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Collectins: pattern recognition molecules involved in first line host defense
Collectins:
pattern
recognition
molecules
involved
in first
line host defense Kedarnath Boston
University
A
School
group
contain
Sastry and R. Alan Ezekowitz
of Medicine
of the
chlmeric
apoproteins whose
molecules
carbohydrate
defined as collectins.
and Children’s
comprising
recognition
in the first
Current
and
proteins,
all qualify
appears to be as pattern
Boston,
globular
domain,
The mannose-binding
A and D and conglutinin
function
Hospital,
as members
in Immunology
Introduction
which
tails
are
surfactant involved
host.
1993, 5:59%66
structure and function of C lq as this molecule ject of a recent review [6].
Non-clonal or innate immunity plays a role in the immediate response to infectious challenge. The direct recognition of pathogens is mediated largely by ‘pattern receptors’ that are expressed on the surface of effector cells such as phagocytes and nahlral killer cells [l]. In addition circulating eRector pattern recognition molecules have been described. They share the ability to discriminate between the patterns of oligosaccharides that are present as the surface components of pathogens from normal self glycoproteins [ 2 1, The prototype of this class of circulating pattern recognition molecule is the s zrum C reactive protein which recognizes the pneumococcus capsule [ 31, The collectins are a new class of structurall) similar pattern recognition molecules that appear to retognize distinct but overlapping carbohydrate ligands that decorate the cell walls of pathogens. The convergence of a number of recent studies has indicated the structural and functional similarities between the serum mannosebinding protein (MBP), pulmonan, surfactant apoprotein (SP)-A and -I>. bovine conglutinin and the first complement component Cl q. The globular domains, except that of Clq, are similar enough to qualify them as members of the ever-growing family of C-type lectins [ 41. The presence of a collagen and lectin domain prompted the term collectin [ 5-1. The collectins are multimeric proteins, the collagen regions of which appear to play a critical role in multimer assembly. The Clqlike collectins, the MBPs and WA, assemble into multimeric proteins conprised of 18 globular heads and collagen tails [ 61. This structural arrangement contrasts with that of the tonglutinin and the SP-D as in these molecules the globular head is arranged radially around collagen spokes [6,7]. The structural assembly of the two groups of collectins has important functional consequences that will be examined in detail below. This review will not discuss the
USA
of this family,
molecules
line of defense In the pre-immune
Opinion
heads,
collagen
pulmonary
recognition
Massachusetts,
The mannose-binding
is the sub-
proteins
MBPs exist in the serum of rabbits [8], rodents [9-I 11 and man [ 12-151 as oligomers of a 32 kD unit that has an amino-terminal domain that is rich in cysteines, a collagenous region consisting of 20 repeats of GLYX-Y (where X and Y represent any amino acid), followed by :I carboxy~terminal carbohydrate recognition domain (0). The structural unit of MBP is a trimer of three 32 kD subunits with three CRDs (96kE); this forms a collagen helix that is stabilized by disulfide bonds between. amino-terminal cyst&es. MHP is synthesized in the liver and circulates in serum as a multimer of five or six trimeric units of apparent molecular weight 570450 kD. Two homologous, yet distinct forms of MBP have been described in rats and mice, namely MBP-A and -C [ 10,16]. The mouse and rat MRP-A are 90 per cent homologous with a single gap in the collagenous region. In addition there is an extra proline in the signal peptide of mouse MHP-A. This form appears to be the predominant serum MBP and in mice its hepatic synthesis is regulated as part of the acute phase response [ 161. The MBP-C forms are characterized hy an insertion of nine amino acids in the amino-terminal cysteine-rich region and are 82 per cent homologous with one another, with no gap in the collagenous region. The expression of mouse MBP-C is not upregulated above a basal level in response to stimuli that induce the acute phase response. Interestingly the alignment of human MBP with the rodent sequences reveals that it has features in common with both MBP-A and MBP-C. In the human protein nine amino acids are inserted into the amino terminus,
Abbreviations BCpbovlne conglutinin; CRD-carbohydrate recognition domain; MBSP-mannose-bindq protein asssociated protease; MBP-mannose-binding protein; HIV-l--human immunodeficiency virus type 1; SP -surfactant apoproteln. @
Current
Biology
Ltd ISSN 0952-7915
59
60
Innate
immunity
However, the crystal structure of the rat MBP-A CRD complexed with an oligomannose asparaginyl-oligosac charide has recently been solved [21**]. The structure reveals a ternary complex of protein, Ca2+ and terminal mannoses. The 3- and d-OH groups of these terminal mannoses are involved in the direct hydrogen bonds between f&and and protein. From this study the importance of these 3- and d-OH groups provides a structural rationale for why MBPs bind II-mannose, N-acety-D-glucosamine, D-glucose and L-fucose, but not D-galactose and its derivatives. The information provided in this and an accompanying paper [22**] go a long way in providing a structural basis for the ability of MBPs to recognize a range of sugars, yet maintaining sufficient constraints to distinguish self from non-self glycoproteins. It is still not clear how the naturally occurring trimer interacts with ligand to mediate high afinity binding. One possible explanation that we have previously proposed is that each single CRD forms one face of the binding site and that the trimeric head is necessary to form one single high afhnity binding site [ 191. Recent studies in which the rat MBP-A CRD [20] or human MBP CRD [23] have been expressed as recombinant proteins indicate that the CRD in the absence of the collagen tail is able to form multimers. Sucrose density experiments with human MBP CRD indicate that monomers, dimers and trimers are formed and that high affinity binding is observed only when the CRD multimerizes. The presence
which is also a feature of MBP-C; however, like MBP-A it also has an extra cysteine in the amino-terminal region. The interruption in the collagen region (a feature of all MBPs) occurs at the eighth repeat in human MBP and rodent MBP-C, while this aberration is at the sixth repeat in mouse and rat MBP-A. The hepatic synthesis of human MBP, like rodent MBP-A, is regulated as part of the acute phase response. The collagen region is over 95 per cent conserved between all forms of MBP and all share 52 invariant amino acids; these features qualify MBPs as members of the ever-growing family of Ctype lectins [4,16] (Fig. 1). MBPs appear to play a role in the first line of host defense as they selectively recognize certain configurations of oligosaccharides that decorate a range of pathogens and virally infected cells, yet they appear unable to recognize the ofigosaccharide patterns of self glycoproteins [a]. The relatively broad array of carbohydrate moieties recognized by MESP [ 17,18] distinguishes this molecule from other proteins that have carbohydrate ligands, such as anti-carbohydrate antibodies and plant lectins (reviewed in [19]>. The specificity of these groups of proteins is dictated by the shape of their respective binding pockets which distinguish subtle alterations in the topology enabling, for example, a distinction between glucose and mannose. In the initial report of the three-dimensional structure of the rat MBP-A CRD the location of the ligand binding site was not obvious from the structure [20].
??
197 222 203 113 104 90
B2
RSP-D SSP-D m%P
HHSFC WISPA RnepA
89
RHSPC! NSP-A
102 107
??
??
? ?
XVNF&.XQRVT ILDGE IJNWQNAFSQ YXKAVLFPDGQAVGF, DSA.. R.W A.N.X .Q.LX A...R ....A ..... .S..D D.As. R.Q.E A.Q.Q VQEL. A.... . ..VX . ..N. .S... XAL. TEHAR I..NL T.SL. XQ..N I.SE IAAIRSELRAImw. ..SIS XX..X R.1 EEXLA WE?Al! I.ILX SXIQL TN.LE A.SH. F2W.X it.1XVXLA WXAE INTLX SXLEL TN.LE A.SM. XXS.X . NI.LX IAALR SELRA HR.W. .L&S XN..X .QAT .BD.R EQIL. TRG.L SIQGS HT.,.
Invariant t
??
APR
c .
??
RNSPC ESP-A
VYSNWADGEP .... . .P... .... . .P... T.T.. NE... R.T.. N.... T.... FXD.. ..GX. T.... XXD...NRV R.T.. W... D.TPV N.T.. YR...
NNSESZGQPEN ..-NG .-A.. .D-.G .-S.D ..AG SD-.D ..lUI .--.D ..EGS --G.D -PN.E .SG.D ..VGS .--.. --AGR .X-.Q
Invariant
tc
FU%PA
lGEIL ...A. ...S. ..NR. ..NRV ..GR.
S.A.F NEA.F .--.F D-I.. -GI.F XTS.F D-V.F WY..
EN
??
RSP-D ESP-D NHSP NHBPC HHSPA
..I..
.F.L. .Y.VS .L.V. .F.V. .Y.HS .V.SS
N.EIH SVKXH NRXXN NNERM SVRRM N.QSI
??
SYSDAEQLCREAXGQUSPRSSAENXAVTQHVRAQXXNAY PFE.. WM.. Q.G.. ..... .AT.. A..Q. L.T.E PFTE. QL..T Q.G.. ..... .A... A.LQ. L.V.X TFEW XA..V lcFQA.9 V.T.. NA... G.IQN LIX-E .LDRV XA..S .FQ.S V.T.. NAE.. S.I-. X.-.X PF.XV XS..T .LQ.T V.I.. NAX.. X.-I. E-V.T PF.XV M..S .LR.T V.I.. NAE.. X.-I. E-V.PLNR. XA..S .LQ.T V.T.. NAE.. R.I-. N.-.X TFDAI QXA.A R.G.R I.V.. NPE.. ..IAS F.XXY
Invariant
Bc
. . . . .
