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Complement Receptors Secondary article Robert Graham Quinton Leslie,Odense University.odense,Denman Artice Contents duction Complement receptors are membrane proteins expressed on the surface of immune cells. They interact specifically with complement factors leading to the removal of antigen from 。The Con ent Receptors for C3b and its Derivative the circulation. ·The Clq Receptors Introduction In addition to promoting microorganism destruction by The Anaphylatoxin Receptors The C5a receptor(C5aR,CD88) tion of blood leucocvtes to a site of inflammation:the induction of granule release and synthesis of cytotoxic immune complexes (ICs)from the circulation:and the Structure induction of a primary B-cell response to antigen.These to the ctivation pro distributed throughout the whole protein.Other members y include the ceptors for C3a,formyl .(2 and pla oinding the fragment and dre nd o and (3)receptors tors.The C5aR gene is located n q13.3-13.4of human chromosome 19.together with the s lectin The general characteristics of the complement receptors are summarized in Table 1.Attention will be primarily and smice focused on the hur diversity (68%conservation between humans,mice,rats canines and bovidae)than do the other members of the c from their human counterparts. spec the int ergen Table 1 The complement receptors Receptor Ligand CD number Protein superfamily Function CsaR C5a;CSa-desarg CD88 G protein-coupled receptors eucocyte chemoattraction,degranulation n-c C3b pled receptor NO习ynthes CD35 sof complemen on of phago CR2 C3dg (iC3b) CD21 Regulators of complement B-cell proliferation,altemative pathway activation activation iC3b CDIIb/CD18 B,integrin ROM/NO synthesis,degranulation CR4 iC3b CDIIc/CD18 B,integrin Phagocytosis,leucocyte migration C1q.MBL,SPA Chemotaxis,promotion of phagocytosis,ROM Syntnesis,plat let aggregation,leucocyte migration Regulation of B-ce ROM,reactive xygen MBL mannan-bindingectin SPA,ung sfactant proteinA ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group/www.els.net

Complement Receptors Robert Graham Quinton Leslie, Odense University, Odense, Denmark Complement receptors are membrane proteins expressed on the surface of immune cells. They interact specifically with complement factors leading to the removal of antigen from the circulation. Introduction In addition to promoting microorganism destruction by lytic attack, the complement system exerts a wide-ranging influence on the activities of cells involved in the immune response. Thus, complement is instrumental in the direction of blood leucocytes to a site of inflammation; the induction of granule release and synthesis of cytotoxic oxygen- and nitrogen-containing compounds by leucocytes of the myeloid lineage; the promotion of particle phagocytosis by these cells; the clearance of soluble immune complexes (ICs) from the circulation; and the induction of a primary B-cell response to antigen. These effects are exerted through interaction of the activation products of complement factors C1, C3 or C5 with specific receptors on the responding cells. The receptors can be divided into three categories: (1) those recognizing the anaphylotoxic polypeptides, C3a, C5a and C5a-desarg, (2) those binding the active C3 fragment, C3b, and its degradation products, iC3b and C3dg, and (3) receptors for C1q and related collagenous lectins. The general characteristics of the complement receptors are summarized in Table 1. Attention will be primarily focused on the human complement receptors, although mention is also made of the receptors in other species; especially where these diverge structurally or functionally from their human counterparts. The Anaphylatoxin Receptors The C5a receptor (C5aR, CD88) C5aR is a membrane glycoprotein of about 42 kDa displaying high affinity for the C5 fragments C5a and C5a-desarg. Structure C5aR belongs to the superfamily of G protein-coupled receptors, which contain seven transmembrane segments distributed throughout the whole protein. Other members of this superfamily include the receptors for C3a, formyl MetLeuPhe (fMLP), interleukin 8 (IL-8) and plateletactivating factor (PAF) as well as the tachykinin, adrenergic and opsin receptors. The C5aR gene is located in q13.3–13.4 of human chromosome 19, together with the fMLPR