Originally published online as doi:10.1189/jlb.0703304 on September 12, 2003
Published online before print September 12, 2003
(Journal of Leukocyte Biology. 2004;75:27-33.)
© 2004
by Society for Leukocyte Biology
Collectins and their role in lung immunity
T. P. Hickling*,
,
H. Clark*,
R. Malhotra*,
and
R. B. Sim*,1
* MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, United Kingdom;
Virus Research Group, Institute of Infection Immunity and Inflammation, School of Clinical Laboratory Sciences, Queen’s Medical Centre, University of Nottingham, United Kingdom; and
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United Kingdom
1Correspondence: MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Rd., Oxford OX1 3QU, UK. E-mail: rbsim{at}bioch.ox.ac.uk
ABSTRACT
The collectins are a small family of secreted glycoproteins
that contain C-type lectin domains and collagenous regions.
They have an important function in innate immunity, recognizing
and binding to microorganisms via sugar arrays on the microbial
surface. Their function is to enhance adhesion and phagocytosis
of microorganisms by agglutination and opsonization. In the
lung, two members of the collectin family, surfactant proteins
A and D, are major protein constituents of surfactant. Another
collectin, mannan-binding lectin, is also present in the upper
airways and buccal cavity and may protect against respiratory
infections. Recent work has shown that collectins have roles
in resistance to allergy and in the control of apoptosis and
clearance of apoptotic macrophage in the lung.
Key Words: surfactant proteins A and D • mannan-binding lectin • C-type lectin • collagenous regions
INTRODUCTION
The lung is an important interface between the host and an environment
that contains a plethora of potentially harmful microorganisms.
The immune defense of the lung involves the pulmonary surfactant,
a complex mixture of lipids, phospholipids, and proteins important
for normal respiratory function [
1
]. Two of the surfactant
proteins, (SP)-A and SP-D, belong to a group of mammalian lectins
that are involved in innate immunity. This family is known as
the collectins, as they contain a collagenous region and a C-type
lectin domain [
2
]. A major biological role of the collectins
is to bind to targets (e.g., microorganisms) by recognizing
patterns of carbohydrate distribution and to enhance phagocytosis/clearance
of the target. Other members of this family include mannan-binding
lectin (MBL), which unlike SP-A and SP-D, activates the complement
system; three bovine collectins, CL-43, CL-46, and conglutinin
(BK); and two recently identified human collectins, CL-L1 and
CL-P1 [
3
4
5
6
]. The collectins that are involved in respiratory
defense are SP-A and SP-D and MBL. The lectin domain of each
collectin binds, with different affinities, to a range of monosaccharides
(
Table 1
), thereby giving each of the collectins a potentially
broad range of specificities [
3
]. The binding of collectins
to carbohydrate ligands on the surface of pathogens fulfills
a recognition function, which can elicit effector functions
via the collagenous region. These effector functions are dependent
on recognition of the collectins by cellular receptors.
COLLECTIN STRUCTURES
The collectins are large, oligomeric glycoproteins, each composed
of identical or very similar polypeptides (
Fig. 1
). Each polypeptide
has four domains or regions: a cysteine-containing N-terminal
portion, followed by a collagen-like sequence, an
-helical coiled
coil neck, and at the C terminus, a C-type lectin domain
(Fig. 1) . The polypeptide chains trimerize to form a single subunit,
which has a "head" composed of three C-type lectin domains and
a "stalk" made up of a collagen triple helix (
Fig. 2
). These
subunits are linked covalently through disulfide bonding or
noncovalently into oligomers of up to six subunits. SP-A and
MBL have the well-known "bunch-of-tulips" (sertiform) shape,
first characterized for the complement protein C1q. SP-D has
four subunits in a cruciform shape. These are very large proteins:
Each subunit has a length of 46 nm in SP-D and 20 nm in SP-A.
Polymerization is variable, particularly for SP-A, but the presumed
major oligomer of each (human) collectin consists of six subunits
(i.e., 18 polypeptides) for SP-A and MBL and four subunits for
SP-D. The bovine collectin BK has four subunits, and CL-43 has
one. The relative in vivo concentrations of the other, smaller,
or larger oligomeric forms of each collectin are currently not
known accurately. The neck region and collagen-like sequence
are involved in the structural formation of the collectin subunit,
and additional interactions within the N-terminal domain appear
to be essential for formation of the larger oligomers. The oligomerization
is important for high-avidity binding and pattern recognition
[
8
,
9
].