_G XF ??
SC RSP-D ESP-D SHW MMEZC MHSPA RNSPA Rnepc ESP-A
??
XIFXTAGAVX ,..RA .NSRE
??
ISNND ...T. ...T. .GIT. .GIT. .GIT. .GIT. .GIT. VGLTE 1
w
??
CVEIF PDGXW NDVPC ..... TN.Q. ..XA. ..... TN... ..RA. ..IJ,LXN.Q. ..... ..V.L GN... ..... ..I.L C4J.L. ..IS. ..T.V DN.L. ..IS. ..VLL lW... .... . ...MY T..Q. ..RN.
ISTEGRFTYP VG... X.... SK... X.... XX... Q.WL VRV.. S.EDL EA... Q.M.V EV... Q.M.V QR..N V.GDL GPSP. D.R.S F
-
??
SXQLL VICXF Gl3.R. .. ... GSXR. .V... .TSE. AV... .DSF.
A....
QASFX AV.. QASRT AV.. .LlSF. .V... LYSR. T....
351 374 355 248 244 239 238 244 248
Fig.1
of
C-type
lectins. The numbers
The
collectin
correspond
to the
amino
in the protein
acid number
family
quence. The amino acids Invariant least eight or nine carbohydrate nition
domarns
are shown
recog-
in lower case
letters.
The amino acids underlined
those
identified
characteristic
by
Drickamer
of C-type
Identity
sequence
of bovine conglutrnin
is
gaps.
marked
man
10th
mannose-binding
human
pulmonary
A; HSP-D, MMBPA,
human mouse
tein A; MMBPC, ing
Every
protein
A dot
the amino
surfactant surfactant
hu-’
HSP-A, protein
protein
mannose-binding mouse
acid
HMBP,
protein;
C; RMBPA,
acrd
(EC). ~
amino
by an asterisk.
are
141 as
lectins.
indicates indicate
with
sein at
D; pro-
mannose-bindrat
mannose-
binding protein A; RMBPC, rat mannosew
XE
I
cv
GWNOC
3
binding protein protein
D.
C; RSP-D,
rat surfactant
Collectins
of six trimeric heads in the mature protein suggests that each subunit clusters around the oligosaccharides on the surface of a pathogen, hence accounting for the nM binding affinities associated with MBP binding to the cell walls of pathogens [ 231. lluman MBP can recognize Gram-negative enteric organisms, such as Salmonella montit tideo, Esclierichia coliJ5 strains, yeast mannans, ~~~focc~~~s [email protected] B streptoccoci [1X], the high mannose glycans present on the envelope glycoprotein of human immunodefi~ cienq virus 1241 and certain influenza virus subtypes [ 251. IYZz?tro studies have demonstrated that native and recombinant human MBP can opsonize kmcteria and enhance clearance by phagoqTes [ 261. MBP bound to a l&and can activate both the alternative [ 27 ] and classical complement pathways [ 281, The higher oligomer states of MBP, which resemble Clq, have been shown to interact with Clr2 and Cls2 [ 291. In addition, a recent report describes the characterization of a novel Cls-like protease, designated MBP-associated protease (MA!%) [29]. MBP-mannan-MASP complexes are able to mediate Cls independent activation of the classical complement pathway. These findings suggest the existence of other novel proteins that may play a key role in regulating MBP function. Further support for MBP as an ‘ante-antibody’ involved in the first line of host defense, comes from studies that indicate that MBP and phagocytic cells are an important component of preimmune host defense against influenza A viral infection. MBP directly inhibits hemag~ glutinin activity of several strains of influenza A virus. and in addition MBP opsonization of the virus not onI) protects polymorphonuclear leukocytes against virally ins duced damage, but also enhances viral clearance in zlitro [25]. The i?z z’itjo role of collectins (MBP in human and mouse sera and conglutinin in bovine sera) as the first line of host defense against certain strains of inn fluenxa virus arises from studies that implicate these two molecules as the beta inhibitors. These were first described in the 1940s as serum proteins involved in preimmune defense against this pathogen. Recent studies indicate that mutant virus Mem71hBeln(f13Nl), which is resistant to collectin hemagglutination, has a single base pair substitution in the hemagglutinin; this results in a loss of a glycosylation site, which is a target for MBP or conglutinin [ 301. It appears likely that these mannosebinding collectins inhibit viral infectivity by binding to the oligosaccharide side chains and thus mask the adjacent cell-binding domain. A vet? attractive hypothesis holds that low levels of MBP predispose children below the age of two years to recurrent infections [31]. Children of this age group are vulnerable to attack by encapsulated organisms and respiratoty viruses as the anti-carbohydrate antibody response is muted until 1X months of age (321. It has been proposed that a MBP genotype, which appears to segregate with low basal MBP levels, also correlates with recurrent infections in three families [ 331. Patients who were homozygous for adenine instead of guanine at base pair 230 were predicted to have an MBP gene that
Sastry and Ezekowitz
encoded a dysfunctional protein (MBP230,) as such a change alters a gtycine for an aspartic acid at the fifth collagen repeat. This substitution was predicted to disrupt the collagen helix and there act as a transdominant negative mutation. However several factors confound this apparent association. Low baseline levels of MBP that reportedly correspond with the clinical phenotype and the genotype are found in 5-7 per cent of the normal population [ 181. In addition, the population predicted to be most vulnerable, i.e. young children, have a baseline level of recurrent infections [32]. Recent findings are more compatible with the idea that MBP exists as two allelic forms. Studies with recombinant proteins that represent both allelic forms of MBP indicate that both are able to assemble as high order muttimers and act as opsonins, !ret the MBP230,, encoded protein is unable to act as a surrogate for C lq in the activation of the classical complement pathwdy. Whether this form of MBP is able to initiate the nlternati\,e complement cascade is yet to be determined. It may be that the MBP230AA allele alone does not account for the putative immunodeficienq phenotype, but rather a lack of MBP-dependent complement activation may predispose to infection in association with another mild immune defect. MBPs, like other collectins detailed below and pattern recognition molecules in general. appear to be most important in the pre-immune host in the earliest stages of infectious challenge. The ultimate verification of this would depend on the identification of a null genotype that expresses a phenotype of susceptibility to a well detined infectious history that can be alleviated by adminstration of recombinant MBP. These ‘proof of principal’ experiments may be best performed in an experimental murine model in which MBP genes have been knocked out by homologous recombination. Susceptibility to infectious challenge could be examined in these MBP-deficient animals.
Surfactant
apoprotein
A
WA is a major surfactant protein with overall structural similarity to C 1~1 and MBP [ 101, In humans, there are two highly homologous genes. which are most likely to be products of gene duplication, encoding WA [34]. It is not clear Lvhether the SPA found in z?!‘o is a heteroor homotrimer. WA has a short stretch of seven amino acids at the amino terminus with a single cysteine, which is likely to form an inter-chain disulphide bridge. This is followed by a collagen-like domain of 23 Gly-X-Y repeats with a single interruption. like MBP, the carboxyl terminal 148 amino acids constitute the CRD [35]. Previously, several studies have shown that S!‘-A does not opsonize Gram-positive bacteria, such as Staplylo coccus aflt+eu.s,or Gram-negative bacteria, such as Escberichia coli and Pseudomortas aerugeno.sa [36]. It can enhance the phagoqtosis of serum opsonized or unopsonized bacteria by stimulation of alveolar macrophages 1361 and opsonized erythrocytes by monoqte-derived macrophages [37], Induction by free SP-A of the chemi-
61
62
Innate immunitv
luminescence response, a measure of oxygen free radical release, is observed in T;tt alveolar macrophages but not in rat peritoneal macrophages, human monoqtes and rat [ 36,381. SPY or human polymorphonuclear leukocytes A appears to enhance uptake of herpes simplex virus by alveolar macrophages [ 391. Maximal enhancement of phagoqtosis was observed after incubation for 15 minutes with 5 F$rnl SP-A and was inhibited by anti~SP-A F(ab’)L. SP-A forms a Clq-like structure (Fig. 2), yet is unable to substitute for Clq in the activation of the classical complement pathway and in this way is similar to the MHP230, allele described above. SP-A is an integral part of the ‘tubulomyelin’ network, a lipid associated framework that stabilizes alveolae. The physiological role for WA may be structural and its role as ‘gatekeeper’ in the lung a secondary hmction. The avid association of WA with lipid, and the internalization of these complexes by alveolar macrophages and pulmonary epithelial type II cells, indicate that WA is not an opsonin in the true sense, but bacteria or other pathogens may be trapped in this complex and then cleared by cells that bind SP-A in the absence of ligand. This feature distinguishes SP-A from MBP, which is not taken up by cells in the absence of ligdnd, and suggests that these two ligands may utilize distinct re-
ceptors. The failure of free Clq to inhibit SPA-mediated uptake by alveolar macrophages appears to support this contention [ 361.