gene with which it displays 34% identity. The C5aR genes in mice, rats and dogs have also been sequenced and show considerably greater interspecies diversity (68% conservation between humans, mice, rats, canines and bovidae) than do the other members of the G protein-coupled receptor family (85–98% conservation); especially in the putative extracellular segments. This diversity is presumed to reflect interspecies divergence of the ligand involved. Article Contents Secondary article . Introduction . The Anaphylatoxin Receptors . The Complement Receptors for C3b and its Derivatives . The C1q Receptors Table 1 The complement receptors ROM, reactive oxygen metabolites; NO, nitric oxide; MBL, mannan-binding lectin; SPA, lung surfactant protein A Receptor Ligand CD number Protein superfamily Function C5aR C5a; C5a-desarg CD88 G protein-coupled receptors Leucocyte chemoattraction, degranulation C3aR C3a – G protein-coupled receptors NO synthesis CR1 C3b CD35 Regulators of complement activation Promotion of phagocytosis, immune complex (IC) clearance, processing of IC-bound C3b CR2 C3dg (iC3b) CD21 Regulators of complement activation B-cell proliferation, alternative pathway activation CR3 iC3b CD11b/CD18 β2 integrin ROM/NO synthesis, degranulation CR4 iC3b CD11c/CD18 β2 integrin Phagocytosis, leucocyte migration cC1qR C1q, MBL, SPA – – Chemotaxis, promotion of phagocytosis, ROM C1qRp C1q, MBL, SPA – – Synthesis, platelet aggregation, leucocyte migration gC1qR C1q – – Regulation of B-cell activity ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 1

Cellular distribution C5aR is expressed on neutrophils, eosinophils, basophils and monocytes, as well as on some nonmyeloid cells, including bronchial and alveolar epithelial cells, vascular endothelial cells, Kupffer cells, stellate cells and, to a lesser extent, sinusoidal epithelial cells in the liver, as well as astrocytes and microglial cells in the brain (Tables 2 and 3). The C5aR on eosinophils is somewhat larger than that on neutrophils (50–55 kDa versus 42 kDa) and this difference is presumed to arise either from alternative splicing of the C5aR gene or from variable posttranslational modification. Expression of C5aR on monocytic cell lines can be upregulated upon stimulation of the cells with interferon g (IFNg) and phorbol myristate acetate (PMA). Function The 42-kDa form of C5aR binds C5a with high affinity (Kd 1 nmol L 2 1 ) and C5a-desarg with an approximately 10- fold lower affinity. On neutrophils, the receptor is expressed as a functionally uniform population at a level of 200 000 copies per cell, whereas on eosinophils, two distinct populations are discerned; one (15 000 sites per cell) with a Kd of 31 pmol L 2 1 and the other (375 000 sites per cell) with a Kd of 100 nmol L 2 1 . Current evidence suggests that a dual binding motif is involved in the interaction with C5a; a recognition site for the N-terminal end and disulfide-linked core of C5a, located in the Nterminal extracellular domain of the receptor, and a secondary site, involving Glu199 and Arg206 of C5aR in binding Lys58 and the terminal arginyl carboxylate group of C5a. Activities initiated in granulocytes and monocytes via C5aR include cytoskeletal remodelling, shedding of Lselectin and upregulating of adhesion molecules/complement receptors (CR1, CR3 and CR4), chemotaxis, granule release and synthesis of cytotoxic reactive oxygen metabolites (ROM). Stimulation of endothelial cells via C5aR results in upregulation of the adhesion molecules Pselectin, E-selectin and intercellular adhesion molecule 1 (ICAM-1), involved in trapping leucocytes, while C5aR triggering in the liver initiates the production of acutephase proteins. Signalling Signalling via C5aR, in which ligand engagement of Arg206 is believed to play a crucial role (Raffetseder et al., 1996), is mediated by receptor-associated, heterotrimeric (abg) GTP-binding proteins, containing the a subunits, Gia2 and Gia3, which are pertussis toxin (PTX)- sensitive, and/or the PTX-insensitive Ga16. GTP-induced release of the bg subunit from a leads to activation, by these subcomponents, of phosphatidylinositol (PI)-specific phospholipase C-b2 and A2 as well as phospholipase D. Their activation leads, in turn, to the generation of phosphatidic acid and diacylglycerol, calcium mobilization, activation of protein