Cr4

(CD11c; p150,95; c*xft-integrin)

CR5 gC1q-R

cC1 q-R C1q-Rp

C3a-R

iC3b = C3dg > C3d > C3b, Epstein-Barr virus, CD23

iC3b, C3dg, C3d, 0-glucan, ICAM-1, fibrinogen, factor X, collagen, heparan sulfate, CD14, CD16, CD87

iC3b, C3dg, fibrinogen

C3d portion of fluid-phase iC3b, C3dg, C3d

C1q globular 'head', as well as vitronectin and high molecular weight kininogen

C1q collagen 'tail'

C1q collagen-like fragment, mannose-binding protein, lung surfactant protein A

C3a, C4a

Four allotypes that vary in size from 160 kDa to 250 kDa due to different numbers of repeating sequence motif units

Made up of repeating sequence motif units similar to CR1; 140 kDa

Two noncovalently linked glycoprotein chains: 165 kDa aM chain (CD11b), 95 kDa ft chain (CD18)

Two noncovalently linked glycoprotein chains: 150 kDa ax chain (CD11c), 95 kDa ft chain (CD 18)

Unknown; 95 kDa candidate molecule expressed by platelets 33 kDa glycoprotein

60 kDa glycoprotein; homologous to calreticulin 126 kDa glycoprotein

Guinea pig platelet: 95-105 kDa

Human mast cell: 57 kDa and 97 kDa

Human leukocyte: 482 amino acids, -54 kDa, seven membrane-spanning domains

47 kDa glycoprotein binding unit with seven membrane-spanning domains expressed as an oligomer of 150-200 kDa

Monocytes, neutrophils: high expression Tissue macrophages: low expression B cells, eosinophils: high expression Kidney podocytes: high expression T cells (-20%): low expression Peripheral nerves: low expression B lymphocytes: high expression Lymph node follicular dendritic cells:

very high expression Thymocytes, pharyngeal epithelial cells: low expression Neutrophils, monocytes: high expression Tissue macrophages: low expression Activated cytotoxic T cells, NK cells, eosinophils: high expression Neutrophils, monocytes: low expression Tissue macrophages: high expression Activated B cells: high expression Activated cytotoxic T cells, NK cells, eosinophils: low expression Neutrophils: low expression Platelets: low expression

All leukocyte types: variable expression Platelets: high expression Endothelial cells: high expression All leukocyte types: variable expression Neutrophils: high expression Monocytes: high expression

Mast cells: high expression Eosinophils, basophils: high expression Neutrophils, monocytes: low expression Guinea pig platelets: high expression Mast cells, neutrophils: high expression Monocytes and tissue macrophages: high expression Eosinophils: high expression Hepatocytes, astrocytes, endothelial cells: high expression

In the mouse there is a closer relationship between CR1 and CR2, and the two membrane glycoproteins are derived from a single gene by alternative splicing of mRNA. As a result, the larger 190 kDa murine CR1 molecule contains the entire 140 kDa CR2

sequence as part of its structure. Monoclonal antibodies to CR2 are therefore equally reactive with CR1 and unable to distinguish the two types of C3 receptors. Murine CR1 appears to be restricted to B cells, and is not expressed on neutrophils or macro-

phages for phagocytosis, nor is it expressed on erythrocytes or platelets where it could function in immune complex clearance. Murine neutrophils and platelets express instead distinct C3b/C4b-binding molecules that appear structurally unrelated to CR1 or CR2.

Complement receptor type 2 (CR2)

CR2 (CD21) is expressed by B lymphocytes, lymph node follicular dendritic cells, pharyngeal epithelial cells and thymocytes. Only minor subsets of T lymphocytes express CR2, and the amount per cell is only 10% of the amount expressed by B cells. CR2 is not only a receptor for C3 fragments but also functions as the cellular attachment site for Epstein-Barr virus (EBV) and the counterligand for CD23. CR2 is specific for the C3d portion of iC3b, C3dg or C3d, and has only a low affinity for C3b. B cell CR2 has been shown to play a major role in primary and secondary antibody responses to protein antigens. In a primary response, natural antibodies form immune complexes with protein antigens, resulting in activation of the classical complement pathway and covalent fixation on to the antigen of C3b that is rapidly degraded by factor I into iC3b and C3dg. This bound C3 promotes efficient antigen uptake by B cells via CR2, and the resulting CR2 stimulation of the B cell lowers the antigen concentration threshold required for antigen recognition by specific surface Ig on the B cell. CR2 signaling results from a B cell membrane complex of glycoproteins that includes CR2, CD 19 and TAPA-1 in which transmembrane signaling occurs via the CD 19 portion of the complex. This pathway for use of complement and CR2 for antigen recognition was initially demonstrated with blocking antibodies to C3 or to CR2, and then later with gene knockout mice deficient in either C3, C4 or B cell CR2. Although an immune response could be generated in these mice with greatly increased antigen doses as compared with those required in normal mice, antibody levels were abnormally low, isotype switching did not occur, and there was no immunologic memory. This pathway for humoral immunity to protein antigens represents an important link between the innate and specific immune systems.