Conglutinin
as an opsonin
Bovine conglutinin (BC ) was the first vertebrate calcium dependent (C-type) lectin to be described; it can promote agglutination of erythrocytes coated with activated complement components [40], The carbohydrate strut ture to which RC hinds is exposed after breakdown of complement component C3. The complete amino acid sequence of BC, determined by Lee et al. [411, reveals a short amino-terminal stretch of 25 amino acids with two cysteines, perhaps involved in inter-chain cross-linking. This is followed by a collagen-like domain probabl? involved in helix formation with 55 repeats of Gly-X-Y. There are two interruptions in the collagen-like domain after the fourth and 32nd repeats. Towards the carboxyl terminus is the CRD of 155 amino acids, of which 16 are invariant, including four cysteines believed to play an important role in intra-chain cross-linkage leading to globular conformation The molecular weight of each BC
45nm
&-
Fig. 2. Ultrastructure
of
tant apoprotein
conglutinln
W-A,
mannose-blnding
VI.
is a hexameric
!
six
bent
surfacand
protean (MBP). (a) Clq structure
collagen
to a globular
Clq,
triple
made up of helices
joined
domain. SP-A is essentially
identical in appearance to Clq when vi-’ suallzed
using the electron
1201. (b) MBP structure,
hut
has
microscope
a similar
when
monomer
isolated
consists
of a range of oligomers
mainly
tetramers
[121. (cl Coglu-
and hexamers
tinln is a much larger protein, of four subunits logenous from
1631.
trimers,
consisting
each made up of a col-
and globular
region.
Adapted
Collectins
polypeptide chain appears to be 43 kD and electronmicroscopic studies reveal predominantly a tetramer of trimers [ 421. Previously, conglutinin has been shown to bind to the cell wall of yeast and also to zymosan particles. BC al>pears to have higher affinity for non-reducing terminal N-acetylglucosamine than N-acetylmannosamine, a property useful in purification of BC from bovine MBP, which has higher affinity for the latter sugar [42]. BC also binds to terminal mannose and fucose residues [43] Recentl) the existence of a conglutinin-like molecule has been reported in human serum [44] which appears to confirm earlier reports on detection in human plasma [45,46]. Administration of BC to mice a day before challenge with Salmorzclla <~bimurium led to rapid clearance of bacteria from the circulation and protected 80 per cent of the mice, compared with only 10 per cent survival in the control (saline) group on day 10 post infection [47]. BC enhanced chemiluminescence of murine spleen cells stimulated with serum opsonized E coli [ 481; maximum enhancement was observed at the highest dose of conglutinin employed (50 l.q+/rnl). Addition of N-acety~ glucosamine along with BC led to inhibition of enhancement, whereas N-acetylgalactosamine was non-inhibitory, The BC used in these experiments was composed of mainly ( > 90 per cent) monomers. E. coli preincubated with serum, washed before addition of BC and washed again before addition to spleen cell cultures, were also killed in a conglutinin-dependent manner. No antibac-terial effect of BC could be demonstrated in similar experiments when 1OmM EDTA was present or when heat-inactivated/factor I deficient serum was used in place of untreated serum. These experiments indicate that the opsonic effect of BC could be due to binding to iC3b deposited on the bacterial surface and subsequent binding of BC to phagocytes via receptors for collagen-like proteins [481. The classical beta inhibitors of influenza virus hernag&tination and infectivity in bovine and mouse sera were previously shown to be calcium-dependent mannoseinhibitable &tins (as stated above). Different characteristics of beta inhibitors from bovine and mouse sem have also been observed. Bovine serum (but not mouse serum) beta inhibitors were resistant to O.lM 2-mercaptoethanol and the inhibition of influenza virus hemagglutination by bovine sera could be reduced by a monoclonal antibody to BC [49]. These studies clearly estab lish that beta inhibitors in bovine and mouse sera are distinct. BC appears to be a beta inhibitor in bovine sera while mannan-binding proteins appear to be the serum beta inhibitors in mouse. Envelope glycoproteins of human immunodeficiency virus type 1 (HIV 1) are known to contain high mannose carbohydrate chains, and in studies similar to those reported earlier with MBP, both BC and human conglutinin-like protein have been shown to bind HIV1 gp120 [24]. Conglutinin, is predominately a pattern recognition molecule of ruminants. It recognizes the cleaved third complement component and is able to bind a range of oligosaccharide structures. It appears that it is able
Sastrv and Ezekowitz
to distinguish self from non-self, like MBP, and may be considered as the major serum lectin of ruminants.
Surfactant
protein
D
A new member of the C-type lectin family, SP-D (formerly called CP-41, is secreted by freshly isolated rat lung type II epithelial cells and non-ciliated brochiolar (CkdEi) cells [WI. Persson rt al. [Sl] showed SP-D to be immunologically distinct from the previously characterized !%A, a major component of surfactant and a C-type lectin. Both SP-A and WD are found to be associated with phospho lipids in lung surfactant. IIowever unlike SP-A, purified, delipidated SP-D does not interact with lipids. SP-D is a 43 kD protein and forms a structural subunit as a trimer but may exist as a dodecamer (516kD) in surfactant [52,53]. Both SP-A and WD have collagen-like domains and the ability of their lectin domains to bind Elrious sugars has been well established [35,54]. SP-D has high affinity for maltose and a slightly lower afinity for glucose, whereas WA has high a affinity for fucose, galactose, glucose and mannose. The primary structure of both rat and human SP-D have been deduced from the cDNA clones [ 55-571. Both rat and human SP-D are 355 amino acids long with 72 per cent homology. Human SP-D has a short amino terminal of 25 amino acids containing two qsteines followed by a collagenlike domain comprising 177 amino acids with 59 uninterrupted repeats of Gly-X-Y and a carboxyl terminal of 153 amino acids that represent a CRD. Interestingly, both rat and human SP-D show greater homology to conglutinin (b&67 per cent homology) than to SP-A (3&37 per cent homolo&T) [ 55-571. Kaun et al. [53] have shown that SP-D mediates agglutination of Graq-negative bacteria, such as E. coli, S. para?@% and Kkbsiell~~prxumoniu. SP-D did not bind Stap@hnw_xxs auras, the only Gram-positive bacteria tested. Rapid specific binding was observed ( > 50 per cent of the maximal binding was in the first 5 min) and was not mediated by lectins known to be present on bacterial pili which may bind to N- or 0 linked sugars on SP-D. The binding could be inhibited by LPS, EDTA, monosaccharides, such as maltose and glucose, but not N~acetylglucosmine. Scatchard analysis revealed a single class of high affinity binding sites with a Kd of 2 x 10~11 M to E. co/iand > 1 700 predicted binding sites per cell assuming SP-D is a dodecamer. Finally, E. coli agglutination was also demonstrated using brochoalveolar large from both rdt and human lung, which could be inhibited by maltose and polyclonal antisera specific for WI), ruling out a role for SPA. These studies indicate an important role for SP-11 in host defense in alveoli [ 531.
Collectin
receptors
Collectin ligand complexes interact specifically with a range of circulating target cells. Experiments in which
63
64
Innate immunitv
globular domains expressed in the absence of collagen tails are unable to mediate binding or internalization of the bound ligand suggest that the collagen tails may be the topology of the molecule that is recognized by the cellular receptor (reviewed in [ 58]). Clq receptors that recognize collagen domains of Clq have been described on B cells, phagoc?;tes and Iymphoblastoid and myeloid cell lines, endothelial cells, hbroblasts and platelets (reviewed in [ 5X]). Variations in the characteristics of the putative Clq receptor have been reported. A molecule isolated by pzssing material from leukocves over an atfinity column that contained the collagenous region of Clq attached to sepharose yielded a 126 kD protein [ 59.1. Antibodies directed against this antigen inhibited Clq mediated enhancement of phagocvosis. Ghebrehiwet and collcdgues [60] reported molecular weights for the Clq receptor in the range 65-85 kD, whereas Sim and coworkers [61-l identified a molecule of molccular weight 53 kD. Subsequent work has revealed that these hv~ proteins are identical and that the apparent differences were due to diRerent gel conditions [62]. This molecule has also been shown to bind other collectins [63]. Very recent work indicates that this latter protein is very similar, but not identical, to a human protein RoSSA/calreticulin, the Onchocerca z~olzwlus antigen (RAL-1) and B50 murine melanoma antigen. The functional significance of these homologies remains unknown and it is also not clear whether this protein is the only Clq receptor and if it is the generic collectin receptor.
Conclusion
References
and recommended
Papers ot particular interest. published re\ie\v. have been highlighted as: . of slwcial interest ot outstanding interest ..
reading
kvtthin the annual
penod
of
I
J,ANFU;:\YCR: Approaching Revolution in Immunology. Hid 19x9, 54:lp13.
2.
E~IXO~I’I’Z RAE Ante-antibody 1:6042.
3
M~l\cr.ror) CRI. A\‘I~K~’ 07‘. The Occurrence During Acute lnfections of a Protein Not Normally Present in Blood. Isolation and Properties of the Reactive Protein. ./ fi.xp .&d 1941. ~~~IH3-190
1.
the Asymptote: Evolution and Cold .Spri~zgIh~,-h $ynzp Ql~rrrt Immunity.
GY). Rio/ 1991,
I)wh.uItd
K: Two Distinct Classes of Carbohydrate-rccognition Domains in Animal Lectins: ,/ Hzol 03~~ 1988, 263~9i57-9i60.
R. liar KI XI 1. ‘I‘HIEI. S. Su4 RB Interaction of Clq Receptor with Lung Surfactant Protein A. ,!%r ./ Imi?r~tzol 1992. 22:1437~l+~i. First reference for the term collectin used to describe Clq, MUP, SP A,
5. ..
bLu~mm4
SP-11 and conglutinin These proteins have collagenous domains and lectm domains (except Clq ), and m part their fimction is to ‘collect’ ligandx for ph:tgoc?ws.