tyrosine kinases, protein kinase C(PKC) and phosphatidylinositol 3-kinase (PI3 kinase) and, ultimately, initiation of the mitogen-activated protein kinase (MAPK) cascade, which is involved in nuclear signalling. In the course of activation, the C5a receptor is transiently phosphorylated, by a G protein-independent, staurosporin-sensitive mechanism, at serine residues in its cytoplasmic tail. In its phosphorylated form, C5aR is rapidly internalized into endosomes that cluster near the nucleus after 10 minutes (Naik et al., 1997). The internalized C5aR may subsequently be recycled to the surface membrane following dephosphorylation. Table 2 Distribution of complement receptors on blood cells in humans a C3aR has been detected on tonsillar B cells. b Present on a minor T-cell subpopulation. c On human and primate cells only. d C3aR is expressed on guinea-pig platelets. e CR1 is expressed on murine and rabbit platelets. Cell type C5aR C3aR CR1 CR2 CR3/4 cC1qR C1qRp gC1qR Monocytes (macrophages) + + + – ++ + – Neutrophils + + + – + + + + Eosinophils + + + – + – – + Basophils (mast cells) + + + – ++ + + Natural killer cells – – + – + –– – B cells – –a + + – + – + T cells – – (+)b (+)b –– – – Erythrocytes – – +c –– – – – Platelets – –d –e – + – + + Complement Receptors 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

The C3a receptor (C3aR) Structure Human C3aR resembles the C5aR in that it contains seven transmembrane segments within its 482 amino acid sequence and shows 37% sequence identity with C5aR (Ames et al., 1996). However, distinctive for C3aR is a 175 amino acid insert in the second extracellular loop, between the fourth and fifth transmembrane segments (Ames et al., 1996; Crass et al., 1996). Murine C3aR shows 65% overall sequence identity with its human counterpart and contains a 165 amino acid insert. Like C5aR, C3aR displays diversity in size; being found as two species of 54–61 kDa and 86–107 kDa on the human mast cell line HMC-1, and in up to three forms on guineapig platelets (83–114 kDa). Cellular distribution C3aR is expressed on monocytes/macrophages, neutrophils, eosinophils and basophils, but rarely on peripheral lymphocytes (Table 2). A single report has described the receptor’s presence on human tonsillar B cells. The receptor is also found on a human hepatoma and some leukaemia cell lines and has been identified in murine testis, brain, liver, lung, muscle and kidney tissue as well as on guinea-pig platelets. Function C3aR exists as two functional variants displaying different affinities for its sole ligand, C3a. The high-affinity form (Kd= 2–5 nmol L 2 1 ) is expressed in relatively low copy numbers (200, 63 000 and 30 000–60 000 per cell on guineapig platelets and macrophages and the HMC-1 cell line, respectively) while the low-affinity receptor (Kd= 30– 150 nmol L 2 1 ) is more prevalent (500, 120 000 and 5– 23 105 per cell, respectively, on the same cells). On human neutrophils, the receptor is found as a single low-affinity species at a level of 40 000 copies per cell. Expression of C3aR on human myeloblastic cell lines is enhanced by treatment with IFNg. The C3aR mediates the chemotaxis of eosinophils and mast cells, but not neutrophils. It also induces histamine release and leucotriene synthesis by mast cells/basophils, ROM synthesis by eosinophils, neutrophils and macrophages and degranulation of eosinophils and neutrophils. In the case of human basophils, the response is greatly increased upon costimulation with either IL-3 or granulocyte–macrophage colony-stimulating factor (GM-CSF). The C3aR has also been reported to suppress human tonsillar B-cell responses to polyclonal activation. Signalling Ligand engagement of C3aR causes a rise in intracellular free Ca2+ which is inhibited by PTX, indicating G protein involvement. In the HMC-1 cell line, internal Ca2+ stores are mobilized, whereas the Ca2+ flux in neutrophils is derived externally. This is in contrast with neutrophil stimulation via the C5aR, where both intra- and extracellular sources may be tapped, depending on ligand concentration. In keeping with this finding, no activation Table 3 Distribution of complement receptors in human tissues a CR3 only. b Present on rat microglial cells. c On bronchial and alveolar cells. d On glomerular podocytes. e Found in association with mitochondria. Tissue and cell type C5aR C3aR CR1 CR2 CR3/4 cC1qR C1qRp gC1qR Lymphoid organs Follicular dendritic cells (FDCs) – – +++a ––– Liver Kupffer cells + – + – + ––– Stellate cells + – ––– – – – Brain Microglia + – –– + – –b – Astrocytes + – – + –– – – Other tissues Vascular endothelial cells + – ––– + + –e Epithelial cells +c – +d – – + – – Gingival fibroblasts – – ––– + – – Complement Receptors ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3

