Biology:CD22

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Short description: Lectin molecule


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins.[1] It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.[2]

CD22 is a sugar binding transmembrane protein, which specifically binds sialic acid with an immunoglobulin (Ig) domain located at its N-terminus. The presence of Ig domains makes CD22 a member of the immunoglobulin superfamily. CD22 functions as an inhibitory receptor for B cell receptor (BCR) signaling. It is also involved in the B cell trafficking to Peyer's patches in mice.[3] In mice, it has been shown that CD22 blockade restores homeostatic microglial phagocytosis in aging brains.[4] File:Microglial cells.tif

Structure

CD22 is a transmembrane protein with a molecular weight of 140 kDa. The extracellular part of CD22 consists of seven immunoglobulin domains and the intracellular part is formed by 141-amino acid cytoplasmic tail.[5]

Extracellular part

The binding site for ligands is located at the extracellular N-terminus, specifically at the last immunoglobulin domain called the V-like domain. This domain binds to ligands containing sialic acid via α2,6-linkage to the galactose residue. Such ligands are commonly expressed on the surface of erythrocytes, monocytes, cytokine-activated endothelial cells, T cells and B cells. To a lesser extent they are present on soluble IgM and on the soluble plasmatic glycoprotein called haptoglobin. Therefore, CD22 can bind ligands in the cis configuration, when they are on the surface of B cells, or in the trans configuration, when they are on the surface of other cells or on soluble glycoproteins or attached to a cell-associated antigen. However, CD22 is masked on most B-cell surfaces, meaning that it cannot bind exogenous ligands, so cis interaction with glycoprotein ligands on the same cell is preferred.[6]

Trans ligands

Trans interactions between CD22 and its ligands are important for B cell adhesion and migration. Specifically, CD22-deficient mice have been shown to have reduced numbers of recirculating B cells and reduced numbers of IgM-secreting plasma cells in the bone marrow. Together, this implies that CD22 interacting with trans ligands is crucial for the homing of mature, recirculating B cells to the bone marrow.[7]

BCR signaling

The intracellular part of CD22 consists of 6 tyrosine residues which contain both ITIM and ITAM motifs suggesting both inhibitory and activation role in signaling.[8] Because of the tyrosine residues, the cytoplasmic domain of CD22 can be phosphorylated. This happens when the BCR is cross-linked by the antigen. Phosphorylation is mediated by Lyn, a protein tyrosine kinase (PTK) of the Src family found in lipid rafts.[6]

Inhibitory role

After CD22 is phosphorylated, the ITIM motifs provide docking sites for the SH2 domain containing protein tyrosine phosphatase called SHP-1. SHP-1 inhibits mitogen-activated protein kinase (MAPK) and dephosphorylates components of BCR signaling. That means that association of CD22 with SHP-1 leads to the inhibition of BCR signaling.[9][6]

Activation role

After CD22 is phosphorylated, the ITAM motifs provide docking sites for the SH2 domain of Lyn or other Syk kinase or Src-family tyrosine kinases. Thus, CD22 positively regulates BCR signaling and thereby promotes B cell survival.[6]

Autoimmunity

Single-nucleotide polymorphisms in the CD22 gene lead to a higher likelihood of autoimmune disease. Specifically, some studies show that polymorphisms in the CD22 gene are associated with susceptibility to systemic lupus erythematosus (SLE) and cutaneous systemic sclerosis. In addition, mutations in enzymes involved in the glycosylation of the CD22 ligand may also lead to the susceptibility to autoimmune diseases. Specifically, mutations in the sialic acid esterase were frequently found in patients with rheumatoid arthritis and SLE. This enzyme is essential for deacetylation of the N-glycan sialic acid present in CD22 ligands and is therefore crucial for ligand binding.[10]

BCR signaling & inhibitory role

As a drug target

Because CD22 is restricted to B cells, it is an excellent target for immunotherapy of B cell malignancies. There are several mechanisms by which this can be achieved, namely monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, radioimmunoconjugates or CAR-T cells.[11]

An immunotoxin, BL22 (CAT-3888), that targets this receptor was developed at the NIH.[12] BL22 was superseded by moxetumomab pasudotox (HA22, CAT-8015).[13] Moxetumomab pasudotox is approved in the EU and USA for treatment of relapsed or refractory hairy cell leukemia.[14][15]

Inotuzumab

It was shown that antibody-drug conjugates work better than naked antibodies. The reason is that CD22 is rapidly internalized rather than being exposed to the extracellular environment making it more suitable for specific delivery of these conjugates.[16] One of such therapeutics is Inotuzumab, which was approved by the FDA for the treatment of relapsed or refractory B cell acute lymphoblastic leukemia in August 2017.[17] Inotuzumab consists of a CD22-targeting immunoglobulin G4 humanized monoclonal antibody conjugated to calicheamicin. The mechanism by which calicheamicin destroys malignant cells is that it binds to DNA, causing DNA double-strand breaks, and this in turn leads to transcription inhibition.[16]

Interactions

CD22 has been shown to interact with Grb2,[18][19] PTPN6,[19][20][21][22][23] LYN,[18][21] SHC1[18] and INPP5D.[18]