6.
TIII~(I. S. Rtim KBM: Structures and Functions Associated With the Group of Mammalian Lectins Containing Collagenlike Sequences. Fkf1.S Left 1989, 250:7%8-i.
7
Lrnr RI.. I.1 J, RI:II, KBM: Structural Similarity Between Bovine Conglutinin and Bovine Lung Surfactant Protein D and Demonstration of Liver as Site of Synthesis of Conglutinin. It~2t~2unolo~~~1993, in press.
8
KA I: Isolation and CharacterKAYAKS T. E’I’OII R. YA~M~SIII ization of a Mannose-binding Protein from Rabbit Liver. HiocI7w~2Mol,ll~s Ke.s c:O~~mu~~1978, 81:101.!&1024.
9.
Y, HAEU%IGI;R Jr.. Characterization of a Mannose N-acetylglucosamine-specific Lectin Present in Rat HepatOCyteS. .J Hid Ckm 1982, 257:3’8%3’94. MAYXARII
and
MBPs and conglutinin are circulating collectins that appear to play a role as primitive opsonins. It is like11 that they also collect at inflamed sites and, therefore, pla) some role in the acute inflammatory response. The surfactant apoproteins have a predominant local role in the lung. SP-D, a soluble molecule that is not usually associated with lipid, and is potentially important as a pattern recognition molecule in alveolar lining fluid. SPA, by contrast, has a structural function and may, by default, play a role in host defense. The characterization of collectin receptors remains a productive ared of inquiry and it is likely that a family of related molecules mediates the overlapping and distinct cellular effects induced by collectin/ligand complexes. A phylogenetic search for collectin homologs in more primitive animals may provide further insights into their importance in first line host de fense.
10
DRICLLVEKK, DORDALMS, KE~wxl)b 1.: Mannose-binding Proteins Isolated from Rat Liver Contain Carbohydrate-recognition Domains Linked to CoIIagenous Tail. .I Rioi Chcm 19X6. 261.6XYi 688’.
I I.
COI.IXY JJ. Core-specitic
12.
TOLVNSENII R. S’FHL
13.
WIIU J, RUHINSUN binding Proteins 210:16’~1-t.
Biosynthesis and Secretion of Rat Lectin. .I Riol Chem 1987, 262:34155421.
P: Isolation and Characterization Mannosc/N-acetylglucosamine/Fucose Binding Protein Rat Liver. Biochrn J 1981, 194:209-21+. 1). WINCHESI’EK
from
Human
of a from
B: Isolation of MannoseLiver. Biocber?l J 1983,
1-t.
SLMME~IEI.U JA, TAYI,OK ME: Mannose-binding Proteins Human Serum: Identification of Mannose-specific Immunoglobulins and a Calcium Dependent Lectin, of Broader Carbohydrate Specificity Secreted by Hepatocytes. Uiochem Hioplq,.yActn 1986. 883:197-206.
IS.
Ex~ww~‘r’z RAB, DAY I., HEKVA’: G: A Human Manose-binding Protein is an Acute-phase Reactant that Shares SequenceHomology with 0ther Vertebrate Lectins. .I fXxp .Cf& 1988, 167:1034&1046.
16.
%S’I’KYK, Lwmi K, Ltue JM, WHITFHFII A, EXKOW’IT%RAB Molecular Characterization of the Mouse Mannose-binding Proteins. The Mannose-binding Protein A but not C is an Acute Phase Reactant. .I Imm~ctzol 1991, 147:692497.
I’.
CHILLIS RA. I:EV.I ‘I’, Y~‘EN CT,
Acknowledgements This work is supported by ;I Grant in Aid from Urtstol-Myers Sqtuhb and NIII (Ki). RA Ezekowitz is an established investigator of the American Heart Awx’iation. We are grateful to K Reid and I’, Sim for communicating results prior to publication and for useful discussions. In addttton. the term ‘collectin’ was first used hy 1~ Sim We thank Andrea Tenner for her useful suggestions.
RAI:NZIGFR J:
Differential Recognition Oligosaccharide Ligands
DRICK.&VER K, QIYXNRERK>.MS: of Core and Terminal Portions of by Carbohydrate Recognition Do-
Collectins
mains of Two Mannose-binding 265:2077&20777. 18.
Proteins.
Srll’t% M, GILLIES SD, FOLEY S, SAXRY Distinct SILVERMAN VJ, E/FKOWI’I% RAB: Functions of AIlelic Forms of Human Protein. A’atltre Gmet 1992, 2:5& 55.
K,
SCHWEINIE
to a Sticky End. Curr
20.
WEIS lW, KAHN R, FOUME R, DKIC~~~ER K, HBNRICKSONWA: Structure of the Calcium-dependent Lectin Domain from a Rat Mannose-binding Protein Determined by MAD Phasing. .Scic>zce 1991, 254:1608~1615.
21 ..
WEISS
DKKKAAMER
K, HENI)KICKSON,WA: Structure of a C-type Mannose-binding Protein Complexed with an Oligosaccharide. Nuture 1992, 3
24.
25.
S~IIWI?IN~ JE, Nrsr%ruksr~M, DING. TQ, SA~~KYK, GILLIES SD, Eze~owr’rz KAE%Truncated Forms of Mannose-binding Protein Multimerize, Bind to Mannose-rich Salmonella montevideou, but Fail to Activate Complement in Vitro. J Rio/ Chem 1992, in press. IARKIN M, CIIII~S RA, MA~IEU’S TJ, THIEL S, Mi%Lloctlr T, LAU’SON AM, SAVIU JS, HASI.XI-I’C, Dr.u. R, FEZI T: Oligosaccharide-mediated Interactions of the Envelope gpl20 of HIV-1 that Are Dependent on CD4 Recognition. AII)s 1989, 3:793-798.
WHrni IMR, EXK~W~TZ RAB, SUPER M, TAI’RFR AI: Human Mannose-binding Protein Functions as an Opsonin for Influenza A Viruses. .I Cl:li)l Irzz’est 1992, in press KUHIMANM, JolNER K, E%EKOWI’I% RAB: The Human Mannosebinding Protein Functions as an Opsonin. .I /?xp .Clcd 1989, 169:1733%1745.
27.
SC~iwWxr! J, EZEKOU~TZRAB, TENNEK A, JOINFK K: Human Mannose-binding Protein Activates the Alternative Complement Pathway and Enhances Serum Bactericidal Activity on a Mannose-rich Isolate of Salmonella. J Clin Irulest 1989, 84:1X21&1829.
29.
35.
~IAAC;SMAN HP, HAw(;oor) S, SumAm T, BIICKLEYD, WHITE RT, DRIC~~EK K. BENSON BJ: The Major Lung Surfactant Protein, SP28-36. is a Calcium Dependent, Carbohydratebinding Protein. .I Rio1 Chem 1987, 262:13877-13880.
36.
\‘AN IWA&X)EN
F, WIX~FZRSB, VERHOEF J, HAAC~SMAY IIP, v~pj GOI.I)E LM: Pulmonary Surfactant Protein A Enhances the Host-defense Mechanism of Rat Alveolar Macrophages. Am ,I Re.pir Cc& .ZJol Riol 1990, 2191 -98.
37.
TENNER
38.
IKFI)A K, SANNoH T, K,%~,L\AKIN, KA~.~AKI T, Y!&lAslIINA 1: Serum Lectin With Known Structure Activates Complement Through the Classical Pathway. ,I Hiol C&n 1987, 262:745 1-7454. LII JIl, THIEI. S, WIEDMANN t1. ‘I‘~vvI. R, RIXI KH Binding of the Pentamer/Hexamer Forms of Mannan-binding protein to zymosaan activates the proenzyme Clr2Cls2 complex of the Classical Pathway of Complement Without Involvement of Clq. .I Inznzut~ol 1990, 144:22X7 2294.
30.
ANIXRS EM, ~~ARTIEYCA, JACKSON DC. Bovine and Mouse Serum B Inhibitors of Influenza A Viruses are Mannosebinding Lectins. Proc Nutl Acad Sci I:.CA 1990, 87:4485%4489.
31.
%IPER M, THI~L S, Lrl J, TIIRNER MW: Association of Low Levels of Mannan-binding Protein With a Common Defect of Opsonization. Luncet 1989, 2:1236-1239. in the 1990s.
Pedutr
32.
SHYLIKSD, HILLHR: Immunodeficiency Infect Dis J 1991, 10:595All.
33.
SUMNA M, SLIPEKM, TAIKINA P, IE\INS~~ RJ, ARAI T, TL’KN’FR MW, SIIMMERFIELI) JA: Molecular Basis of Opsonic Defect in Immunodelicient Children. Lancet 1991, 337:1663-1670.
AJ, RCX%IXSON SL, BORCHELT J, WtuC;H’r JR: Human Pulmonary Surfactant Protein (SP-A). a Protein Structurally Homologous to Clq, Can Enhance FcR- and CRl-mediated Phagocytosis. .I Viol Chem 1989, 26413923 13928. IWAAKDEN
JF, SHI,MLZI’ H, V.ANGOl.IX HM, VOELKEKDR, Rat Surfactant Protein D Enhances the Production of Oxygen Radicals by Rat Alveolar Macrophagea l~iocizer12,I 1992, 286.5 8. \A\
VAN GOLIX
Lbl
39
I\IIAIHoK’rAR, HAIX~N J, THIEL S, %I RB Interaction of Clq Receptor with Lung Surfactant Protein A. /?~*r ,I Immzrnol 1992, 22:1i37+14ri.
