COMPLEMENT RECEPTORS
Complement Receptor Type 1 (CR1)
Human CR1 is a large and multifunctional member of the RCA protein family [5]. A common feature of these proteins are repeats of sequentially arranged modules of about 60 amino acids, referred to as short consensus repeats (SCRs).
Seven or more SCRs are further grouped to form larger structural elements called long homologous repeats (LHRs), each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. In total four polymorphic forms of human CR1 are known, which differ in the number of SCRs (up to 34) or LHRs. The distribution of the respective allele frequencies varies between 0.83 for CR1*1 and 0.01 for CR1 *4 [6]. The ligand binding sites for C3b and C4b are mapped in LHR B (SCR 8-10) and LHR C (SCR 1517). LHR A harbours an additional C4b binding region. These modular arrangements provide the basis for multivalent CR1-C3b/C4b interactions [5]. A further important feature of CR1 is its decay accelerating activity for classical and alternative C3 and C5 convertases, which is also located in LHR A [5]. The tissue distribution of CR1 covers a broad spectrum of peripheral blood cells. Only platelets, NK cells and T cell subsets are CR1 negative. In germinal centres (GC) of the lymphoid follicles, follicular dendritic cells (FDCs) express CR1, which may be of importance in the induction of immunological memory. Due to the numerical predominance of erythrocytes about 90% of the total CR1 in the body is expressed on this cell type. A main function of CR1 on erythrocytes is the transport of C3b/C4b-opsonized immune complexes (IC) to the liver and spleen. In these organs, IC are transferred to phagocytic cells and are finally removed [5].Complement Receptor Type 2 (CR2)
CR2 (CD21) belongs to the family of complement regulatory proteins and consists of 15 or 16 SCRs. The two isoforms are differentially expressed; CD21L, the long isoform, is found on FDCS, while the shorter isoform CD21S is expressed on B lymphocytes, endothelial cells and some activated T cells [4].
Although the main ligand is the terminal degradation product of C3 cleavage, C3d, CR2 also interacts with C3dg and iC3b. On B lymphocytes, CR2 is non-covalently associated in a receptor complex with CD19 and CD81 within lipid rafts [7,8]. The CR2/CD19/CD81 complex bridges innate and adaptive immunity by decreasing the threshold level for B cell activation through the cross-linking opsonized antigens with the surface immunoglobulin receptor and the CR2 [9]. In GC reactions, CR2 is involved in antibody maturation and B cell memory [7].Complement Receptor Type 3 and 4 (CR3 and CR4)
In contrast to CR1 and CR2, which are single chain receptors and belong to the RCA family, CR3 is a representative of the family of β2 integrins, a superfamily of heterodimeric adhesion molecules [10]. These receptors consist of non-covalently associated α and β chains. The α chain is a 165 kD molecule (CD11b), whereas the independently anchored β chain has a molecular weight of 95 kD (CD18). In addition to CR3, LFA-1 (CD11a/CD18) and CR4 (CD11c/CD18) belong to the β2 integrin family [10].The α chain of CR3 is a transmembrane protein with 7 tandem repeats of approximately 65 amino acids at its amino terminus. It contains the I-domain harbouring the binding sites for most ligands and binds C3-fragments in a Ca++ dependent manner [11]. Among all C3 fragments interacting with CR3, iC3b exhibits the highest affinity for this receptor. Additionally other molecules ligate CR3 including ICAM-1 (CD54) and ICAM-2, proteins of the clotting system like fibrinogen, kininogen and factor X or molecules of microbial origin [10]. CR3 is present on a number of different cell types including monocytes, macrophages, T lymphocytes, dendritic cells, follicular dendritic cells, granulocytes, natural killer cells, microglia, synovial cells, osteoclasts as well as histocytes [20].
A further member of the β2 integrin family is CR4, consisting of CD11c and CD18 [4].
Due to these structural similarities the ligand specificities of CR3 and CR4 resemble each other. Tissue distribution of CD11c/CD18 is comparable to CR3, although CR4 seems to be more prominent on distinct dendritic cell subsets.Anaphylatoxin Receptors C3a and C5a (C3aR and C5aR)
Activation of the complement system by pathogens leads to the N-terminal cleavage of components C3, C4 and C5, thereby generating complement fragments C3a, C4a and C5a [12,13]. These anaphylatoxins have been shown to mediate many biological effects: chemotactic migration, cellular adhesion, stimulation of oxidative metabolism, and release of lysosomal enzymes and numerous mediators of inflammation, such as histamine and cytokines [13].
The functional responses mediated by C3a and C5a are due to high-affinity binding of these fragments to the cell surface receptors C3aR and C5aR. C3aR and C5aR (CD88) belong to the rhodopsin subfamily of G protein-coupled receptors with seven transmembrane segments [14,15]. C3aR and C5aR share 37% nucleotide identity with the highest homology in the transmembrane regions and in the second intracellular loop. C3aR is unique among this family since it has an unusually large extracellular domain between the fourth and fifth transmembrane region [14,15].
The expression of the genes for C3aR and C5aR was, until recently, thought to be largely restricted to cells of the myeloid lineage, such as neutrophils, macrophages, eosinophils, basophils and mast cells. However, in recent years, many studies have demonstrated widespread localization of these receptors throughout many tissues and cell types outside the immune system, including epithelial, endothelial and smooth muscle cells, the human liver and lung, human keratinocytes of the inflamed skin, as well as astrocytes, microglia and neurons [16,17].