Alternative titles; symbols
HGNC Approved Gene Symbol: CR2
Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38): 1:207,454,328-207,489,892 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.2 | ?Immunodeficiency, common variable, 7 | 614699 | Autosomal recessive | 3 |
| {Systemic lupus erythematosus, susceptibility to, 9} | 610927 | 3 |
Complement component receptor-2 (CR2, CD21) is the membrane protein on B lymphocytes to which the Epstein-Barr virus (EBV) binds during infection of these cells. See also CR1 (120620). Yefenof et al. (1976) found complete overlapping of EBV receptors and C3 (120700) receptors on human B lymphocytes.
CD21, together with CD19 (107265), CD81 (186845), and CD225 (IFITM1; 604456), forms the B-cell coreceptor complex, which lowers the activation threshold of the B-cell antigen receptor (summary by Thiel et al., 2012).
Rodriguez de Cordoba and Rubinstein (1986) demonstrated that quantitative variations of the C3b/C4b receptor (CR1) in human erythrocytes are controlled by genes within the regulator of complement activation (RCA) gene cluster. Rodriguez de Cordoba and Rubinstein (1986) symbolized this gene as C3bRQ. Moore et al. (1987) presented the nucleotide and derived amino acid sequence of the CR2 gene. They pointed out the close similarity to CR1 and to factor H, which are closely linked loci in 1q32.
Szakonyi et al. (2001) described the x-ray structure of CR2 in complex with its ligand C3d at 2.0 angstroms. The structure revealed extensive main chain interactions between C3d and only 1 short consensus repeat (SCR) of CR2 and substantial SCR side-to-side packing.
The 2 N-terminal SCRs (SCR1-SCR2) of CD21 interact with the EBV glycoprotein gp350/220 and also with the natural CD21 ligand, C3d. Prota et al. (2002) described the crystal structure of the CD21 SCR1-SCR2 fragment in the absence of ligand and demonstrated that it is able to bind EBV. Based on a functional analysis of wildtype and mutant CD21 and molecular modeling, they identified a likely region for EBV attachment and demonstrated that this region is not involved in the interaction with C3d. A comparison with the structure of CD21 SCR1-SCR2 in complex with C3d showed that, in both cases, CD21 assumes compact V-shaped conformations. However, the analysis revealed a surprising degree of flexibility at the SCR1-SCR2 interface, suggesting that the interactions between the 2 domains are not specific.
Using surface plasmon resonance analysis and ELISA, Asokan et al. (2006) showed that IFNA (IFNA1; 147660) bound CR2 in the same affinity range as the CR2 ligands EBV-gp350, C3d/iC3b, and CD23 (FCER2; 151445). IFNA interacted with SCR1 and SCR2 within the same region of CR2 that serves as the binding site for the other CR2 ligands. Treatment of B cells with anti-CR2 diminished induction of IFNA-responsive genes. Asokan et al. (2006) proposed that the roles of CR2 and IFNA in development of autoimmunity may be mechanistically linked to pathogenesis of systemic lupus erythematosus (SLE; 152700).
Weis et al. (1987) demonstrated by Southern analysis of DNA from somatic cell hybrids and by in situ hybridization using partial cDNA clones that the CR2 gene is located on band 1q32.
Susceptibility to Systemic Lupus Erythematosus
Wu et al. (2007) found evidence of linkage at chromosome 1q32.2 in a targeted genome scan of 1q21-q43 in 126 SLE multiplex families (see SLEB9, 610927) containing 151 affected sib pairs (nonparametric linkage score, 2.52; p = 0.006). The authors then analyzed the CR2 gene in 1,416 individuals from 258 Caucasian and 142 Chinese SLE simplex families and demonstrated that a common 3-SNP haplotype (120650.0001) was associated with SLE susceptibility (p = 0.00001) with a 1.54-fold increased risk for development of disease. Wu et al. (2007) concluded that the CR2 gene is likely a susceptibility gene for SLE.
Common Variable Immunodeficiency 7
In a patient with a mild form of common variable immunodeficiency-7 (CVID7; 614699), Thiel et al. (2012) identified compound heterozygous mutations in the CD21 gene (120650.0002 and 120650.0003). Both mutations caused functionally null alleles, with lack of CD21 expression on the patient's B cells. The patient had hypogammaglobulinemia and recurrent infections. However, antibodies against recall antigens, such as measles, mumps, and varicella, were normal, and he had antibodies against EBV, suggesting that CD21 is not absolutely required for EBV entry. The B cells showed a mature antigen phenotype, but there was a reduction in class-switched memory B cells. Together with the demonstrated defects in CD19 (107265) and CD81 (186845), this CD21 deficiency was the third genetic defect affecting the B-cell coreceptor complex in humans. All 3 defects share the features of severely decreased memory B-cell numbers, hypogammaglobulinemia, and recurrent infections.
