CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins.[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 of autoimmune diseases.[5]
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.[8]
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.[9]
Trans interactions between CD22 and its ligands are important for B celladhesion 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.[10]
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.[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 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.[13]
An immunotoxin, BL22 (CAT-3888), that targets this receptor was developed at the NIH.[15] BL22 was superseded by moxetumomab 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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Crocker PR, Clark EA, Filbin M, Gordon S, Jones Y, Kehrl JH, et al. (February 1998). "Siglecs: a family of sialic-acid binding lectins". Glycobiology. 8 (2): v. doi:10.1093/oxfordjournals.glycob.a018832. PMID9498912.
^Hatta Y, Tsuchiya N, Matsushita M, Shiota M, Hagiwara K, Tokunaga K (April 1999). "Identification of the gene variations in human CD22". Immunogenetics. 49 (4): 280–6. doi:10.1007/s002510050494. PMID10079291. S2CID22947237.
^Clinical trial number NCT00074048 for "BL22 Immunotoxin in Treating Patients Previously Treated With Cladribine for Hairy Cell Leukemia" at ClinicalTrials.gov