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
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ABSTRACT
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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
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INTRODUCTION
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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.
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COLLECTIN STRUCTURES
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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
].
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Figure 1. The collectin polypeptide. Each collectin is an oligomer of polypeptides organized into four regions: cysteine (cys)-rich, collagenous, coiled-coil "neck", and C-type lectin domain or CRD. The length of the collagen domain varies considerably in different collectins, from 59 amino acids in MBL to 171 in SP-D [7
].
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Figure 2. The assembly of the collectins. As described in the text, groups of three polypeptide chains trimerize to form a single subunit with a stalk made up of a collagen triple helix and a head made up of three lectin domains (CRDs). The subunits assemble to form the full-size native collectins.
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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
].
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THE SURFACTANT PROTEINS A AND D
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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.
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BIOLOGY OF SURFACTANT-ASSOCIATED COLLECTINS
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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
].
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SURFACTANT-ASSOCIATED COLLECTINS IN INFLAMMATORY DISEASE
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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.
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MBL
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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
].
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MBL SERUM LEVELS
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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.
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MBL AND COMPLEMENT
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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
].
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COLLECTIN RECEPTORS
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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 Ca2+-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...