Fairweather et al. (2006) found that mice deficient in both Cr1 and Cr2 had increased acute myocarditis and pericardial fibrosis due to coxsackievirus B3 (CVB3), leading to early progression to dilated cardiomyopathy and heart failure. Increased inflammation was not associated with increased viral replication. Immunofluorescence microscopy demonstrated increased numbers of macrophages, higher Il1b (147720) levels, and immune complex deposition in the heart. The mouse complement regulatory protein, Crry, was increased in cardiac macrophages, while immature B cells were increased in mutant mice after CVB3 infection. Fairweather et al. (2006) concluded that CR1/CR2 expression is not necessary for CVB3 clearance, but it is involved in protection against immune-mediated damage to the heart.
By constructing knockin mice expressing mutant Cr2 that bound C3d (186790) ligands but did not signal through Cd19, Barrington et al. (2009) showed that uncoupling of Cr and Cd19 significantly diminished survival of germinal center B cells and secondary antibody titers. However, B-cell memory was less impaired than it was in mice with complete B-cell Cr deficiency. Barrington et al. (2009) concluded that the interaction of CR and CD19 is important for T-dependent humoral immunity and that CR may have a role in B-cell memory independent of CD19.
Wu et al. (2007) analyzed the CR2 gene in 1,416 individuals from 258 Caucasian and 142 Chinese SLE simplex (610927) families and demonstrated that the major allele 3-SNP haplotype (+21T-C, rs3813946; a synonymous G-A SNP, rs1048971; and a G-A SNP resulting in an S639N substitution, rs17615) was associated with SLE susceptibility (p = 0.00001) with a 1.54-fold increased risk for development of disease. Studies using luciferase constructs revealed that the +21T-C SNP located in the 5-prime untranslated region alters transcriptional activity.
In a 28-year-old man with common variable immunodeficiency-7 (CVID7; 614699), Thiel et al. (2012) identified compound heterozygosity for 2 mutations in the CR2 gene: a G-to-C transversion in the donor site of exon 6 (1225+1G-C), resulting in the in-frame skipping of exon 6, and a 2297G-A transition in exon 13, resulting in a trp766-to-ter (W766X; 120650.0003) substitution, which was demonstrated to result in nonsense-mediated mRNA decay. The splice site mutation resulted in a shorter mRNA that putatively codes for a truncated CD21 protein predicted to lack the extracellular short consensus repeats 5 and 6. Each unaffected parent was heterozygous for 1 of the mutations, neither of which were found in 100 controls. Transfection of the mutations in 293T cells showed absence of CD21 expression at the cell surface, consistent with complete absence of CD21 on the patient's B cells. The patient had recurrent infections, splenomegaly, and hypogammaglobulinemia affecting mainly IgG. IgA values were slightly reduced and IgM levels were low-normal. Antibodies against recall antigens, such as measles, mumps, and varicella, were normal, and he had antibodies against EBV, suggesting that CD21 is not absolutely required for EBV entry. The B cells showed a mature antigen phenotype, but there was a reduction in class-switched memory B cells. Patient B cells showed reduced binding to a C3d (see 120700)-containing immune complex and to EBV compared to control cells, and also showed no costimulatory activity via the B-cell receptor complex. Patient cells showed normal proliferative response and production of immunoglobulin upon stimulation with anti-IgM and anti-CD40 (109535), and the patient mounted a normal antibody response to protein vaccination, although his response to pneumococcal polysaccharide vaccination was somewhat impaired.
For discussion of the trp766-to-ter (W766X) mutation in the CR2 gene that was found in compound heterozygous state in a patient with CVID7 (614699) by Thiel et al. (2012), see 120650.0002.