References

  1. ↑ "Siglecs: a family of sialic-acid binding lectins". Glycobiology 8 (2): v. February 1998. doi:10.1093/glycob/8.2.0. PMID 9498912. 
  2. ↑ "Identification of the gene variations in human CD22". Immunogenetics 49 (4): 280–6. April 1999. doi:10.1007/s002510050494. PMID 10079291. 
  3. ↑ "Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing". Nature Immunology 15 (10): 982–95. October 2014. doi:10.1038/ni.2983. PMID 25173345. 
  4. ↑ "CD22 blockade restores homeostatic microglial phagocytosis in aging brains". Nature 568 (7751): 187–192. April 11, 2019. doi:10.1038/s41586-019-1088-4. PMID 30944478. Bibcode: 2019Natur.568..187P. 
  5. ↑ Tedder, T. F.; Tuscano, J.; Sato, S.; Kehrl, J. H. (1997). "CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling". Annual Review of Immunology 15: 481–504. doi:10.1146/annurev.immunol.15.1.481. ISSN 0732-0582. PMID 9143697. https://pubmed.ncbi.nlm.nih.gov/9143697. 
  6. ↑ 6.0 6.1 6.2 6.3 Walker, Jennifer A.; Smith, Kenneth G. C. (March 2008). "CD22: an inhibitory enigma". Immunology 123 (3): 314–325. doi:10.1111/j.1365-2567.2007.02752.x. ISSN 1365-2567. PMID 18067554. 
  7. ↑ Nitschke, Lars (July 2009). "CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions". Immunological Reviews 230 (1): 128–143. doi:10.1111/j.1600-065X.2009.00801.x. ISSN 1600-065X. PMID 19594633. https://pubmed.ncbi.nlm.nih.gov/19594633. 
  8. ↑ Poe, J. C.; Fujimoto, M.; Jansen, P. J.; Miller, A. S.; Tedder, T. F. (2000-06-09). "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry 275 (23): 17420–17427. doi:10.1074/jbc.M001892200. ISSN 0021-9258. PMID 10748054. 
  9. ↑ Sato, S.; Tuscano, J. M.; Inaoki, M.; Tedder, T. F. (August 1998). "CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor". Seminars in Immunology 10 (4): 287–297. doi:10.1006/smim.1998.0121. ISSN 1044-5323. PMID 9695185. https://pubmed.ncbi.nlm.nih.gov/9695185. 
  10. ↑ Clark, Edward A.; Giltiay, Natalia V. (2018). "CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity". Frontiers in Immunology 9: 2235. doi:10.3389/fimmu.2018.02235. ISSN 1664-3224. PMID 30323814. 
  11. ↑ Shah, Nikesh N.; Sokol, Lubomir (2021). "Targeting CD22 for the Treatment of B-Cell Malignancies". ImmunoTargets and Therapy 10: 225–236. doi:10.2147/ITT.S288546. ISSN 2253-1556. PMID 34262884. 
  12. ↑ Clinical trial number NCT00074048 for "BL22 Immunotoxin in Treating Patients Previously Treated With Cladribine for Hairy Cell Leukemia" at ClinicalTrials.gov
  13. ↑ http://www.cambridgeantibody.com/__data/assets/pdf_file/10857/CAT-3888,_CAT-8015_and_CAT-5001_Nov06.pdf CAT URL Redirects to Medimmune home page
  14. ↑ "Lumoxiti EPAR". 9 December 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/lumoxiti. .
  15. ↑ "Moxetumomab pasudotox-tdfk FDA Approval". https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=248707. 
  16. ↑ 16.0 16.1 Wynne, Joseph; Wright, David; Stock, Wendy (2019-01-08). "Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia". Blood Advances 3 (1): 96–104. doi:10.1182/bloodadvances.2018026211. ISSN 2473-9537. PMID 30622147. 
  17. ↑ Research, Center for Drug Evaluation and (2019-02-09). "FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL" (in en). FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inotuzumab-ozogamicin-relapsed-or-refractory-b-cell-precursor-all. 
  18. ↑ 18.0 18.1 18.2 18.3 "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry 275 (23): 17420–7. June 2000. doi:10.1074/jbc.M001892200. PMID 10748054. 
  19. ↑ 19.0 19.1 "CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1". The Journal of Biological Chemistry 276 (47): 44315–22. November 2001. doi:10.1074/jbc.M105446200. PMID 11551923. 
  20. ↑ "Definition of the sites of interaction between the protein tyrosine phosphatase SHP-1 and CD22". The Journal of Biological Chemistry 274 (4): 2303–7. January 1999. doi:10.1074/jbc.274.4.2303. PMID 9890995. 
  21. ↑ 21.0 21.1 "CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1". Journal of Immunology 162 (9): 5278–86. May 1999. doi:10.4049/jimmunol.162.9.5278. PMID 10228003. 
  22. ↑ "CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation". The Journal of Experimental Medicine 183 (2): 547–60. February 1996. doi:10.1084/jem.183.2.547. PMID 8627166. 
  23. ↑ "SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates". The Journal of Biological Chemistry 276 (28): 26648–55. July 2001. doi:10.1074/jbc.M100997200. PMID 11356834. 

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