CD22, or
cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
-22, is a molecule belonging to the
SIGLEC family of
lectin
Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in rec ...
s.
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.
CD22 is a sugar binding
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
, which specifically binds
sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone.
The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this gr ...
with an
immunoglobulin (Ig) domain located at its
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
. The presence of Ig domains makes CD22 a member of the
immunoglobulin superfamily
The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ...
. CD22 functions as an inhibitory receptor for
B cell receptor
The B cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, ...
(BCR) signaling. It is also involved in the B cell trafficking to
Peyer's patch
Peyer's patches (or aggregated lymphoid nodules) are organized lymphoid follicles, named after the 17th-century Swiss anatomist Johann Conrad Peyer.
* Reprinted as:
* Peyer referred to Peyer's patches as ''plexus'' or ''agmina glandularum'' (c ...
es in mice. In mice, it has been shown that CD22 blockade restores homeostatic microglial phagocytosis in aging brains.
Structure
CD22 is a
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
with a molecular weight of 140 kDa. The extracellular part of CD22 consists of seven
immunoglobulin
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
domains and the intracellular part is formed by 141-amino acid cytoplasmic tail.
Extracellular part
The binding site for ligands is located at the extracellular
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
, specifically at the last immunoglobulin domain called the V-like domain. This domain binds to ligands containing
sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone.
The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this gr ...
via α2,6-linkage to the
galactose
Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...
residue. Such ligands are commonly expressed on the surface of
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s, cytokine-activated endothelial cells,
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s and
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s. To a lesser extent they are present on soluble
IgM
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
and on the soluble plasmatic glycoprotein called
haptoglobin
Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the ''HP'' gene. In blood plasma, haptoglobin binds with high affinity to ''free'' hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative ...
. Therefore, CD22 can bind ligands in the ''cis'' configuration, when they are on the surface of
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s, 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
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
ligands on the same cell is preferred.
Trans ligands
Trans interactions between CD22 and its
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s are important for
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
adhesion
Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another).
The forces that cause adhesion and cohesion can be ...
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 cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s to the
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
.
BCR signaling
The
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
part of CD22 consists of 6
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
residues which contain both ITIM and ITAM motifs suggesting both inhibitory and activation role in signaling. Because of the tyrosine residues, the cytoplasmic domain of CD22 can be
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
. This happens when the BCR is
cross-link
In chemistry and biology a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
ed by the antigen.
Phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
is mediated by Lyn, a
protein tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
(PTK) of the
Src family found in
lipid raft
The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial ...
s.
Inhibitory role
After CD22 is
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, the ITIM motifs provide docking sites for the
SH2 domain containing protein tyrosine phosphatase called
SHP-1
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
.
SHP-1
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
inhibits
mitogen-activated protein kinase (MAPK) and dephosphorylates components of BCR signaling. That means that association of CD22 with
SHP-1
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
leads to the inhibition of BCR signaling.
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.
Autoimmunity
Single-nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
s in the CD22 gene lead to a higher likelihood of
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
disease. Specifically, some studies show that polymorphisms in the CD22 gene are associated with susceptibility to
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(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
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
diseases. Specifically, mutations in the sialic acid esterase were frequently found in patients with
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
and
SLE
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
. This enzyme is essential for
deacetylation of the N-glycan sialic acid present in CD22 ligands and is therefore crucial for ligand binding.
As a drug target
Because CD22 is restricted to B cells, it is an excellent target for
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
of
B cell malignancies. There are several mechanisms by which this can be achieved, namely
monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
,
bispecific antibodies
A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. ...
,
antibody-drug conjugate
Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...
s,
radioimmunoconjugates or
CAR-T cells.
An immunotoxin,
BL22 (CAT-3888), that targets this receptor was developed at the
NIH
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
.
BL22 was superseded by
moxetumomab pasudotox
Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti- CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, includin ...
(HA22, CAT-8015).
[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] Moxetumomab pasudotox is approved in the EU and USA for treatment of relapsed or refractory hairy cell leukemia.
[.]
Inotuzumab
It was shown that
antibody-drug conjugate
Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...
s work better than naked
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
. The reason is that CD22 is rapidly
internalized
Internalization ( or internalisation) is the process of making something internal, with more specific meanings in various fields. It is the opposite of externalization.
Psychology and sociology
In psychology, internalization is the outcome of ...
rather than being exposed to the extracellular environment making it more suitable for specific delivery of these conjugates.
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.
Inotuzumab consists of a CD22-targeting immunoglobulin G4 humanized
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
conjugated to
calicheamicin. The mechanism by which calicheamicin destroys malignant cells is that it binds to DNA, causing DNA
double-strand breaks
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
, and this in turn leads to
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
inhibition.
Interactions
CD22 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
Grb2,
PTPN6
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
,
LYN,[ ]SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of pro ...
[ and ]INPP5D
Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the ''INPP5D'' gene in humans. SHIP1 is expressed predominantly ...
.[
]
References
External links
*
*
*
{{Immunoglobulin superfamily immune receptors
Lectins
SIGLEC