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 transloca￾tion 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 follow￾ing antigenic stimulation. However, an equally important role for CR1 on B cells may be the conversion of antigen￾bound 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 inap￾propriate 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 C3b￾bearing 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 cell￾regulating 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 antibody￾secreting 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