lesser frequency (around 15%). MBL deficiency is linked with
frequent pyogenic infection including pneumococcal infection
in infants and young children, severe pneumococcal disease is
also reported in patients with MASP2 deficiency. MBL deficiency
is 2–3 times as common in patients in with SLE as in the general
In syndromes as diverse as common Variable Immuno
Deficiency (CVID), HIV/AIDS and chemotherapy-induced
neutropenia, the presence of variant MBL alleles is associated
with earlier, more frequent and more severe infection.
Presumably the co-existence of MBL deficiency increases
infection susceptibility, allowing further rapidly progressive
lung and liver disease. Thus MBL deficiency may affect
susceptibility to a disease (e.g. meningococcal disease) or alter
the natural history of a disease such as cystic fibrosis, CVID and
chronic granulomatous disease.3,14,19
During an active phase of renal involvement in SLE, the C1q
levels are decreased because of activation of the classical pathway
of complement activation, triggered by the interaction of C1q
with immune complexes. A second cause of reduced C1q levels
is the presence of anti-C1q. Genetic deficiency of C1q is strongly
correlated with the development of SLE. Association of reduced
MBL levels (as a consequence of gene polymorphism) with SLE
has been reported previously. Anti-MBL, similarly to anti C1q,
could be a cause of low MBL levels in SLE patients. Higher MBL
levels were found in sera of SLE patients. Anti-MBL autoantibody
levels were higher in patients with high MBL concentration.9,10
Thus complement system, consisting of more than 30 proteins,
represents an important component of the innate immune system
and plays a central role in the host defense against microbes.
However, enhanced complement activation may also induce
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