B cell isotype switching to IgE production also involves CR2 and its ability to form membrane complexes with the IgE receptor CD23. However, in a subversion of its normal function, CR2 is utilized by EBV to gain entry into B cells, permitting virus infection (infectious mononucleosis) or a malignant transformation of B cells or epithelial cells (Burkitt's lymphoma or nasopharyngeal carcinoma, respectively).

CR2 consists of a single polypeptide chain of

140 kDa with the same type of SCR structure as CR1. The CR2 gene is closely linked to the CR1 gene, and, in the mouse, a single gene transcribes both receptor proteins via alternative RNA splicing.

Complement receptor type 3 (CR3)

CR3 (also known as CDllb/CD18, Mac-1, or «M/S2-integrin) is a multifunctional membrane protein that serves as both a membrane receptor to trigger phagocyte and natural killer (NK) cell cytotoxic events and as an adhesion molecule used by leukocytes for dia-pedesis across the endothelium (via attachment to ICAM-1) or the extracellular matrix (via attachment to heparan sulfate or fibrin). The I domain of CD11 b binds with high avidity to opsonizing iC3b attached to microorganisms, and with lower avidity to opsonizing C3dg or C3d. However, its receptor function is complex, because CR3 not only recognizes exogenous target cell-associated ligands directly but also extends its effective ligand specificity by coupling itself to certain other endogenous leukocyte membrane receptors that utilize CR3 for their transmembrane signaling function. Critical to both forms of receptor activity is a lectin site located C-terminal to the I domain of CDllb and involved in recognition of either microbial cell wall polysaccharides or the leukocyte membrane glycoproteins that couple to CR3 for transmembrane signaling. Bacteria or yeast that bear opsonizing iC3b trigger CR3 activation because of simultaneous recognition of microbial cell wall polysaccharides via the CR3 lectin site and bound iC3b via the I domain. Potential target particles that bear fixed iC3b but lack specific polysaccharides recognized by this lectin site of CR3 do not stimulate cellular activation, despite avid adhesion of the particles to CR3 via the fixed iC3b. Ligation of polysaccharides to the lectin site of CDllb induces a tyrosine kinase- and magnesium divalent cation-dependent conformational change in CDllb that is associated with generation of a primed state of CR3 capable of stimulating cellular cytotoxic activation events (e.g. phagocytosis, degranulation) when CR3 subsequently attaches to target cell-bound iC3b via its I domain-localized binding site. Three neutrophil membrane receptors that are attached to membranes via surface phosphatidylinositol glycolipid (PIG) bridges acquire transmembrane signaling function by forming lectin site-dependent complexes with the transmembrane CR3 molecule: 1) the IgG Fc receptor FcyRIIIA (CD16), 2) the urokinase plasminogen activator receptor (uPAR or CD87), and 3) the lipo-polysaccharide (LPS) receptor (C.D14).

Unlike C-type (calcium-dependent) lectins, the potysaccharide-binding site of CR3 does not require divalent cations and has a relatively broad reactivity with certain polysaccharides containing mannose or N-acetyl-glucosamine, as well as glucose (/31,3-glucans).

Unstimulated phagocytes express small amounts of membrane CR3 and retain large stores of CR3 in cytoplasmic granules. Following stimulation with C5a or a variety of cytokines, much of the initial membrane surface CR3 becomes linked to the actin cytoskeleton in a way that renders it capable of mediating phagocytosis or extracellular adhesion to ICAM-1. Simultaneously, specific granules come to the cell surface, where their membranes fuse with the outer cell membrane, greatly increasing the expression of membrane surface CR3. However, this granule-derived CR3 is not linked to the cytoskeleton and is thus incapable of mediating firm cellular adhesions or phagocytosis. This more abundant but loosely associated CR3 is very mobile within the membrane and functions to promote phagocyte attachment to iC3b-coated target cells, allowing their subsequent phagocytic recognition by the less mobile but cytoskeleton-bound CR3 (or CR4).