The quaternary structures of SP-A and MBL are very similar to
that of the complement component C1q, which is not a collectin,
as its head region consists of domains that recognize charge
motifs (such as are found on immunoglobulins in immune complexes
or on exposed lipid A on bacteria). In contrast, the heads of
collectins recognize neutral sugar arrays. It was partly the
resemblance in shape of C1q and SP-A that stimulated research
to show that SP-A and other collectins have, like C1q, a major
role in innate immunity [
9
]. Further evidence to support the
role of collectins as important molecules of the innate-immune
system is derived from the concept of pattern recognition, which
is thought to have been a key stage in the evolutionary development
of host immune functions [
10
].
The crystallization of rat MBL-A, with and without bound ligand, showed that the individual carbohydrate-binding site of one C-type lectin domain forms only a small, low-affinity contact area with a single sugar (e.g., mannose) so that multiple interactions of several C-type lectin domains with a sugar array are required to provide high-avidity binding [11
]. The three C-type lectin domains in a single collectin subunit are 
5 nm apart—too far apart for a single trimer to bind multivalently to a typical mammalian, high-mannose oligosaccharide. Therefore, MBL and the other collectins can selectively recognize microorganisms, as opposed to host, by binding avidly only to the widely spaced, repetitive sugar arrays on microbial surfaces [12
].
THE SURFACTANT PROTEINS A AND D
SP-A and SP-D are synthesized by alveolar type II and Clara
cells in the lung [
7
,
13
] and are most abundant in lung surfactant.
SP-D is also found on mucosal surfaces outside the lung [
14
].
These proteins function in innate immunity by recognition and
binding to nonself or altered self and promoting clearance/phagocytosis
by opsonization or agglutination. Pulmonary surfactant consists
of 83% phospholipid and 7% protein by weight. There are four
surfactant-associated proteins that are distributed: SP-A, 5.3%;
SP-B, 0.7%; SP-C, 0.4%; and SP-D, 0.6%. SP-A and SP-D are of
relatively low abundance in healthy subjects, and so, the majority
of research with native proteins is performed on material purified
from pulmonary alveolar proteinosis patients. Full-size recombinant
forms are difficult to make, because of the need for post-translational
modification of the collagenous sequences (hydroxylation and
glycosylation). However, MBL has now been made and polymerized
successfully in several mammalian cell systems (e.g., ref. [
15
]),
and SP-D has been expressed [
16
] in Chinese hamster ovary cells.
SP-A is more difficult to synthesize, as it is composed of two
types of polypeptide chains that differ by only a few amino
acids but are the products of two different genes. MBL and SP-D
each contain only one polypeptide type.
SP-A and SP-D probably exist in vivo as a mixture of polymers. SP-A in lung lavage fluid is present in forms with one to six collectin subunits. The relative quantities of each oligomer vary between individuals and may be related to lung disease [17
]. As noted above, the binding affinity of a single lectin domain for carbohydrate is very low. Three lectin domains, held together as a single subunit of the collectins, have a higher avidity for carbohydrate-rich surfaces, as shown for CL-43 [18
]. Therefore, the greater multiplicity of lectin domains found in higher-order multimers of SP-A, MBL, and SP-D is required to give high-avidity binding to carbohydrate-bearing surfaces. Isolated SP-A has been regarded as being mainly hexameric in structure, i.e., six subunits each with three polypeptides. The mechanisms controlling the degree of polymerization are unclear, but the initial formation of oligomers may depend on disulfide bonding in the cysteine-rich N-terminal region [19
]. Oxidation of isolated SP-A leads to depolymerization and loss of binding to targets (e.g., whole-pollen grains) [20
]. From this observation, it was hypothesized that the quaternary structural breakdown was a result of oxidative cleavage of disulfide bonds. Although the factors controlling polymerization/depolymerization are poorly understood, the evidence suggests a dependence on disulfide bonding, which may be influenced by redox changes in the lung. Depolymerization would be expected to lead to the loss of binding affinity for carbohydrate-rich surfaces [7
, 20
] with loss or alteration of biological function.
BIOLOGY OF SURFACTANT-ASSOCIATED COLLECTINS
The biological functions of SP-A and SP-D are primarily twofold,
namely surfactant homeostasis [
21
] and host defense [
22
].