of PI3 kinase is observed upon C3aR stimulation, while inositol trisphosphate (IP3) generation is detectable. C3aR-mediated activation is also staurosporine sensitive, although not to the degree seen with PMA stimulation, indicating that a protein kinase other than PKCmay be involved. The Complement Receptors for C3b and its Derivatives Complement receptor type 1 (CR1) Complement receptor type 1 (CR1, CD35) is a 210–290 kDa membrane glycoprotein with specificity for the complement products C3b, C4b and, with lower affinity, iC3b. Structure CR1 shares structural similarities with a group of proteins, including factor H, C4-binding protein (C4bp), decayaccelerating factor (DAF), membrane cofactor protein (MCP), CR2, C1r, IL-2 receptor, b2-glycoprotein 1, haptoglobin a chain and factor XIIIb, many of which are involved in the control of complement activity. These proteins are known as the regulators of complement activation (RCA) family. The extracellular domain of CR1 consists of an array of 30 or more homologous units (short consensus repeats, SCRs) comprising of 60–65 amino acids, of which 10–15 are highly conserved in all members of the family; including four half-cystines linking in a first– third, second–fourth arrangement to create a triple-loop structure within each SCR (Figure 1a). Distinctive for CR1 is the arrangement of the SCRs in three to six long homologous repeats (LHR) comprising seven SCR units and displaying 70–95% identity between each LHR. The transmembrane region of CR1 consists of 25 hydrophobic amino acids followed by four positively charged residues and the C-terminal cytoplasmic domain consists of 39 amino acids. The LHRs have probably arisen from duplication of gene segments encoding the constituent SCRs of an LHR, while the variability in the size of CR1 reflects allotypic polymorphism involving different numbers of LHR. Thus, the two most prevalent CR1 alleles among Caucasians (F and S, gene frequency = 80% and 20%, respectively) are composed of four and five LHRs, while two rarer allotypes contain three and six LHRs, respectively. In humans, the CR1 gene is located on the long arm of chromosome 1, band q32, in close association with the genes encoding CR2, DAF, factor H and C4bp. Murine CR1 differs from its human counterpart in that it is expressed as part of a composite receptor consisting of a six SCR N-terminal segment with CR1 activity and a 15 SCR core corresponding to murine CR2 (see below). The CR1/2 composite receptor and CR2 arise from alternative splicing of a gene which is located on murine chromosome 1. Cellular distribution CR1 is expressed on monocytes/macrophages, neutrophils, eosinophils, basophils, natural killer (NK) cells, B cells and some T cells, as well as follicular dendritic cells (FDC), glomerular podocytes, Kupffer cells and, in the case of most primates, erythrocytes (Tables 2 and 3). Although the number of CR1 molecules expressed on the erythrocytes (about 250 per cell) is 25- to 50-fold lower than that on blood leucocytes, the preponderance of erythrocytes in whole blood ensures that 85–90% of the cell-bound CR1 pool resides on these cells. The surface expression of CR1 on neutrophils is highly susceptible to modulation, being rapidly upregulated 5- to 10-fold by the chemotactic peptides fMLP and C5a-desarg, by GM-CSF and even by changes in temperature, and downregulated by 60–70% by PMA. The internal pool of CR1, responsible for the rapid upregulation, is located in smooth-surfaced vesicles distinct from the granulocyte’s primary and secondary granules. A soluble form of CR1 (sCR1), present in low concentration (about 30 ng mL 2 1 ) LHR-A CR1 LHR-B LHR-C LHR-D SCR C4b C4d C3b iC3b C3dg C3b CR2 (a) CR2 (b) CD19 C3dg Ag α α β β mlg Vav PI3-K Fyn Lyn Figure 1 Structure and function of CR1 and CR2. (a) The most prevalent allele of CR1 is comprised of 30 short consensus repeats (SCRs) arranged