CR3 consists of two noncovalently associated glycoprotein chains known as aM or CDllb (165 kDa) and j82 or CD18 (95 kDa). CR3 is one of four members of the leukocyte /32-integrins that share the common /32-integrin structure linked to a distinct a-chain type. The other three leukocyte 02-integrins are LFA-1 (CD1 la/CD18), CR4 (CDllc/CD18 or pl50,95) and CDlld/CD18.

Complement receptor type 4 (CR4)

CR4 (CD1 lc/CDl 8 or pl50,95), the third member of the leukocyte /32-integrins, is closely related to CR3. The CR4 a chain (CDllc, 150 kDa) is -87% homologous in sequence to CDllb, and recognizes similar ligands including iC3b, fibrinogen and, according to some reports, even ICAM-1. CR4 is expressed preferentially on tissue macrophages that bear only small amounts of CR1 and CR3. Phagocyte CR3 and CR4 differ in cytoplasmic domain structure and attachment to the actin cytoskeleton, and this is thought to provide a mechanism for differential regulation of cellular adhesion or phagocytosis. The relative importance of CR4 as a receptor for iC3b is unclear, as most of the iC3b receptor function of leukocytes, including tissue macrophages, is blocked by use of antibodies to CR3 alone.

Complement receptor type 5 (CR5)

CR5 appears to be specific for the C3d portion of iC3b, C3dg and C3d, but reacts only with these fragments in the fluid phase and not when they are fixed via their normal covalent site. CR5 activity has been defined with fluid-phase dimers of C3dg labeled with l2,I. Neutrophil uptake of l25l-C3dg dimers was blocked by competing unlabeled iC3b, C3dg and C3d, but not by C3b. At one time it was believed that the C3dg dimer receptor might be the same as the receptor for erythrocyte C3dg rosette formation, and so both receptor activities were designated CR4. Later, however, the receptor activity responsible for rosette formation was shown to have several properties that distinguished it from the C3dg dimer receptor, and so the C3dg dimer receptor was named CR5. The binding of CR4 to fixed iC3b was prevented by ethylene diamine tetraacetic acid (F.DTA), whereas EDTA had no effect on the uptake of l2T-C3dg dimers. Although CR5 activity has been identified on neutrophils and platelets, it is unknown whether the same molecule is responsible for this activity on both cell types. A platelet membrane glycoprotein of 95 kDa identified by affinity labeling techniques has been shown to function as a C3dg receptor. In the absence of sequence data established from a molecular clone, the existence of CR5 as a distinct entity is less certain than the other C3 receptors.

C1q receptors (C1q-R)

Three distinct types of Clq-R have been described: one that binds to the globular 'head' portion and two that react with the collagen 'tail'. All three of the receptors have been shown to react with other molecules in addition to Clq, such as vitronectin, kinin-ogen and mannose-binding protein. A 33 kDa glycoprotein with affinity for the Clq globular head, 'gClq-R', and a 60 kDa glycoprotein that reacts with the collagen tail, 'cClq-R', were first identified on Raji B lymphoblastoid cells. Antibodies to these two molecules have now shown a wider cell type distribution, and gClq-R is particularly expressed on platelets and endothelial cells, as well as eosinophils. A second type of receptor for the collagen portion of Clq is a 126 kDa monocyte and neutrophil membrane glycoprotein that has been termed Clq-Rr because of its ability to enhance phagocytosis mediated via CR1. The cDNAs for all three of these molecules have been cloned, and gClq-R has been expressed as a recombinant molecule that retains Clq-binding activity. Although the two have novel sequences, the 60 kDa cC1q-R has considerable homology with calreticulin and may represent a membrane surface variant of this cytoplasmic protein. The 33 kDa gClq-R is the product of a single gene localized to chromosome 17 and has a specificity similar to the Fc region of Ig. By contrast, cClq-R and C1q-Rn do not compete with Ig Fc, and thus can promote cellular uptake of immune complexes bearing Clq linked to Ig. These latter types of Clq-R bind immune complex-associated Clq preferentially, because single Clq molecules have a low affinity for cClq-R or Clq-Rp, and the Clq binding site in native CI is masked by Clr and Cls. The collagen binding site in Clq is exposed by CI inhibitor that complexes with activated Clr and Cls, separating them away from Clq.