Further, to these important functions, SP-A and SP-D have been
identified as having antioxidative potential [
23
]. This review
focuses on the host-defense functions of the surfactant-associated
collectins. SP-A and SP-D bind and agglutinate microorganisms
and other particulate material entering the lungs. The surfactant-associated
collectins have also recently been shown to have a direct antimicrobial
activity by increasing bacterial cell-membrane permeability
in
Escherichia coli [
24
]. The full spectrum of in vivo targets
of SP-A and SP-D has not been systematically investigated. However,
a growing number of respiratory pathogens to which the surfactant-associated
collectins bind have been identified. This list consists of
bacteria, viruses, and fungi (
Table 2
) [
25
,
26
].
SP-A and SP-D form part of a generalized response of the lung
to acute injury by modulating local inflammatory and immune
responses. The collectins have been shown to promote attachment,
uptake, and killing of respiratory pathogens by phagocytes,
e.g., alveolar macrophage. SP-A is essential for host defense,
as SP-A knockout mice are susceptible to infection from each
class of pathogen [
27
]. Furthermore, SP-A and SP-D appear to
play a more complex role in modulating immune responses by regulating
cytokine production. Alveolar macrophages recruit additional
phagocytic cells to the site of pulmonary infections through
the release of cytokines [
28
]. This function requires a careful
control to ensure the correct balance when recruiting inflammatory
cells, such as neutrophils, which have the potential to damage
lung tissue. The SP-A knockout mouse shows an increase in inflammatory
cytokines after challenge by a number of pathogens [
22
], indicating
the capacity of SP-A to limit the extent of cytokine release.
In addition to binding respiratory pathogens, the collectins also bind allergenic particles, including house dust-mite extracts and pollen-grain granules [29
].
SURFACTANT-ASSOCIATED COLLECTINS IN INFLAMMATORY DISEASE
Inflammation in the lung, as in other tissues, is often essential
for the host to mount a successful immune response. However,
excessive, local inflammation is a symptom of allergic diseases,
such as asthma. The role of surfactant components in the course
of asthmatic disease has recently been reviewed [
30
]. The surfactant-associated
collectins appear to be involved in health and disease beyond
their role in pathogen recognition. The level of SP-A was reduced
in patients suffering from asthma [
31
]. An inflammatory response,
similar to that seen in asthma, occurs in the lungs of allergy
patients when starch granules are released from inhaled pollen
grains. An increasing weight of evidence now suggests a critical
role for surfactant-associated collectins in modulation of asthma
and allergic disease. The degree of polymerization of SP-A has
been shown to be lower in birch-pollen allergy patients than
in healthy individuals [
17
]. SP-A has been shown to decrease
the proliferative response of dust-mite allergen and phytohemagglutinin-stimulated
lymphocytes from children with stable asthma [
32
]. Allergen-induced
bronchial inflammation is associated with a decreased level
of SP-A in a murine model of asthma [
33
].
The later stages of asthmatic disease are characterized by remodeling the airways. This remodeling leads to the production of goblet cells at the expense of Clara cells. Goblet-cell hyperplasia was thought to be an exclusively pathophysiological process until the recent demonstration that these cells produced SP-D in a murine model of asthma [34
]. Production of SP-D suggests an anti-inflammatory and immunomodulatory role for goblet cells, providing a homeostatic mechanism to compensate for goblet-cell hyperplasia [35
].
The importance of SP-A and SP-D in allergic processes in vivo has been highlighted recently in mouse models of allergy. SP-A and SP-D down-regulated allergic responses to fungal allergens [36
], and a recombinant form of SP-D reduced airway hyper-responsiveness in mouse models of allergy to fungal [37
] and house dust-mite allergens [38
, 39
]. There is emerging evidence that surfactant-associated collectins may instruct adaptive-immune responses through involvement in antigen presentation via dendritic cells [40
, 41
]. This may provide a possible mechanism by which they exert antiallergic effects, for example, by favoring polarization of T helper (Th) responses from allergic Th-2 responses to more protective Th-1 responses [37
]. Further research in the area of antigen presentation is required to reveal the true role of SP-A and SP-D in protection against inflammatory disease. Other possible mechanisms by which SP-A and SP-D exert antiasthmatic effects may involve direct inhibition of allergen-induced histamine [42
] or inhibition of lymphocyte proliferation [32
, 43
].
A further role of SP-A and SP-D in lung inflammation appears to be in the clearance of apoptotic cells. This has also been reported for MBL [44
45
46
]. Thus, the recent findings that SP-A and SP-D may be important in the clearance of apoptotic cells in the lung indicate that these proteins are important in limiting inflammation in the response of the lung to injury. SP-D-deficient mice have an increased burden of apoptotic cells in the airways and spontaneously develop emphysema and pulmonary fibrosis [45
], which raises the intriguing possibility that SP-D may also play a role in minimizing pathological airway remodeling in chronic asthma.
