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]
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.[9]
Trans ligands
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]
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.[11] 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.[9]
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.[12][9]
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.[9]
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.[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]
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.[19] 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.[20] 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.[19]
^"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