Alternative titles; symbols
HGNC Approved Gene Symbol: CD22
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,329,187-35,347,361 (from NCBI)
The human B-lymphocyte-restricted antigen CD22 is expressed early in B-cell development in pro-B cells, as a cytoplasmic protein, and later in B-cell development, at the late pre-B-cell stage, as a cell surface protein. Once expressed as a membrane protein, CD22 persists on B cells until they differentiate into plasma cells. The presence of cytoplasmic CD22 is a useful marker for B-cell precursor acute lymphocytic leukemia. CD22 appears to be a heterodimer consisting of 130- and 140-kD glycoproteins with protein cores of 80 and 100 kD, respectively. The 2 subunits are thought to be independently transported to the surface and originate from 2 separate precursor molecules. Studies of the structure of the 2 proteins and cDNA cloning suggested that the 2 proteins arise from differential RNA processing of the same gene, with the larger subunit being composed of an extracellular portion of 7 immunoglobulin domains, 1 V-like and 6 C-like, and a smaller subunit of 5 Ig domains, 1 V-like and 4 C-like. The CD22 polypeptide is structurally related to myelin-associated glycoprotein (MAG; 159460), neural cell adhesion molecule (NCAM; 116930), and carcinoembryonic antigen (CEA; 114890). Consistent with the structural similarities to the adhesion molecules, CD22 participates in adhesion between B cells and other cell types. Wilson et al. (1991) cloned a full-length cDNA corresponding to the B-cell membrane protein CD22.
Nonhuman mammalian cells express N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Human cells contain only Neu5Ac because of an exon deletion/frameshift mutation in cytidine monophospho-sialic acid hydroxylase (CMAH; 603209), which converts Neu5Ac to Neu5Gc. Sialic acid-binding immunoglobulin-like lectins, or SIGLECs, such as CD22 (SIGLEC2), recognize sialic acids. Brinkman-Van der Linden et al. (2000) showed that human SIGLEC1 (SN; 600751) strongly prefers Neu5Ac over Neu5Gc. Sequence analysis of SIGLEC2 cDNA found that while the chimpanzee sequence is 97% homologous to human, bonobo and gorilla are only 96% homologous, and the orangutan is only 93% homologous. Using regions of SIGLEC2 proteins from mouse, chimpanzee, orangutan, and human fused to the Fc region of human IgG, and flow cytometry analysis, Brinkman-Van der Linden et al. (2000) showed that all bound well to chimpanzee Epstein-Barr virus (EBV)-transformed B cells, which expressed high levels of Neu5Gc. Except for mouse, all bound well to human EBV-transformed B cells, which expressed high levels of Neu5Ac.
In a review of immune inhibitory receptors, Ravetch and Lanier (2000) pointed out that autoimmune disorders may result from the disruption of inhibitory receptors, particularly in their conserved intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). ITIMs are sites for alternative phosphorylation, typically by a Src kinase, and dephosphorylation, either by the tyrosine phosphatase SHP1 (176883) or the inositol phosphatase SHIP (601582), transducing signals to distinct pathways. Ravetch and Lanier (2000) noted that CD22 has ITIMs that interact with SHP1 and oppose activation mediated by the B cell receptor.
Using murine B-cell lines, Wakabayashi et al. (2002) demonstrated that CD22 downmodulates signaling through the IgM and IgD B-cell receptors (BCRs), but not through the IgG BCR, because the IgG cytoplasmic tail prevents CD22 phosphorylation and actually enhances IgG-BCR signaling. Wakabayashi et al. (2002) proposed that enhanced IgG-BCR signaling may be involved in efficient IgG production, which is crucial for protective immunity against pathogens.
Using yeast 2-hybrid and coprecipitation analyses, John et al. (2003) found that tyr843 or tyr863 in the cytoplasmic tail of CD22 interacted with AP50 (AP2M1; 601024), the medium chain subunit of the AP2 complex. Studies on B cells showed that internalization of CD22 was dependent on its association with the AP2 complex via tyrosine-based internalization motifs.
Pluvinage et al. (2019) combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the antiphagocytic effect of alpha-2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-beta (104760) oligomers, and alpha-synuclein (163890) fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprogrammed microglia towards a homeostatic transcriptional state and improved cognitive function in aged mice. Pluvinage et al. (2019) concluded that their findings elucidated a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the aging brain.