MBL
MBL is also known as mannan-binding protein (MBP) or mannose-binding
lectin, as it binds to yeast mannan as well as to mannose coupled
to Sepharose. Previous names for MBL include core-specific lectin,
from its interaction with the core motif of N-linked oligosaccharide,
and Ra reactive factor, as it binds to Ra chemotype strains
of Salmonella. The term MBL is now used in preference to MBP
to avoid confusion with identically abbreviated proteins (e.g.,
major basic protein and myelin basic protein) and to emphasize
its lectin character. MBL is made in the liver and is most abundant
in blood but is present in most body fluids, e.g., in buccal
cavity and upper airway secretions, saliva (for summary, see
ref. [
47
]).
MBL has a quaternary structure similar to SP-A, and it has similar, but not identical, target-binding specificity. Unusually, disulfide bridging within and between subunits is incomplete and variable so that, for example, the common six-subunit form in humans is heterogeneous, consisting of a number of isoforms with different disulfide bridging. This is evident from sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of nonreduced MBL and comparison with analyses made by nondenaturing hydrodynamic methods [48
]. Several publications (e.g., refs. [49
, 50
]) suggest that native MBL in serum or plasma occurs in oligomeric forms of different sizes, ranging from one to six subunits in human, but it appears likely that the six-subunit oligomer is by far the major form [51
]: Smaller oligomers may form on storage or processing of plasma. Other proteins with similar quaternary structure also show variable polymerization: C1q, for example, has a six-head and a minor two-head form. As for SP-A and SP-D, the oligomerization of MBL allows avid binding to carbohydrate ligands as a result of the multiple lectin domains present: Forms with a lower degree of polymerization bind less-avidly to carbohydrate surfaces and are defective in activating complement [48
].
MBL SERUM LEVELS
MBL serum levels can be extremely varied, ranging from 0 to
over 3 µg/ml in humans. MBL deficiency is common (5% or
more of the population, depending on the threshold concentration
used to define deficiency) and is associated with severe and
repeated infections in infants. Soothill and Harvey [
52
] described
a group of infants with recurrent pyogenic infections, whose
serum failed to opsonize
Saccharomyces cerevisiae. A similar
opsonic defect was found in
5% of an apparently healthy adult,
control population. Super and colleagues [
53
] identified this
common opsonization deficiency with low MBL expression.
The variation in MBL levels can be attributed to the three structural mutations of the MBL gene, which are likely to result in defective polymerization, interacting with several polymorphisms in the MBL promoter region that influence the level of expression. The structural mutations occur at high frequency (generally 15% or greater cumulative allele frequency in most populations studied) and are single-base changes resulting in amino acid changes in the collagen region of MBL, resulting in an altered capacity to form the collagen triple helix [54
, 55
]. The concentration and biochemical forms of MBL present in the airways are currently not known.
MBL AND COMPLEMENT
MBL is the only one of the collectin family of proteins to activate
the complement system. MBL can act directly as an opsonin by
binding to carbohydrates on pathogens and then interacting with
MBL receptors on phagocytic cells. However, it can also trigger
the opsonic activity of complement, resulting in deposition
of C3b/iC3b on targets and stimulation of phagocytic uptake
via the C3 receptors, CR1, CR3, and CR4.
The complement system is a major mediator of innate-immune defense and contributes to many innate-immune system functions including inflammation, opsonization, and lysis. It consists of more than 30 proteins, soluble in serum and bound to cell membranes. The complement system can be activated via three pathways, the classical, lectin, or alternative upon recognition of pathogen-associated molecular patterns. Currently, it is not clear whether complement activation by MBL would be likely to have an important role in the respiratory tract, as in healthy individuals, the concentrations of complement proteins are very low in body fluids other than blood plasma. MBL may be associated with the activation of other extracellular enzyme systems. MBL is associated with three proteases, mannan-binding lectin-associated serine proteases (MASPs; for review, see refs. [56
, 57
]). The MASPs (MASP1, MASP2, and MASP3) are homologues of the classical pathway proteases C1r and C1 s, with identical domain organization. The MASPs are activated from proenzymic to active form when MBL binds to a target. MASP2 activates the complement proteins C2 and C4 and so, is responsible for further complement activation. MASP1 and MASP3 do not however appear to activate complement. MASP1 will cleave fibrinogen and coagulation factor XIII in vitro and so, may have a role in localized coagulation, although it is not clear if these are physiological substrates. No substrate has yet been found for MASP3 [47
, 56
, 57
].
