| CD22 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | CD22, SIGLEC-2, SIGLEC2, CD22 molecule | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:107266;MGI:88322;HomoloGene:31052;GeneCards:CD22;OMA:CD22 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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CD22, orcluster of differentiation-22, is a molecule belonging to theSIGLEC family oflectins.[4] 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 ofautoimmune diseases.[5]
CD22 is a sugar bindingtransmembrane protein, which specifically bindssialic acid with animmunoglobulin (Ig) domain located at itsN-terminus. The presence of Ig domains makes CD22 a member of theimmunoglobulin superfamily. CD22 functions as an inhibitory receptor forB cell receptor (BCR) signaling. It is also involved in the B cell trafficking toPeyer's patches in mice.[6] In mice, it has been shown that CD22 blockade restores homeostaticmicroglialphagocytosis in aging brains.[7]
CD22 is atransmembrane protein with a molecular weight of 140kDa. The extracellular part of CD22 consists of sevenimmunoglobulin domains and the intracellular part is formed by 141-amino acid cytoplasmic tail.[8]
The binding site for ligands is located at the extracellularN-terminus, specifically at the last immunoglobulin domain called theV-like domain. This domain binds to ligands containingsialic acid via α2,6-linkage to thegalactose residue. Such ligands are commonly expressed on the surface oferythrocytes,monocytes, cytokine-activated endothelial cells,T cells andB cells. To a lesser extent they are present on solubleIgM and on the soluble plasmatic glycoprotein calledhaptoglobin. Therefore, CD22 can bind ligands in thecis configuration, when they are on the surface ofB cells, or in thetrans 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 mostB-cell surfaces, meaning that it cannot bind exogenous ligands, so cis interaction withglycoprotein ligands on the same cell is preferred.[9]
Trans interactions between CD22 and itsligands are important forB celladhesion and migration. Specifically, CD22-deficient mice have been shown to have reduced numbers of recirculating B cells and reduced numbers of IgM-secretingplasma cells in the bone marrow. Together, this implies that CD22 interacting with trans ligands is crucial for the homing of mature, recirculatingB cells to thebone marrow.[10]
Theintracellular part of CD22 consists of 6tyrosine residues which contain bothITIM andITAM motifs suggesting both inhibitory and activation role in signaling.[11] Because of the tyrosine residues, the cytoplasmic domain of CD22 can bephosphorylated. This happens when the BCR iscross-linked by the antigen.Phosphorylation is mediated by Lyn, aprotein tyrosine kinase (PTK) of theSrc family found inlipid rafts.[9]
After CD22 isphosphorylated, the ITIM motifs provide docking sites for theSH2 domain containing protein tyrosine phosphatase calledSHP-1.SHP-1 inhibitsmitogen-activated protein kinase (MAPK) and dephosphorylates components of BCR signaling. That means that association of CD22 withSHP-1 leads to the inhibition of BCR signaling.[12][9]
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.[9]
Single-nucleotide polymorphisms in the CD22 gene lead to a higher likelihood ofautoimmune disease. Specifically, some studies show that polymorphisms in the CD22 gene are associated with susceptibility tosystemic 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 toautoimmune diseases. Specifically, mutations in the sialic acid esterase were frequently found in patients withrheumatoid arthritis andSLE. This enzyme is essential fordeacetylation of the N-glycan sialic acid present in CD22 ligands and is therefore crucial for ligand binding.[13]
Because CD22 is restricted to B cells, it is an excellent target forimmunotherapy ofB cell malignancies. There are several mechanisms by which this can be achieved, namelymonoclonal antibodies,bispecific antibodies,antibody-drug conjugates,radioimmunoconjugates orCAR-T cells.[14]
An immunotoxin,BL22 (CAT-3888), that targets this receptor was developed at theNIH.[15] BL22 was superseded bymoxetumomab pasudotox (HA22, CAT-8015).[16] Moxetumomab pasudotox is approved in the EU and USA for treatment of relapsed or refractory hairy cell leukemia.[17][18]
It was shown thatantibody-drug conjugates work better than nakedantibodies. The reason is that CD22 is rapidlyinternalized rather than being exposed to the extracellular environment making it more suitable for specific delivery of these conjugates.[19] One of such therapeutics isinotuzumab, which was approved by the FDA for the treatment of relapsed or refractoryB cell acute lymphoblastic leukemia in August 2017.[20] Inotuzumab consists of a CD22-targetingimmunoglobulin G4humanized monoclonal antibody conjugated tocalicheamicin. The mechanism by which calicheamicin destroys malignant cells is that it binds to DNA, causing DNAdouble-strand breaks, and this in turn leads totranscription inhibition.[19]
CD22 has been shown tointeract withGrb2,[21][22]PTPN6,[22][23][24][25][26]LYN,[21][24]SHC1[21] andINPP5D.[21]
