Complement Receptor 2 (CR2)

Complement Receptors of Complement System: CR2 Structure

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.

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.

Complement Receptors of Complement System: CR2 Cellular Distribution

Complement receptor type 2 (CR2, CD21) is expressed on mature B cells (about 8000 per cell), some T cells, FDCs, pharyngeal epithelial cells, astrocytes and platelets (in humans). The receptor is not expressed on pre-B or immature B cells and disappears upon differentiation of activated B cells to antibodysecreting plasma cells.

Complement Receptors of Complement System: CR2 Function

Complement receptor type 2 (CR2, CD21) 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 complement receptor type 2 in primary antibody responses against T cell-dependent antigen has been demonstrated in mice 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 covalently 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. 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.

Complement Receptors of Complement System: CR2 Signalling

Complement receptor type 2 (CR2, CD21) 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. The enhancement 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 kinasedependent mechanism, distinct from the phospholipase Cg-mediated mobilization initiated by BCR.

Complement Receptors of Complement System: CR2 reference

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2. Leslie R G Q, et al. (2009). Complement receptors. eLS.
3. Szakonyi G, et al. (2001). Structure of complement receptor 2 in complex with its C3d ligand. Science, 292(5522), 1725-1728.
4. Isnardi I, et al. (2010). Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood, 115(24), 5026-5036.