COLLECTIN RECEPTORS
The interaction among collectins, microorganisms, and inflammatory
cells is complicated, and the identification of genuine receptors
has proven difficult. A number of potential receptors for the
collectins have been identified, yet strong evidence is available
only for one of these candidates. The receptor first described
as the collectin receptor in 1990 was shown to be a common receptor
for SP-A, MBL, and C1q [
58
]. This C1q receptor, which became
known as cC1qR ("c", indicating interaction with the collagen
region of C1q), was demonstrated to mediate the uptake of opsonized
particles into phagocytic cells. Amino acid sequence comparisons
led to the identification of a putative binding site for cC1qR
within the N-terminal portion of the collagenous domains of
C1q and the collectins. Collectin binding is competitive with
that of C1q, indicating that the ligands bind to the same or
overlapping sites on cC1qR. The cC1qR-ligand binding is Ca
2+-independent,
and the lectin domain of the collectin is not involved in this
interaction. Studies of binding of intact and truncated BK to
cC1qR identified the receptor-binding site within the N-terminal
54 amino acids of BK [
59
], as these residues are missing in
a truncated form of BK, which does not bind to cC1qR. Comparison
of this region of C1q, MBL, BK, CL43, and SP-A led to the identification
of a possible receptor-binding site within the N-terminal half
of the collagenous region of the collectins. This site is composed
of five collagen repeats (Gly-Xaa-Yaa triplets), containing
many charged residues in the Xaa and Yaa positions [
59
]. This
receptor is found on a wide variety of cell lines, including
most leukocytes, endothelial cells, platelets, and fibroblasts
(reviewed in ref. [
60
]). A number of C1q-mediated, cellular
responses have been described, including the enhancement of
monocyte-phagocytic activity, stimulation of fibroblast adhesion,
stimulation of oxidative burst in neutrophils, and enhancement
of phagocytosis by pulmonary endothelial cells. Different collectins
binding to the same cell types may produce the same cellular
responses. The receptor cC1qR was subsequently identified as
the calcium-binding chaperone protein calreticulin [
60
]. The
idea that calreticulin could be a cell-surface receptor was
initially not widely accepted as a result of the lack of evidence
for a mechanism of cell-surface expression for calreticulin.
Other candidate receptors emerged, including C1qRp (C1qR, which
mediates phagocytosis), which was reported to be associated
with phagocytosis stimulated by C1q, MBL, or SP-A [
61
]. This
putative receptor has recently been reported to be an adhesion
receptor, identical to CD93, which does not in fact bind directly
to any of C1q, MBL, or SP-A [
62
]. In addition, the receptor
for complement component C3b, CR1, has been shown to interact
with C1q and MBL and remains a possible candidate for a universal
collectin receptor [
63
]. Other potential receptors have included
a 210-kD SP-A-binding protein from whole rat lung [
64
], a 200-kD
SP-A receptor from rat type II cells [
65
], a 30-kD alveolar
cell membrane protein identified by anti-idiotype antibodies
found in pig and human [
66
], and gp340, which was found associated
with alveolar macrophage and was suggested to be a SP-D-binding
protein [
67
]. None of these potential receptors has gained
further credibility.
Further evidence is directed toward calreticulin as the main candidate receptor. The recent description of a calreticulin/CD91 complex explains how calreticulin may be anchored to the surface of cells [68
]. This complex has since been shown to mediate the phagocytic uptake of apoptotic cells via MBL [69
]. Further work from the same laboratory has shown that SP-A, SP-D, and C1q use this receptor complex for the clearance of apoptotic cells in vitro and in vivo [46
]. Calreticulin could also be anchored to the cell-surface membrane by the major histocompatibility complex class I molecule to form a functional cC1qR [70
]. Coprecipitation studies indicate that these two molecules interact on the cell surface as well as in the endoplasmic reticulum, where calreticulin acts as a chaperone for class I molecules. Further research is required to determine the full range of collectin receptors and their activities.
Received July 1, 2003;
revised August 6, 2003;
accepted August 7, 2003.
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BIOLOGY OF SURFACTANT-ASSOCIATED...
SURFACTANT-ASSOCIATED COLLECTINS...