Asokan, R., Hua, J., Young, K. A., Gould, H. J., Hannan, J. P., Kraus, D. M., Szakonyi, G., Grundy, G. J., Chen, X. S., Crow, M. K., Holers, V. M. Characterization of human complement receptor type 2 (CR2/CD21) as a receptor for IFN-alpha: a potential role in systemic lupus erythematosus. J. Immun. 177: 383-394, 2006. [PubMed: 16785534] [Full Text: https://doi.org/10.4049/jimmunol.177.1.383]
Barrington, R. A., Schneider, T. J., Pitcher, L. A., Mempel, T. R., Ma, M., Barteneva, N. S., Carroll, M. C. Uncoupling CD21 and CD19 of the B-cell coreceptor. Proc. Nat. Acad. Sci. 106: 14490-14495, 2009. [PubMed: 19706534] [Full Text: https://doi.org/10.1073/pnas.0903477106]
Fairweather, D., Frisancho-Kiss, S., Njoku, D. B., Nyland, J. F., Kaya, Z., Yusung, S. A., Davis, S. E., Frisancho, J. A., Barrett, M. A., Rose, N. R. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1-beta, and immune complex deposition in the heart. J. Immun. 176: 3516-3524, 2006. [PubMed: 16517720] [Full Text: https://doi.org/10.4049/jimmunol.176.6.3516]
Moore, M. D., Cooper, N. R., Tack, B. F., Nemerow, G. R. Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes. Proc. Nat. Acad. Sci. 84: 9194-9198, 1987. [PubMed: 2827171] [Full Text: https://doi.org/10.1073/pnas.84.24.9194]
Prota, A. E., Sage, D. R., Stehle, T., Fingeroth, J. D. The crystal structure of human CD21: implications for Epstein-Barr virus and C3d binding. Proc. Nat. Acad. Sci. 99: 10641-10646, 2002. [PubMed: 12122212] [Full Text: https://doi.org/10.1073/pnas.162360499]
Rodriguez de Cordoba, S., Lublin, D. M., Rubinstein, P., Atkinson, J. P. Human genes for three complement components that regulate the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195, 1985. [PubMed: 3157763] [Full Text: https://doi.org/10.1084/jem.161.5.1189]
Rodriguez de Cordoba, S., Rubinstein, P. Quantitative variations of the C3b/C4b receptor (CR1) in human erythrocyte are controlled by genes within the regulator of complement activation (RCA) gene cluster. J. Exp. Med. 164: 1274-1283, 1986. [PubMed: 2944984] [Full Text: https://doi.org/10.1084/jem.164.4.1274]
Szakonyi, G., Guthridge, J. M., Li, D., Young, K., Holers, V. M., Chen, X. S. Structure of complement receptor 2 in complex with its C3d ligand. Science 292: 1725-1728, 2001. [PubMed: 11387479] [Full Text: https://doi.org/10.1126/science.1059118]
Thiel, J., Kimmig, L., Salzer, U., Grudzien, M., Lebrecht, D., Hagena, T., Draeger, R., Volxen, N., Bergbreiter, A., Jennings, S., Gutenberger, S., Aichem, A., and 10 others. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J. Allergy Clin. Immun. 129: 801-810, 2012. Note: Erratum: J. Allergy Clin. Immun. 133: 604 only, 2014. [PubMed: 22035880] [Full Text: https://doi.org/10.1016/j.jaci.2011.09.027]
Weis, J. H., Morton, C. C., Bruns, G. A. P., Weis, J. J., Klickstein, L. B., Wong, W. W., Fearon, D. T. A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32. J. Immun. 138: 312-315, 1987. [PubMed: 3782802]
Weis, J. J., Tedder, T. F., Fearon, D. T. Identification of a 145,000 M(r) membrane protein as the C3d receptor (CR2) of human B lymphocytes. Proc. Nat. Acad. Sci. 81: 881-885, 1984. [PubMed: 6230668] [Full Text: https://doi.org/10.1073/pnas.81.3.881]
Wu, H., Boackle, S. A., Hanvivadhanakul, P., Ulgiati, D., Grossman, J. M., Lee, Y., Shen, N., Abraham, L. J., Mercer, T. R., Park, E., Hebert, L. A., Rovin, B. H., and 13 others. Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus. Proc. Nat. Acad. Sci. 104: 3961-3966, 2007. [PubMed: 17360460] [Full Text: https://doi.org/10.1073/pnas.0609101104]
Yefenof, E., Klein, G., Jondal, M., Oldstone, M. B. A. Surface markers on human B- and T-lymphocytes. IX. Two color immunofluorescence studies on the association between EBV receptors and complement receptors on the surface of lymphoid cell lines. Int. J. Cancer 17: 693-700, 1976. [PubMed: 181330] [Full Text: https://doi.org/10.1002/ijc.2910170602]