Factor H receptor (fH-R)

A fH-R activity has been detected on B lymphocytes, monocytes and neutrophils, but no structural comparison of the fH-R on these cell types has been carried out and the molecular entity representing fH-R has not been identified. Since plasma did not block cellular uptake of radiolabeled factor H, it was proposed that fH-R were unreactive with 'native' plasma factor H, and that either purification procedures or immune complex attachment might alter factor H in a way that exposed a binding site for fH-R. Subsequently, purified factor H preparations were shown to contain two species of factor H, designated <j!)i and (¡>2, that could be separated by phenyl-Sepharose hydrophobic affinity chromatography. Only the (j>2 form of factor H bound specifically to lymphoid cells, but it is unknown whether this <f>2 form of factor H exists in plasma or if it is generated by H interaction with immune complexes. The first attempt at isolation of the fH-R from lymphoblas-toid cells used either antifactor H idiotypic antibody or factor H-Sepharose and identified a protein complex of >150 Mr with 100 kDa and 50 kDa components. A second study using factor H agarose affinity chromatography detected a single protein species of 170 kDa on the surface of B lymphoblastoid cells and tonsil B cells. This 170 kDa protein bound specifically to factor H agarose, and in soluble form, prevented rosettes with factor H-coated erythrocytes. B cells have been shown to release endogenous stores of factor I in response to fluid-phase or immune complex-associated factor H, and purified H has been reported to serve as a growth factor for the maintenance of B cell lines.

C5a receptor (C5a-R)

The inflammatory functions of C5a are mediated via specific C5a-R (CD88) expressed on a variety of cell types including mast cells, phagocytes, bronchial and alveolar epithelial cells, hepatocytes, astrocytes and vascular endothelial cells. The action of C5a is regulated both by serum carboxypeptidase N (SCPN), which removes the C-terminal arginine (forming C5adcsArg), and by neutrophil catabolism of C5a following specific uptake by C5a-R. Although C5atlt.s ArK has reduced binding affinity as compared with C5a, it is a major ligand for C5a-R in vivo because of the serum protein ('cochemotaxin') that combines with the C5adcsAr(, and enhances its action with C5a-R. Cochemotaxin is identical to GC globulin or vitamin D-binding protein. The -47 kDa C5a-R glycoprotein is a member of the family of related G protein-linked chemokine receptors that have seven membrane-spanning domains. A two-site model has been suggested in which part of the N-terminal extracellular domain of the receptor recognizes the N-terminal and disulfide-linked core of C5a. This is then thought to be followed by interaction of the C-terminus of C5a with a second region of the receptor that is linked to G protein and responsible for the activating signal. Both the contractile responses of smooth muscle cells and the increased vascular permeability produced by C5a are thought to result from histamine release by mast cells or basophils that express the same C5a-R structure. C5a-R mediate a wide range of leukocyte responses, including chemotaxis, homo-typic aggregation (clumping), activation of CR3 to expose its high-affinity binding site for ICAM-1 (thus promoting leukocyte adhesion to endothelium), and upregulation of the number of CR1, CR3 and CR4 exposed on external membrane surfaces. Larger doses of C5a cause degranulation and a respiratory burst. Because of the importance of C5a in mediating inflammatory responses, C5a-R antagonist drugs have been widely sought as therapeutic agents for autoimmune and inflammatory disease syndromes.

Receptor for C3a and C4a (C3a-R)