in four long homologous regions (LHRs), where the ligand-binding sites are contained in the four N-terminal SCRs of each of the first three LHRs, while the ligand-binding site of the 15 (or 16) SCR CR2 is located in SCR1/2. On B cells, CR1 and CR2 are found in noncovalent association with each other. As a cofactor for factor I, CR1 promotes degradation of its ligand C3b, to iC3b and then C3dg, thus providing CR2 with its ligand. (b) The association of CR2 with CD19 ensures recruitment of the latter to the B cell receptor (BCR) complex upon BCR/CR2crosslinking by opsonized antigen. By binding and activating the protein tyrosine kinases Lyn and Fyn, and PI3 kinase, CD19 supplements the signalling transduced through BCR upon antigen engagement. (Figure 1b is adapted from O’Rourke L, Tooze R and Fearon DT (1997) Co-receptors of B lymphocytes. Current Opinion in Immunology 9: 324–329.) Complement Receptors 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Complement Receptors Signalling leucocyte There is no evidence that crl in its nonphosphorylated resting state,is capable of inducing signal transduction neutrophils Function CRI binds to the PMA 5×10Lmo to C4b with similar affinity,and to iC3b triggering such activities as phagocytosis.However,the signal transduction mechanisms employed by activated wit about 100- -fold lower affinity CR contains CRI have not yet been characterizec withi in the of the first LHR. Complement receptor type 2(CR2) acting as a receptor,CRI regulates complement acti Complement re ceptor type 2 (CR2,CD21)is a 145-kDa by promoting factor 2.6×10Lmol ent of I in isotonic saline Barr vir (EBV). mononucleosis CRI triggering of activities such as phagocytosis Structure 69 este Like CR1.CR2 is ar nember of the RCA family.CR2 is pinui ively spli in n lies hetw en SCR10 and SCRI of the tion of nuclear factor-KB (NF-KB)and prostagla onger nocytes o a CR shorter CR2.C-terminal to the SCR lies a 24 amino acid on activated Bcells to imm cells folloy ing antigenic stimulation.However,an equally important role for CR1 on m y be been reported for both versions In humans and primate er throcyte-borne CRI plays a Cellular distribution critical role in the clearance of soluble immune complexes CR2 is ex ature B cells (abou 8000 per cell) ang C3 not expn sed on pre-Bor immature B cells and disap such as the capillaries or kidney glomeruli.and consequent tissue destruction by inflammatory responses,is prevented ecreting plasma with blood Function the CR2 hinds icah cad (with high affinity)C3h hvdrolysed C3(C3i)(with low afinity),as well as gp350/ (1)competing with leucocyte CRIin the binding of C3b 220 of EBV via a site,or sites,located in the first two SCRs bearing IC and legrading IC-bound to C3dg of t Howev CK4 may also be inte neut to a potentially B cell- mechanism that involves the formation of a C3iBbP regulating stimulus via CR2(Nielsen et al..1997).The complex(i.e.the AP convertase)at the ligand-binding site importance of this clearance mechanis In vitro,the activation,on norm B cells,results in the mplex m an SI E sucir the ervthroevtes to cope with the circulating Ic load results in CR2 while the naturally occurring deposition in vivo is capillary and kidney damage leading to renal failure.In about 10-fold lower of complexes may involve plate aga ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net

in normal plasma, is thought to arise from cleavage of membrane CR1 from blood leucocytes. Function CR1 binds to the active complement fragment, C3b, with an association constant (Ka), for dimer, of 2– 5 107L mol 2 1 , to C4b with similar affinity, and to iC3b with about 100-fold lower affinity. Each CR1 contains multiple C3b-binding sites located within the first four SCRs of each LHR and a single, high-affinity C4b-binding site in the same region of the first LHR. In addition to acting as a receptor, CR1 regulates complement activation by promoting factor I-mediated degradation of C3b to iC3b and, subsequently, C3c and C3dg, and of C4b to C4c and C4d. CR1 also binds C1q with a Ka of 2.6 108L mol 2 1 in isotonic saline. CR1 triggering of activities such as phagocytosis generally requires other forms of priming or enhancing stimuli (e.g. phorbol esters, fMLP, fibronectin, C1q, mannan-binding lectin or the pulmonary surfactant protein SPA). However, induction