40.
LACH~ZAN
-II.
IEE YM, LEISV KR, AIL* J, PAIUS K, LEKCH B, OKmrv1.4 TB: Primary Structure of Bovine Conglutinin, a Member of the C Type of Animal Lectin Family. J Rio/ Chem 1991, 2&2715%2723.
-tL.
ANIXKSICN 0.
FRIIS P, IIOI&I NE, VII_%AAR~ K. L&LIE RG. SVEHAC;SE: Purification, Subunit Characterization and UItrastructure of Three Soluble Bovine Lectins: Conglutinin, Mannose Binding Protein and the Pentraxin Serum Amyloid P Component. Stand J Immzrnol 1992, 36:131-141.
t3.
In\lIIs.SS Ku’, FEIZI T, CHILI& RA, MIZ~XXHI T, ST0I.I. MS, 0Il)KOYD RG. IACtlMANN PJ: Bovine Serum Conglutinin is a Lectin which Binds Non-reducing Terminal N-acetylglucosamine, Mannose and Fucose Residues. Riocbenz J 1989, 258:109-113.
ii.
I’SHIJI~IA II. SCHROIXK IiC, PoZNAN~\~C S, GASIC MJ, ~~t\rri~es E, MC~LLEK WE: Inhibition of Human Immunodeficiency Virus 1 Infection by Human Conglutinin-like Protein: in Vitro Studies. ,@tz .I C~rizcrl- Res 1992, 83:458A64.
45.
Br\ATKLTPG. THIEI S, ISACIER 11, SLFHAG SE, JENSENICSJC: Demonstration in HUmU Plasma of a Lectin Activity Analogous to that of Bovine Conglutinin. Sca?~d,/ 1mmu~zol 1987, 26:355%361.
46.
‘1‘~rrEr.S, Ibfirru G, FRII~ Cl’. S\XHAC;SE, JENSFNIX JC: Characterization of a Lectin in Human Plasma Analogous to Bovine Conglutinin. Sca,rc/ J Imnzurzo/ 1987, 26461468.
~~ARTSHOKN KL. S.&TRY K,
26.
28.
FI~ROS J, STEIN~K~NKR, JACOBS K, PtrEt.rs D ET AL: Isolation and Characterisation of cDNA Clones for the 35-kD Pulmonary Surfactant-associated Protein. J Biol Chem 1986 261, 9029-9033.
Bid
EZEKOU[~TZ RAB: Antigens 1992, 2.147-149.
and Ezekowitz
34.
J-E,
and Overlapping Mannose-binding
19.
Wl,
Coming
./ RioI Chem 1990,
Sastrv
47.
PJ: Conglutinin munoL 1967, 6~79-527.
FKIIS Cl’, 0,
‘I‘HIFI
and Immunoconglutinins.
S, SvtHAG SE,
IAI’RSEN SB, J~NSENII~ JC:
DESSAY K, Svmi)se?;
Adz’ Im-
P, ANDERSEN
In
Viuo and in Vitro Antibacterial Activity of Conglutinin, a Mammalian Plasma Lectin. .Scm?zdJ 1??z???/~>io1 1990, 31:453-460.
48.
FfuIS P, SYEHAC; SE,
AUlXRSEN0, GAHRN 1x3, IR\I.IF KG: Conglutinin Exhibits a Complement Dependent Enhancement of the Respiratory Burst of Phagocytes Stimulated by E. coli. fmnzu~zolo~~~ 1991, 74:6X&684.
‘19.
MAIHOTRA
nent
R, SIM RB:
Clq.
Rio&em
Receptor for Complement J 1989, 2623625-631.
Subcompo-
50.
C~or’cti E, PARCHI D. KLIAN SF, PFKSS~N A: Surfactant Protein D: Subcellular Localization in Nonciliated Bronchiolar Epithelial Cells. Am J Hgsiol 1992, 263:LbGLbG.
51.
FIXSON
A,
CIIAX
I>,
CKOLKH E: Purification
R~‘sT K, Moxr.~Y M, LO~~OIE W, and Biochemical Characterization
65
66
Innate immunitv
of CP4 (SP-D), a Collagenous Surfactant-associated Biochemistry 1989, 286361-6367.
Protein.
52.
PEWON A, RL’ST K, CHANG D, MOXIXY M, I.ONC;MORF W, CKOL~CH E: CP4: a Pneumocyte-derived Collagenous Surfactant-associated Protein. Evidence for Heterogeneity of Collagenous Surfactant Proteins. Biocbemistty 1988, 27:85768584.
53.
K~IAN SF, RIIST K, CROliCH E: Interactions of Surfactant Protein D with Bacterial Lipopolysaccharides. Surfactant Protein D is an Escherichia co&binding Protein in Bronchoalveolar Lavage. .I Clirz hzr,cst 1992, 90:97T106.
5-r.
PERSSONA, CHANG D, CKOLICH E: Surfactant
Protein D is a Divalent Cation-dependent Carbohydrate-binding Protein. J Biol Chem 1990, 265:5755%5760.
55.
S~IIMID. H, FISHFKJH, PAPST P, BENWN B, IAC K, M&ON KJ, VOELKERDR: Primary Structure of Pulmonary Surfactant Pro-
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Amino
Acid Sequence.
59. .
GAI!N EN, BIIRGESS,WH, ROBINSONSL, GOODMAN, EB MCTICIJE Cell Molecules that Bind the KJ, TENN~~RAJ: Phagocytic
Collagen-like Region of Clq. Involvement in Clq-mediated Phagocytosis. J 13iol Chem 1991, 2&20345-20355. Inhthition studies suggest that a putative Clq receptor plays a key role in Clq mediated phagocytosis. 60.
GHERRFHIWETB, BOSSONE S, ERDEI A, REID KBM: Reversible
Biotinylation of Clq with Cleavable Biotinyl Derivative. ApJ Immunol .Mefh plication in Clq Receptor Purification. 1988, 110:251-260. 61. ..
MALHOI‘RAR, WILLISAC, JEN%XII’SJ<, JACKSONJ. SIM RB: Clq Receptor (Collectin Receptor): Similarity to a Component of RoSSA. In~wtrnolo~~ 1993, in press. First sequence information on a collectin receptor. 62.
PFERSCF~ EIB. IM~~,t~~~~ R, GHEHRFHNCTTB, REID KBM, WILLISAC, SIM RB: Isolation of a Human Endothelial Cell Clq Receptor ./ Lrzrko~~Vr Biol 1993, in press
6.1.
MALH~~IU R. THIEL S, &IL) KBM, SIM RB: Human LeukocyteClq Receptor Binds Other Soluble Proteins With Collagen Domains. .I Fxp ‘Wed 1990, 172:955-959.
,I R~ol
56.
RITXTK, GROSSO I., ZHANC V, CHANG D. PERSSONA, LONG,MOKE W, CAI GZ, CRWCH E: Human Surfactant Protein D: SP-D Contains a C-type Lectin Carbohydrate Recognition Domain. Arch Bic&em Biop@.~ 1991. 290:11&126.
57.
LU J, WILLIS AC, REIV KL: Purification, Characterization and cDNA Cloning of Human Lung Surfactant Protein D. Biochem J 1992, 284:795-802.
K Sastty, Department of Patholog)‘, Boston Ilniversiv School of Medicine, 80 East Concord Street, Boston, Massachusetts 02118, LJSA.
KBM, TURNER MW: Mammalian Lectins in Activation and Clearance Mechanisms Involving the Complement System. Springer Srmin lmmrrnopathol 1993. in press.
RA Ezekowtz, Department of Hematology/Oncology and Infectious Diseases, Children’s Hospital, Harvard Department of Pediatrics, 300 bngwood Avenue, Boston, Massachusetts 02115, USA.
58.
ND
pattern
recognition
molecules
involved
in first
line host defense Kedarnath Boston
University
A
School
group
contain
Sastry and R. Alan Ezekowitz
of Medicine
of the
chlmeric
apoproteins whose
molecules
carbohydrate
defined as collectins.
and Children’s
comprising
recognition
in the first
Current
and
proteins,
all qualify
appears to be as pattern
Boston,
globular
domain,
The mannose-binding
A and D and conglutinin
function
Hospital,
as members
in Immunology
Introduction
which
tails
are
surfactant involved
host.
1993, 5:59%66
structure and function of C lq as this molecule ject of a recent review [6].