A single type of receptor is believed to be responsible for responses to C3a or C4a. This receptor activity was first characterized on mast cells, and later a similar C3a-R was demonstrated on basophils, eosinophils, neutrophils and guinea pig platelets. The first successful molecular cloning of the C3a-R was reported with cDNA libraries generated from differentiated HL-60 cells or U-937 cells. As with C5a. smooth muscle spasmogenic responses occur with nanomolar concentrations of C3a or C4a that stimulate mast cell secretion of histamine. Although disputed for many years, the chemotactic activity of C3a has now been shown with eosinophils and is likely to occur also with neutrophils or monocytes that express C3a-R. As with C5a, SCPN removes a C-terminal arginine from both C3a and C4a, greatly reducing, if not totally eliminating, the ability of these anaphylatoxins to stimulate cellular responses. Not only are all spasmogenic and leukocyte-associa-ted activities of C3a and C4a absent in C3a,i,.s Al(! and s Argi but also no cochemotaxin-like serum factor has been identified that restores C3a/C4aJ(.s All. activity in the same way as has been shown for C5atk.s Ar|i. Attempts to identify a C3a-R with l2T-C3a coupled to heterobifunctional cross-linking reagents identified a putative C3a-R only on guinea pig platelets and failed to identify a C3a-R on human platelets and neutrophils; however, similar methods were successful with a human mast cell line, HMC-1. These studies identified two putative guinea pig platelet C3a-R candidate molecules of 95 kDa and 105 kDa, and two human mast cell C3a-R species of 57 kDa and 97 kDa. Sequence homology with both the C5a-R (37% at the nucleotide level) and the fMLP-receptor allowed molecular cloning of the C3a-R. Cells expressing recombinant C3a-R exhibited the same reactivity with C3a as the native receptor, including the failure to bind C5a. Northern blotting with the 4.3 kb cDNA for C3a-R demonstrated transcripts of both 2.3 kb and 3.9 kb, perhaps explaining the two different sized receptors noted in cross-linking experiments. Based on the 2.3 kb transcript, a polypeptide of 482 residues was predicted with the typical seven membrane-spanning domains of the G protein-linked receptor family.

See also: Adhesion molecules; Anaphylatoxins; Complement, alternative pathway; Chemokines; Complement, classical pathway; Complement, genetics; Epstein-Barr virus, infection and immunity; Immune adherence; Integrins; Opsonization; Phagocytosis; Viruses, infection of immune cells by.

Further reading

Birmingham DJ (1995) Erythrocyte complement receptors.

Critical Reviews in Immunology 15: 133-154. Crass T, Raffetseder U, Martin U et al (1996) Expression cloning of the human C3a anaphylatoxin receptor (C3aR) from differentiated U-937 cells. European Journal of Immunology 26: 1944-1950. Croix DA, Ahearn JM, Rosengard AM et al (1996) Antibody response to a T-dependent antigen requires B cell expression of complement receptors. Journal of Experimental Medicine 183: 1857-1864.

Fearon DT and Carter RH (1995) The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annual Review of Immunology 13: 127-149.

Ghebrehiwet B, Lu PD, Zhang W et al (1996) Identification of functional domains on gClQ-R, a cell surface protein that binds to the globular 'heads' of C1Q, using monoclonal antibodies and synthetic peptides. Hybridoma 15: 333-342.

Guan E, Robinson SI., Goodman EB and Tenner AJ (1994) Cell-surface protein identified on phagocytic cells modulates the Clq-mediated enhancement of phagocytosis. Journal of Immunology 152: 4005-4016.

Holmskov U, Malhotra R, Sim RB and Jensenius JC (1994) Collectins: collagenous C-type lectins of the innate immune defense system. Immunology Today 15: 67-74.

Molina H, Kinoshita T, Webster CB and Holers VM (1994) Analysis of C3b/C3d binding sires and factor I cofactor regions within mouse complement receptors 1 and 2. Journal of Immunology 153: 789-795.

Petty HR and Todd RF III (1993) Receptor-receptor interactions of complement receptor type 3 in neutrophil membranes. Journal of Leukocyte Biology 54: 492-494.

Quigg RJ and Holers VM (1995) Characterization of rat complement receptors and regulatory proteins: CR2 and Crry are conserved, and the C3b receptor of neutrophils and platelets is distinct from CR1. Journal of Immunology 155: 1481-1488.

Thornton BP, Vetvicka V, Pitman M, Goldman RC and Ross GD (1996) Analysis of the sugar specificity and molecular location of the /3-glucan-binding lectin site of complement receptor type 3 (CD11 b/CD18). Journal of Immunology 156: 1235-1246.

Vetvicka V, Thornton BP and Ross GD (1996) Soluble ¡3-glucan polysaccharide binding to the lectin site of neutrophil or NK cell complement receptor type 3 (CDllb/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. Journal of Clinical Investigation 98: 50-61.

Wetsel RA (1995) Structure, function and cellular expression of complement anaphylatoxin receptors. Current Opinion in Immunology 7: 48-53.

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