mice by blocking cr2 function with monoclonal antibody CD18)are heterodimeric glvcoproteins with a shared B that recognizes the binding site,or by infusion of soluble chain (CD18).Both receptors show specificity for the ic3b out mice.In all case fragment. na as Structure lenuly linked to two or mor framents was found to enhance the antibody response by up to 10000-fold. CR3 and CR4 are members of the integrin superfamily of compared to wit tigen alone (Dempsey their EDC have (LFA-1,CDIla/CD18),they contain the same Bsubunit:a that CR2 on B cells plays an in nt role in initiating a 5-kDa transmembrane glycoprotein,encoded by a genein while FDC CR2 is essential for the the q22 region of human chro humoral respons ma cid ex n 57 CyS nembr 乙m吧mC2 which 24 occur in three repeating units each with eight alve (the 'low-affinity residues.a 23 amino acid transmembrane segment and a 46 either mino acid Ihe subuni on the B cell it or on other int racting cells Glu235.which contributes to the ligand-binding activity ng CRI above).while association with the signalling molecule. of the intact receptor.The subunit of CR3 is a 155-kDa CD19,ens of the latter to the B cell glycoprotein,compr ga1092 amino acid ex (BCR) recruitmen (Figur b).T nin tail.The CR nd the 63%sequence identity with that of CR4,a 150-kDa res scue ofactivated Bcells from apoptosis by CD23-bearng FDCs in the germinal centres n the bands d Signalling p13.1 on human chromosome 16.The striking mon CR2po cytoplasmic tail and is sunlikely eatures of thes two proteins re their highly (87%) mologous divalen binding sites iation with the trimolecuar glycoprotein comple CDI9/CD81(TAPA-1 a pivotal rolein A 02b0200a 1)/Leu 13,CR2 plays cation-binding sites.This extra insert or to op domain lisplays homology wit complement factors B and C2 with BCR reduces the threshold for ture of the I do n sh stimulation via BCR by at least two orders of magnitude. upon ligation rdination ne ki nas d E. Ra Cellular distribution ble for Cr3 and cr4 are both present on neutrophils.eosino activating the MAPK cascade (Figure 1b).The enhance hasonhils mon cytes/macrophages. NK cells ment of BCR signal transduction by CD19 is thought to CDI9-b at men and BCR o expr on FDCs( CR1,CR3on op Csa PMA dependent mechanism().distinct from the ionophore A23187 and IL-4,and it has been suggested that the intracellular pool of CR s located in the same xocytic vesicle compartment as CR Complement receptors types 3 and 4(CR3 and Function CR4) CR3 and CR4 both bind iC3b,in a Mg-dependen a receptor for fibrinogen.ICAM-1 (CD54).bacterial 6 ENCYCLOPEDIA OF LIFE SCIENCES/2001N s.nemice by blocking CR2 function with monoclonal antibody that recognizes the binding site, or by infusion of soluble CR2, and by developing CR2 knockout mice. In all cases, major impairment of the humoral immune response was observed. Conversely, immunization with antigen cova￾lently linked to two or more C3dg fragments was found to enhance the antibody response by up to 10 000-fold, compared to immunization with antigen alone (Dempsey et al., 1996). Studies in mice, which were manipulated to express CR2 only on their B cells or their FDC, have shown that CR2 on B cells plays an important role in initiating a humoral response while FDCCR2 is essential for the maintenance of this response CR2 forms noncovalent binary complexes with three other membrane glycoproteins, CR1, CD19 and CD23 (the ‘low-affinity immunoglobulin E’ receptor), present either on the B cell itself or on other interacting cells. Association with B-cell CR1 is presumed to enhance the effectiveness of the transfer of opsonized antigen to CR2, following CR1 processing of antigen-bound C3b (see above), while association with the signalling molecule, CD19, ensures recruitment of the latter to the B cell receptor (BCR) signal complex (Figure 1b). Two roles have been proposed for CR2 complex formation with CD23; the regulation of immunoglobulin E production, and the rescue of activated