of lactoferrin release from granulocytes and IL-1 production, nuclear translocation of nuclear factor-kB (NF-kB) and prostaglandin synthesis by monocytes occurs upon stimulation via CR1 alone. CR1 has been reported to promote differentiation of activated B cells to immunoglobulin-secreting cells following antigenic stimulation. However, an equally important role for CR1 on B cells may be the conversion of antigenbound C3b to C3dg, thereby facilitating attachment of the opsonized antigen to CR2 (Figure 1a). In humans and primates, erythrocyte-borne CR1 plays a critical role in the clearance of soluble immune complexes (ICs) from the circulation. By transporting C3b-bearing complexes to the liver for disposal by Kupffer cells, erythrocytes ensure that ICdeposition in sensitive sites such as the capillaries or kidney glomeruli, and consequent tissue destruction by inflammatory responses, is prevented. Furthermore, by competing directly with the blood leucocytes in binding the ICs, erythrocytes hinder inappropriate activation of these cells by the ICs. In this connection, erythrocyte CR1 performs a dual function by (1) competing with leucocyte CR1 in the binding of C3bbearing IC and (2) degrading IC-bound C3b to C3dg, rather than to the intermediate product, iC3b; thereby changing the ICfrom an inflammatory stimulus, acting via neutrophil or monocyte CR3, to a potentially B cellregulating stimulus via CR2 (Nielsen et al., 1997). The importance of this clearance mechanism is illustrated in the so-called immune complex-associated diseases, such as systemic lupus erythematosus (SLE), where failure of the erythrocytes to cope with the circulating ICload results in capillary and kidney damage leading to renal failure. In nonprimates, the clearance of complexes may involve platelets bearing C3b-binding receptors. Signalling There is no evidence that CR1, in its nonphosphorylated, resting state, is capable of inducing signal transduction. Phosphorylation of CR1 occurs in neutrophils and monocytes (but not B cells), following activation of PKC with platelet-activating factor or PMA, and converts the receptor to an activated state, in which it is capable of triggering such activities as phagocytosis. However, the signal transduction mechanisms employed by activated CR1 have not yet been characterized. Complement receptor type 2 (CR2) Complement receptor type 2 (CR2, CD21) is a 145-kDa glycoprotein with specificity for the complement fragments iC3b and C3dg. It is also the site of attachment for Epstein– Barr virus (EBV), the causative agent of infectious mononucleosis. Structure Like CR1, CR2 is a member of the RCA family. CR2 is expressed as two alternatively spliced gene products encoding 15 or 16 SCRs; where the additional SCR in the longer version lies between SCR10 and SCR11 of the shorter CR2. C-terminal to the SCR lies a 24 amino acid transmembrane segment and 34 amino acid cytoplasmic tail. Electron microscopy of CR2 has revealed that the extracellular portion of the receptor is highly flexible. Allelic polymorphism (at least three alleles in humans) has been reported for both versions. Cellular distribution CR2 is expressed on mature B cells (about 8000 per cell), some T cells, FDCs, pharyngeal epithelial cells, astrocytes and platelets (in humans) (Tables 2 and 3). The receptor is not expressed on pre-B or immature B cells and disappears upon differentiation of activated B cells to antibodysecreting plasma cells. Function CR2 binds iC3b, C3dg (with high affinity), C3b, and hydrolysed C3 (C3i) (with low affinity), as well as gp350/ 220 of EBV via a site, or sites, located in the first two SCRs of the molecule. However, SCR3 and SCR4 may also be required for binding to C3b and C3i. CR2 can also activate the alternative pathway (AP) of complement by a mechanism that involves the formation of a C3iBbP complex (i.e. the AP convertase) at the ligand-binding site. In vitro, the activation, on normal B cells, results in the deposition of predominantly C3dg fragments in an approximately 5-fold excess over the number of expressed CR2, while the naturally occurring deposition in vivo is about 10-fold lower. A central role for CR2 in primary antibody responses against T cell-dependent antigen has been demonstrated in Complement Receptors ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5