Wilson et al. (1993) used a nearly full-length cDNA clone of CD22 to isolate genomic clones that spanned the gene. The gene covers 22 kb of DNA and comprises 15 exons.
By fluorescence in situ hybridization, Wilson et al. (1993) showed that the CD22 locus is located within band 19q13.1.
O'Keefe et al. (1996) made observations in mice with a targeted disruption of the CD22 gene indicating that CD22 is a negative regulator of antigen receptor signaling whose onset of expression at the mature B cell stage may serve to raise the antigen concentration threshold required for B cell triggering. Splenic B cells from CD22 knockout mice were found to be hyperresponsive to receptor signaling. Heightened calcium fluxes and cell proliferation were obtained at lower ligand concentrations. The mice gave augmented immune response, had an expanded peritoneal B-1 cell population, and contained increased serum titers of autoantibody.
Chen et al. (2004) expressed mouse Cd22 in mouse and chicken B-cell lines devoid of Cd22 and examined B cells from mice deficient in Cd22 or Pmca4 (108732). They identified an activation-dependent interaction between phosphorylated Cd22 and Pmca4 and found that Cd22 together with Shp1 (PTPN6; 176883) provided negative control of B-cell activation by enhancing Pmca4-mediated calcium efflux after B-cell receptor stimulation.
Brinkman-Van der Linden, E. C. M., Sjoberg, E. R., Juneja, L. R., Crocker, P. R., Varki, N., Varki, A. Loss of N-glycolylneuraminic acid in human evolution: implications for sialic acid recognition by siglecs. J. Biol. Chem. 275: 8633-8640, 2000. [PubMed: 10722703] [Full Text: https://doi.org/10.1074/jbc.275.12.8633]
Chen, J., McLean, P. A., Neel, B. G., Okunade, G., Shull, G. E., Wortis, H. H. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nature Immun. 5: 651-657, 2004. [PubMed: 15133509] [Full Text: https://doi.org/10.1038/ni1072]
John, B., Herrin, B. R., Raman, C., Wang, Y., Bobbitt, K. R., Brody, B. A., Justement, L. B. The B cell coreceptor CD22 associates with AP50, a clathrin-coated pit adapter protein, via tyrosine-dependent interaction. J. Immun. 170: 3534-3543, 2003. [PubMed: 12646615] [Full Text: https://doi.org/10.4049/jimmunol.170.7.3534]
O'Keefe, T. L., Williams, G. T., Davies, S. L., Neuberger, M. S. Hyperresponsive B cells in CD22-deficient mice. Science 274: 798-801, 1996. [PubMed: 8864124] [Full Text: https://doi.org/10.1126/science.274.5288.798]
Pluvinage, J. V., Haney, M. S., Smith, B. A. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., Shuken, S. R., Gate, D., Scott, M., Khatri, P., Luo, J., Bertozzi, C. R., Bassik, M. C., Wyss-Coray, T. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568: 187-192, 2019. [PubMed: 30944478] [Full Text: https://doi.org/10.1038/s41586-019-1088-4]
Ravetch, J. V., Lanier, L. L. Immune inhibitory receptors. Science 290: 84-89, 2000. [PubMed: 11021804] [Full Text: https://doi.org/10.1126/science.290.5489.84]
Wakabayashi, C., Adachi, T., Wienands, J., Tsubata, T. A distinct signaling pathway used by the IgG-containing B cell antigen receptor. Science 298: 2392-2395, 2002. [PubMed: 12493916] [Full Text: https://doi.org/10.1126/science.1076963]
Wilson, G. L., Fox, C. H., Fauchi, A. S., Kehrl, J. H. cDNA cloning of the B cell membrane protein CD22: a mediator of B-B cell interactions. J. Exp. Med. 173: 137-146, 1991. [PubMed: 1985119] [Full Text: https://doi.org/10.1084/jem.173.1.137]
Wilson, G. L., Najfeld, V., Kozlow, E., Menniger, J., Ward, D., Kehrl, J. H. Genomic structure and chromosomal mapping of the human CD22 gene. J. Immun. 150: 5013-5024, 1993. [PubMed: 8496602]