Non-clonal or innate immunity plays a role in the immediate response to infectious challenge. The direct recognition of pathogens is mediated largely by ‘pattern receptors’ that are expressed on the surface of effector cells such as phagocytes and nahlral killer cells [l]. In addition circulating eRector pattern recognition molecules have been described. They share the ability to discriminate between the patterns of oligosaccharides that are present as the surface components of pathogens from normal self glycoproteins [ 2 1, The prototype of this class of circulating pattern recognition molecule is the s zrum C reactive protein which recognizes the pneumococcus capsule [ 31, The collectins are a new class of structurall) similar pattern recognition molecules that appear to retognize distinct but overlapping carbohydrate ligands that decorate the cell walls of pathogens. The convergence of a number of recent studies has indicated the structural and functional similarities between the serum mannosebinding protein (MBP), pulmonan, surfactant apoprotein (SP)-A and -I>. bovine conglutinin and the first complement component Cl q. The globular domains, except that of Clq, are similar enough to qualify them as members of the ever-growing family of C-type lectins [ 41. The presence of a collagen and lectin domain prompted the term collectin [ 5-1. The collectins are multimeric proteins, the collagen regions of which appear to play a critical role in multimer assembly. The Clqlike collectins, the MBPs and WA, assemble into multimeric proteins conprised of 18 globular heads and collagen tails [ 61. This structural arrangement contrasts with that of the tonglutinin and the SP-D as in these molecules the globular head is arranged radially around collagen spokes [6,7]. The structural assembly of the two groups of collectins has important functional consequences that will be examined in detail below. This review will not discuss the
USA
of this family,
molecules
line of defense In the pre-immune
Opinion
heads,
collagen
pulmonary
recognition
Massachusetts,
The mannose-binding
is the sub-
proteins
MBPs exist in the serum of rabbits [8], rodents [9-I 11 and man [ 12-151 as oligomers of a 32 kD unit that has an amino-terminal domain that is rich in cysteines, a collagenous region consisting of 20 repeats of GLYX-Y (where X and Y represent any amino acid), followed by :I carboxy~terminal carbohydrate recognition domain (0). The structural unit of MBP is a trimer of three 32 kD subunits with three CRDs (96kE); this forms a collagen helix that is stabilized by disulfide bonds between. amino-terminal cyst&es. MHP is synthesized in the liver and circulates in serum as a multimer of five or six trimeric units of apparent molecular weight 570450 kD. Two homologous, yet distinct forms of MBP have been described in rats and mice, namely MBP-A and -C [ 10,16]. The mouse and rat MRP-A are 90 per cent homologous with a single gap in the collagenous region. In addition there is an extra proline in the signal peptide of mouse MHP-A. This form appears to be the predominant serum MBP and in mice its hepatic synthesis is regulated as part of the acute phase response [ 161. The MBP-C forms are characterized hy an insertion of nine amino acids in the amino-terminal cysteine-rich region and are 82 per cent homologous with one another, with no gap in the collagenous region. The expression of mouse MBP-C is not upregulated above a basal level in response to stimuli that induce the acute phase response. Interestingly the alignment of human MBP with the rodent sequences reveals that it has features in common with both MBP-A and MBP-C. In the human protein nine amino acids are inserted into the amino terminus,
Abbreviations BCpbovlne conglutinin; CRD-carbohydrate recognition domain; MBSP-mannose-bindq protein asssociated protease; MBP-mannose-binding protein; HIV-l--human immunodeficiency virus type 1; SP -surfactant apoproteln. @
Current
Biology
Ltd ISSN 0952-7915
59
60
Innate
immunity
However, the crystal structure of the rat MBP-A CRD complexed with an oligomannose asparaginyl-oligosac charide has recently been solved [21**]. The structure reveals a ternary complex of protein, Ca2+ and terminal mannoses. The 3- and d-OH groups of these terminal mannoses are involved in the direct hydrogen bonds between f&and and protein. From this study the importance of these 3- and d-OH groups provides a structural rationale for why MBPs bind II-mannose, N-acety-D-glucosamine, D-glucose and L-fucose, but not D-galactose and its derivatives. The information provided in this and an accompanying paper [22**] go a long way in providing a structural basis for the ability of MBPs to recognize a range of sugars, yet maintaining sufficient constraints to distinguish self from non-self glycoproteins. It is still not clear how the naturally occurring trimer interacts with ligand to mediate high afinity binding. One possible explanation that we have previously proposed is that each single CRD forms one face of the binding site and that the trimeric head is necessary to form one single high afhnity binding site [ 191. Recent studies in which the rat MBP-A CRD [20] or human MBP CRD [23] have been expressed as recombinant proteins indicate that the CRD in the absence of the collagen tail is able to form multimers. Sucrose density experiments with human MBP CRD indicate that monomers, dimers and trimers are formed and that high affinity binding is observed only when the CRD multimerizes. The presence
which is also a feature of MBP-C; however, like MBP-A it also has an extra cysteine in the amino-terminal region. The interruption in the collagen region (a feature of all MBPs) occurs at the eighth repeat in human MBP and rodent MBP-C, while this aberration is at the sixth repeat in mouse and rat MBP-A. The hepatic synthesis of human MBP, like rodent MBP-A, is regulated as part of the acute phase response. The collagen region is over 95 per cent conserved between all forms of MBP and all share 52 invariant amino acids; these features qualify MBPs as members of the ever-growing family of Ctype lectins [4,16] (Fig. 1). MBPs appear to play a role in the first line of host defense as they selectively recognize certain configurations of oligosaccharides that decorate a range of pathogens and virally infected cells, yet they appear unable to recognize the ofigosaccharide patterns of self glycoproteins [a]. The relatively broad array of carbohydrate moieties recognized by MESP [ 17,18] distinguishes this molecule from other proteins that have carbohydrate ligands, such as anti-carbohydrate antibodies and plant lectins (reviewed in [19]>. The specificity of these groups of proteins is dictated by the shape of their respective binding pockets which distinguish subtle alterations in the topology enabling, for example, a distinction between glucose and mannose. In the initial report of the three-dimensional structure of the rat MBP-A CRD the location of the ligand binding site was not obvious from the structure [20].
??
197 222 203 113 104 90
B2
RSP-D SSP-D m%P
HHSFC WISPA RnepA
89
RHSPC! NSP-A
102 107
??
??
? ?
XVNF&.XQRVT ILDGE IJNWQNAFSQ YXKAVLFPDGQAVGF, DSA.. R.W A.N.X .Q.LX A...R ....A ..... .S..D D.As. R.Q.E A.Q.Q VQEL. A.... . ..VX . ..N. .S... XAL. TEHAR I..NL T.SL. XQ..N I.SE IAAIRSELRAImw. ..SIS XX..X R.1 EEXLA WE?Al! I.ILX SXIQL TN.LE A.SH. F2W.X it.1XVXLA WXAE INTLX SXLEL TN.LE A.SM. XXS.X . NI.LX IAALR SELRA HR.W. .L&S XN..X .QAT .BD.R EQIL. TRG.L SIQGS HT.,.
Invariant t
??
APR
c .
??
RNSPC ESP-A
VYSNWADGEP .... . .P... .... . .P... T.T.. NE... R.T.. N.... T.... FXD.. ..GX. T.... XXD...NRV R.T.. W... D.TPV N.T.. YR...
NNSESZGQPEN ..-NG .-A.. .D-.G .-S.D ..AG SD-.D ..lUI .--.D ..EGS --G.D -PN.E .SG.D ..VGS .--.. --AGR .X-.Q
Invariant
tc
FU%PA
lGEIL ...A. ...S. ..NR. ..NRV ..GR.
S.A.F NEA.F .--.F D-I.. -GI.F XTS.F D-V.F WY..
EN
??
RSP-D ESP-D NHSP NHBPC HHSPA
..I..
.F.L. .Y.VS .L.V. .F.V. .Y.HS .V.SS
N.EIH SVKXH NRXXN NNERM SVRRM N.QSI
??
SYSDAEQLCREAXGQUSPRSSAENXAVTQHVRAQXXNAY PFE.. WM.. Q.G.. ..... .AT.. A..Q. L.T.E PFTE. QL..T Q.G.. ..... .A... A.LQ. L.V.X TFEW XA..V lcFQA.9 V.T.. NA... G.IQN LIX-E .LDRV XA..S .FQ.S V.T.. NAE.. S.I-. X.-.X PF.XV XS..T .LQ.T V.I.. NAX.. X.-I. E-V.T PF.XV M..S .LR.T V.I.. NAE.. X.-I. E-V.PLNR. XA..S .LQ.T V.T.. NAE.. R.I-. N.-.X TFDAI QXA.A R.G.R I.V.. NPE.. ..IAS F.XXY
Invariant
Bc
. . . . .
_G XF ??
SC RSP-D ESP-D SHW MMEZC MHSPA RNSPA Rnepc ESP-A
??
XIFXTAGAVX ,..RA .NSRE
??
ISNND ...T. ...T. .GIT. .GIT. .GIT. .GIT. .GIT. VGLTE 1
w
??
CVEIF PDGXW NDVPC ..... TN.Q. ..XA. ..... TN... ..RA. ..IJ,LXN.Q. ..... ..V.L GN... ..... ..I.L C4J.L. ..IS. ..T.V DN.L. ..IS. ..VLL lW... .... . ...MY T..Q. ..RN.
ISTEGRFTYP VG... X.... SK... X.... XX... Q.WL VRV.. S.EDL EA... Q.M.V EV... Q.M.V QR..N V.GDL GPSP. D.R.S F
-
??
SXQLL VICXF Gl3.R. .. ... GSXR. .V... .TSE. AV... .DSF.
A....
QASFX AV.. QASRT AV.. .LlSF. .V... LYSR. T....
351 374 355 248 244 239 238 244 248
Fig.1
of
C-type
lectins. The numbers
The
collectin
correspond
to the
amino
in the protein
acid number
family
quence. The amino acids Invariant least eight or nine carbohydrate nition
domarns
are shown
recog-
in lower case
letters.