B cells from apoptosis by CD23-bearing FDCs in the germinal centres. Signalling CR2 possesses only a short cytoplasmic tail and is unlikely to act directly as a signal transducer. However, by virtue of its association with the trimolecular glycoprotein complex CD19/CD81(TAPA-1)/Leu 13, CR2 plays a pivotal role in augmenting the B-cell response to opsonized antigen by bringing CD19 into close proximity with the BCR. Coligation of CD19 with BCR reduces the threshold for stimulation via BCR by at least two orders of magnitude. CD19 becomes tyrosine phosphorylated upon ligation with BCR and associates with the protein tyrosine kinases (PTK), Lyn and Fyn, PI3 kinase and the Rac guanine nucleotide exchange factor Vav, which is responsible for activating the MAPK cascade (Figure 1b). The enhance￾ment of BCR signal transduction by CD19 is thought to involve at least two elements: (1) phosphorylation, by CD19-bound Lyn, of potential substrates in the BCR complex and (2) Ca2+ mobilization by a PI3 kinase￾dependent mechanism (Buhl et al., 1997), distinct from the phospholipase Cg-mediated mobilization initiated by BCR. Complement receptors types 3 and 4 (CR3 and CR4) Complement receptor type 3 (CR3, Mac-1, CD11b/CD18) and complement receptor type 4 (CR4, p150/95, CD11c/ CD18) are heterodimeric glycoproteins with a shared b chain (CD18). Both receptors show specificity for the iC3b fragment. Structure CR3 and CR4 are members of the integrin superfamily of adhesion proteins. They are termed b2 integrins because, in common with leucocyte function-associated molecule 1 (LFA-1, CD11a/CD18), they contain the same b subunit; a 95-kDa transmembrane glycoprotein, encoded by a gene in the q22 region of human chromosome 21 and in chromo￾some 10 in mice. The human b2 is comprised of a 678 amino acid extracellular domain containing 57 Cys residues, of which 24 occur in three repeating units each with eight residues, a 23 amino acid transmembrane segment and a 46 amino acid cytoplasmic tail. The subunit contains a putative metal ion-dependent adhesion site (MIDAS) involving the residues Asp134, Ser136, Asp232 and Glu235, which contributes to the ligand-binding activity of the intact receptor. The a subunit of CR3 is a 155-kDa glycoprotein, comprising a 1092 amino acid extracellular domain, a 26 amino acid transmembrane segment and a 19 amino acid cytoplasmic tail. The CR3 a subunit shows 63% sequence identity with that of CR4, a 150-kDa glycoprotein, in which the extracellular domain, trans￾membrane segment and cytoplasmic tail consist of 1081, 26 and 29 amino acids, respectively. Both proteins are encoded by genes located between the bands p11 and p13.1 on human chromosome 16. The striking common features of these two proteins are their highly (87%) homologous divalent cation-binding sites, contained in three tandem repeats of approximately 60 amino acids, and a domain of about 200 amino acids, lying N-terminal to the cation-binding sites. This extra insert or ‘I’ domain displays homology with complement factors B and C2. The crystal structure of the I domain shows that it adopts a classic a/b ‘Rossman’ fold and displays a MIDAS-type Mg2+-coordination site at its surface. Cellular distribution CR3 and CR4 are both present on neutrophils, eosino￾phils, basophils, monocytes/macrophages, NK cells, Kupffer cells, microglial cells and platelets, while CR3 is also expressed on FDCs (Tables 2 and 3). Like CR1, CR3 on the neutrophils is rapidly upregulated by a range of stimulants, including GM-CSF, fMLP, C5a, PMA, ionophore A23187 and IL-4, and it has been suggested that the intracellular pool of CR3 is located in the same exocytic vesicle compartment as CR1. Function CR3 and CR4 both bind iC3b, in a Mg2+-dependent fashion, with an affinity for monomeric ligand of about 2 106L mol 2 1 , in the case of CR3. CR3 also functions as a receptor for fibrinogen, ICAM-1 (CD54), bacterial Complement Receptors 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net