The amino acids underlined
those
identified
characteristic
by
Drickamer
of C-type
Identity
sequence
of bovine conglutrnin
is
gaps.
marked
man
10th
mannose-binding
human
pulmonary
A; HSP-D, MMBPA,
human mouse
tein A; MMBPC, ing
Every
protein
A dot
the amino
surfactant surfactant
hu-’
HSP-A, protein
protein
mannose-binding mouse
acid
HMBP,
protein;
C; RMBPA,
acrd
(EC). ~
amino
by an asterisk.
are
141 as
lectins.
indicates indicate
with
sein at
D; pro-
mannose-bindrat
mannose-
binding protein A; RMBPC, rat mannosew
XE
I
cv
GWNOC
3
binding protein protein
D.
C; RSP-D,
rat surfactant
Collectins
of six trimeric heads in the mature protein suggests that each subunit clusters around the oligosaccharides on the surface of a pathogen, hence accounting for the nM binding affinities associated with MBP binding to the cell walls of pathogens [ 231. lluman MBP can recognize Gram-negative enteric organisms, such as Salmonella montit tideo, Esclierichia coliJ5 strains, yeast mannans, ~~~focc~~~s [email protected] B streptoccoci [1X], the high mannose glycans present on the envelope glycoprotein of human immunodefi~ cienq virus 1241 and certain influenza virus subtypes [ 251. IYZz?tro studies have demonstrated that native and recombinant human MBP can opsonize kmcteria and enhance clearance by phagoqTes [ 261. MBP bound to a l&and can activate both the alternative [ 27 ] and classical complement pathways [ 281, The higher oligomer states of MBP, which resemble Clq, have been shown to interact with Clr2 and Cls2 [ 291. In addition, a recent report describes the characterization of a novel Cls-like protease, designated MBP-associated protease (MA!%) [29]. MBP-mannan-MASP complexes are able to mediate Cls independent activation of the classical complement pathway. These findings suggest the existence of other novel proteins that may play a key role in regulating MBP function. Further support for MBP as an ‘ante-antibody’ involved in the first line of host defense, comes from studies that indicate that MBP and phagocytic cells are an important component of preimmune host defense against influenza A viral infection. MBP directly inhibits hemag~ glutinin activity of several strains of influenza A virus. and in addition MBP opsonization of the virus not onI) protects polymorphonuclear leukocytes against virally ins duced damage, but also enhances viral clearance in zlitro [25]. The i?z z’itjo role of collectins (MBP in human and mouse sera and conglutinin in bovine sera) as the first line of host defense against certain strains of inn fluenxa virus arises from studies that implicate these two molecules as the beta inhibitors. These were first described in the 1940s as serum proteins involved in preimmune defense against this pathogen. Recent studies indicate that mutant virus Mem71hBeln(f13Nl), which is resistant to collectin hemagglutination, has a single base pair substitution in the hemagglutinin; this results in a loss of a glycosylation site, which is a target for MBP or conglutinin [ 301. It appears likely that these mannosebinding collectins inhibit viral infectivity by binding to the oligosaccharide side chains and thus mask the adjacent cell-binding domain. A vet? attractive hypothesis holds that low levels of MBP predispose children below the age of two years to recurrent infections [31]. Children of this age group are vulnerable to attack by encapsulated organisms and respiratoty viruses as the anti-carbohydrate antibody response is muted until 1X months of age (321. It has been proposed that a MBP genotype, which appears to segregate with low basal MBP levels, also correlates with recurrent infections in three families [ 331. Patients who were homozygous for adenine instead of guanine at base pair 230 were predicted to have an MBP gene that
Sastry and Ezekowitz
encoded a dysfunctional protein (MBP230,) as such a change alters a gtycine for an aspartic acid at the fifth collagen repeat. This substitution was predicted to disrupt the collagen helix and there act as a transdominant negative mutation. However several factors confound this apparent association. Low baseline levels of MBP that reportedly correspond with the clinical phenotype and the genotype are found in 5-7 per cent of the normal population [ 181. In addition, the population predicted to be most vulnerable, i.e. young children, have a baseline level of recurrent infections [32]. Recent findings are more compatible with the idea that MBP exists as two allelic forms. Studies with recombinant proteins that represent both allelic forms of MBP indicate that both are able to assemble as high order muttimers and act as opsonins, !ret the MBP230,, encoded protein is unable to act as a surrogate for C lq in the activation of the classical complement pathwdy. Whether this form of MBP is able to initiate the nlternati\,e complement cascade is yet to be determined. It may be that the MBP230AA allele alone does not account for the putative immunodeficienq phenotype, but rather a lack of MBP-dependent complement activation may predispose to infection in association with another mild immune defect. MBPs, like other collectins detailed below and pattern recognition molecules in general. appear to be most important in the pre-immune host in the earliest stages of infectious challenge. The ultimate verification of this would depend on the identification of a null genotype that expresses a phenotype of susceptibility to a well detined infectious history that can be alleviated by adminstration of recombinant MBP. These ‘proof of principal’ experiments may be best performed in an experimental murine model in which MBP genes have been knocked out by homologous recombination. Susceptibility to infectious challenge could be examined in these MBP-deficient animals.
Surfactant
apoprotein
A
WA is a major surfactant protein with overall structural similarity to C 1~1 and MBP [ 101, In humans, there are two highly homologous genes. which are most likely to be products of gene duplication, encoding WA [34]. It is not clear Lvhether the SPA found in z?!‘o is a heteroor homotrimer. WA has a short stretch of seven amino acids at the amino terminus with a single cysteine, which is likely to form an inter-chain disulphide bridge. This is followed by a collagen-like domain of 23 Gly-X-Y repeats with a single interruption. like MBP, the carboxyl terminal 148 amino acids constitute the CRD [35]. Previously, several studies have shown that S!‘-A does not opsonize Gram-positive bacteria, such as Staplylo coccus aflt+eu.s,or Gram-negative bacteria, such as Escberichia coli and Pseudomortas aerugeno.sa [36]. It can enhance the phagoqtosis of serum opsonized or unopsonized bacteria by stimulation of alveolar macrophages 1361 and opsonized erythrocytes by monoqte-derived macrophages [37], Induction by free SP-A of the chemi-
61
62
Innate immunitv
luminescence response, a measure of oxygen free radical release, is observed in T;tt alveolar macrophages but not in rat peritoneal macrophages, human monoqtes and rat [ 36,381. SPY or human polymorphonuclear leukocytes A appears to enhance uptake of herpes simplex virus by alveolar macrophages [ 391. Maximal enhancement of phagoqtosis was observed after incubation for 15 minutes with 5 F$rnl SP-A and was inhibited by anti~SP-A F(ab’)L. SP-A forms a Clq-like structure (Fig. 2), yet is unable to substitute for Clq in the activation of the classical complement pathway and in this way is similar to the MHP230, allele described above. SP-A is an integral part of the ‘tubulomyelin’ network, a lipid associated framework that stabilizes alveolae. The physiological role for WA may be structural and its role as ‘gatekeeper’ in the lung a secondary hmction. The avid association of WA with lipid, and the internalization of these complexes by alveolar macrophages and pulmonary epithelial type II cells, indicate that WA is not an opsonin in the true sense, but bacteria or other pathogens may be trapped in this complex and then cleared by cells that bind SP-A in the absence of ligand. This feature distinguishes SP-A from MBP, which is not taken up by cells in the absence of ligdnd, and suggests that these two ligands may utilize distinct re-
ceptors. The failure of free Clq to inhibit SPA-mediated uptake by alveolar macrophages appears to support this contention [ 361.
Conglutinin
as an opsonin
Bovine conglutinin (BC ) was the first vertebrate calcium dependent (C-type) lectin to be described; it can promote agglutination of erythrocytes coated with activated complement components [40], The carbohydrate strut ture to which RC hinds is exposed after breakdown of complement component C3. The complete amino acid sequence of BC, determined by Lee et al. [411, reveals a short amino-terminal stretch of 25 amino acids with two cysteines, perhaps involved in inter-chain cross-linking. This is followed by a collagen-like domain probabl? involved in helix formation with 55 repeats of Gly-X-Y. There are two interruptions in the collagen-like domain after the fourth and 32nd repeats. Towards the carboxyl terminus is the CRD of 155 amino acids, of which 16 are invariant, including four cysteines believed to play an important role in intra-chain cross-linkage leading to globular conformation The molecular weight of each BC
45nm
&-
Fig. 2. Ultrastructure
of
tant apoprotein
conglutinln
W-A,
mannose-blnding
VI.
is a hexameric
!
six
bent
surfacand
protean (MBP). (a) Clq structure
collagen
to a globular
Clq,
triple
made up of helices
joined
domain. SP-A is essentially
identical in appearance to Clq when vi-’ suallzed
using the electron
1201. (b) MBP structure,
hut
has
microscope
a similar
when
monomer
isolated
consists
of a range of oligomers
mainly
tetramers
[121. (cl Coglu-
and hexamers
tinln is a much larger protein, of four subunits logenous from
1631.
trimers,
consisting
each made up of a col-
and globular
region.
Adapted
Collectins
polypeptide chain appears to be 43 kD and electronmicroscopic studies reveal predominantly a tetramer of trimers [ 421. Previously, conglutinin has been shown to bind to the cell wall of yeast and also to zymosan particles. BC al>pears to have higher affinity for non-reducing terminal N-acetylglucosamine than N-acetylmannosamine, a property useful in purification of BC from bovine MBP, which has higher affinity for the latter sugar [42]. BC also binds to terminal mannose and fucose residues [43] Recentl) the existence of a conglutinin-like molecule has been reported in human serum [44] which appears to confirm earlier reports on detection in human plasma [45,46]. Administration of BC to mice a day before challenge with Salmorzclla <~bimurium led to rapid clearance of bacteria from the circulation and protected 80 per cent of the mice, compared with only 10 per cent survival in the control (saline) group on day 10 post infection [47]. BC enhanced chemiluminescence of murine spleen cells stimulated with serum opsonized E coli [ 481; maximum enhancement was observed at the highest dose of conglutinin employed (50 l.q+/rnl). Addition of N-acety~ glucosamine along with BC led to inhibition of enhancement, whereas N-acetylgalactosamine was non-inhibitory, The BC used in these experiments was composed of mainly ( > 90 per cent) monomers. E. coli preincubated with serum, washed before addition of BC and washed again before addition to spleen cell cultures, were also killed in a conglutinin-dependent manner. No antibac-terial effect of BC could be demonstrated in similar experiments when 1OmM EDTA was present or when heat-inactivated/factor I deficient serum was used in place of untreated serum. These experiments indicate that the opsonic effect of BC could be due to binding to iC3b deposited on the bacterial surface and subsequent binding of BC to phagocytes via receptors for collagen-like proteins [481. The classical beta inhibitors of influenza virus hernag&tination and infectivity in bovine and mouse sera were previously shown to be calcium-dependent mannoseinhibitable &tins (as stated above). Different characteristics of beta inhibitors from bovine and mouse sem have also been observed. Bovine serum (but not mouse serum) beta inhibitors were resistant to O.lM 2-mercaptoethanol and the inhibition of influenza virus hemagglutination by bovine sera could be reduced by a monoclonal antibody to BC [49]. These studies clearly estab lish that beta inhibitors in bovine and mouse sera are distinct. BC appears to be a beta inhibitor in bovine sera while mannan-binding proteins appear to be the serum beta inhibitors in mouse. Envelope glycoproteins of human immunodeficiency virus type 1 (HIV 1) are known to contain high mannose carbohydrate chains, and in studies similar to those reported earlier with MBP, both BC and human conglutinin-like protein have been shown to bind HIV1 gp120 [24]. Conglutinin, is predominately a pattern recognition molecule of ruminants. It recognizes the cleaved third complement component and is able to bind a range of oligosaccharide structures. It appears that it is able
Sastrv and Ezekowitz
to distinguish self from non-self, like MBP, and may be considered as the major serum lectin of ruminants.
Surfactant
protein
D
A new member of the C-type lectin family, SP-D (formerly called CP-41, is secreted by freshly isolated rat lung type II epithelial cells and non-ciliated brochiolar (CkdEi) cells [WI. Persson rt al. [Sl] showed SP-D to be immunologically distinct from the previously characterized !%A, a major component of surfactant and a C-type lectin. Both SP-A and WD are found to be associated with phospho lipids in lung surfactant. IIowever unlike SP-A, purified, delipidated SP-D does not interact with lipids. SP-D is a 43 kD protein and forms a structural subunit as a trimer but may exist as a dodecamer (516kD) in surfactant [52,53]. Both SP-A and WD have collagen-like domains and the ability of their lectin domains to bind Elrious sugars has been well established [35,54]. SP-D has high affinity for maltose and a slightly lower afinity for glucose, whereas WA has high a affinity for fucose, galactose, glucose and mannose. The primary structure of both rat and human SP-D have been deduced from the cDNA clones [ 55-571. Both rat and human SP-D are 355 amino acids long with 72 per cent homology. Human SP-D has a short amino terminal of 25 amino acids containing two qsteines followed by a collagenlike domain comprising 177 amino acids with 59 uninterrupted repeats of Gly-X-Y and a carboxyl terminal of 153 amino acids that represent a CRD. Interestingly, both rat and human SP-D show greater homology to conglutinin (b&67 per cent homology) than to SP-A (3&37 per cent homolo&T) [ 55-571. Kaun et al. [53] have shown that SP-D mediates agglutination of Graq-negative bacteria, such as E. coli, S. para?@% and Kkbsiell~~prxumoniu. SP-D did not bind Stap@hnw_xxs auras, the only Gram-positive bacteria tested. Rapid specific binding was observed ( > 50 per cent of the maximal binding was in the first 5 min) and was not mediated by lectins known to be present on bacterial pili which may bind to N- or 0 linked sugars on SP-D. The binding could be inhibited by LPS, EDTA, monosaccharides, such as maltose and glucose, but not N~acetylglucosmine. Scatchard analysis revealed a single class of high affinity binding sites with a Kd of 2 x 10~11 M to E. co/iand > 1 700 predicted binding sites per cell assuming SP-D is a dodecamer. Finally, E. coli agglutination was also demonstrated using brochoalveolar large from both rdt and human lung, which could be inhibited by maltose and polyclonal antisera specific for WI), ruling out a role for SPA. These studies indicate an important role for SP-11 in host defense in alveoli [ 531.
Collectin
receptors
Collectin ligand complexes interact specifically with a range of circulating target cells. Experiments in which
63
64
Innate immunitv
globular domains expressed in the absence of collagen tails are unable to mediate binding or internalization of the bound ligand suggest that the collagen tails may be the topology of the molecule that is recognized by the cellular receptor (reviewed in [ 58]). Clq receptors that recognize collagen domains of Clq have been described on B cells, phagoc?;tes and Iymphoblastoid and myeloid cell lines, endothelial cells, hbroblasts and platelets (reviewed in [ 5X]). Variations in the characteristics of the putative Clq receptor have been reported. A molecule isolated by pzssing material from leukocves over an atfinity column that contained the collagenous region of Clq attached to sepharose yielded a 126 kD protein [ 59.1. Antibodies directed against this antigen inhibited Clq mediated enhancement of phagocvosis. Ghebrehiwet and collcdgues [60] reported molecular weights for the Clq receptor in the range 65-85 kD, whereas Sim and coworkers [61-l identified a molecule of molccular weight 53 kD. Subsequent work has revealed that these hv~ proteins are identical and that the apparent differences were due to diRerent gel conditions [62]. This molecule has also been shown to bind other collectins [63]. Very recent work indicates that this latter protein is very similar, but not identical, to a human protein RoSSA/calreticulin, the Onchocerca z~olzwlus antigen (RAL-1) and B50 murine melanoma antigen. The functional significance of these homologies remains unknown and it is also not clear whether this protein is the only Clq receptor and if it is the generic collectin receptor.
Conclusion
References
and recommended
Papers ot particular interest. published re\ie\v. have been highlighted as: . of slwcial interest ot outstanding interest ..
reading
kvtthin the annual
penod
of
I
J,ANFU;:\YCR: Approaching Revolution in Immunology. Hid 19x9, 54:lp13.
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E~IXO~I’I’Z RAE Ante-antibody 1:6042.
3
M~l\cr.ror) CRI. A\‘I~K~’ 07‘. The Occurrence During Acute lnfections of a Protein Not Normally Present in Blood. Isolation and Properties of the Reactive Protein. ./ fi.xp .&d 1941. ~~~IH3-190
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5. ..
bLu~mm4
SP-11 and conglutinin These proteins have collagenous domains and lectm domains (except Clq ), and m part their fimction is to ‘collect’ ligandx for ph:tgoc?ws.
6.
TIII~(I. S. Rtim KBM: Structures and Functions Associated With the Group of Mammalian Lectins Containing Collagenlike Sequences. Fkf1.S Left 1989, 250:7%8-i.
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KA I: Isolation and CharacterKAYAKS T. E’I’OII R. YA~M~SIII ization of a Mannose-binding Protein from Rabbit Liver. HiocI7w~2Mol,ll~s Ke.s c:O~~mu~~1978, 81:101.!&1024.
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MBPs and conglutinin are circulating collectins that appear to play a role as primitive opsonins. It is like11 that they also collect at inflamed sites and, therefore, pla) some role in the acute inflammatory response. The surfactant apoproteins have a predominant local role in the lung. SP-D, a soluble molecule that is not usually associated with lipid, and is potentially important as a pattern recognition molecule in alveolar lining fluid. SPA, by contrast, has a structural function and may, by default, play a role in host defense. The characterization of collectin receptors remains a productive ared of inquiry and it is likely that a family of related molecules mediates the overlapping and distinct cellular effects induced by collectin/ligand complexes. A phylogenetic search for collectin homologs in more primitive animals may provide further insights into their importance in first line host de fense.
10
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Ex~ww~‘r’z RAB, DAY I., HEKVA’: G: A Human Manose-binding Protein is an Acute-phase Reactant that Shares SequenceHomology with 0ther Vertebrate Lectins. .I fXxp .Cf& 1988, 167:1034&1046.
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%S’I’KYK, Lwmi K, Ltue JM, WHITFHFII A, EXKOW’IT%RAB Molecular Characterization of the Mouse Mannose-binding Proteins. The Mannose-binding Protein A but not C is an Acute Phase Reactant. .I Imm~ctzol 1991, 147:692497.
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CHILLIS RA. I:EV.I ‘I’, Y~‘EN CT,
Acknowledgements This work is supported by ;I Grant in Aid from Urtstol-Myers Sqtuhb and NIII (Ki). RA Ezekowitz is an established investigator of the American Heart Awx’iation. We are grateful to K Reid and I’, Sim for communicating results prior to publication and for useful discussions. In addttton. the term ‘collectin’ was first used hy 1~ Sim We thank Andrea Tenner for her useful suggestions.
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58.
ND