CD22

CD22 is a transmembrane glycoprotein primarily expressed on B cells, where it regulates immune responses by modulating B cell receptor (BCR) signaling. As a key inhibitory co-receptor, CD22 plays a critical role in maintaining immune homeostasis and preventing excessive immune activation. Given its involvement in B cell malignancies and autoimmune diseases, CD22 has been extensively studied as a therapeutic target.

NCBI Gene ID: 933

UniProtKB ID: P20273

Structure of CD22

CD22 is a type I transmembrane protein composed of seven extracellular immunoglobulin-like domains, a transmembrane region, and a cytoplasmic tail containing multiple immunoreceptor tyrosine-based inhibitory motifs (ITIMs).

Figure 1. Three-dimensional structure of human CD22. Crystal structure of the three N-terminal Ig domains of human CD22 (d1–d3) represented as a schematic diagram, secondary structure cartoon, and transparent surface. (Ereño-Orbea, et al., 2017)

Function of CD22

Upon binding to the B cell receptor (BCR), CD22 acts as a key negative regulator by recruiting the Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1). This phosphatase dephosphorylates key signaling molecules, resulting in the downregulation of BCR-mediated signaling cascades and a reduction in B cell activation. By dampening excessive immune responses, CD22 plays a critical role in maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), in which overactive B cells contribute to disease pathology.

In addition to its role in BCR signaling, CD22 also functions as an adhesion molecule, interacting with sialylated ligands on neighboring cells. These interactions are essential for B cell migration, homing, and retention in specific tissues, allowing for proper immune surveillance and response modulation. By regulating the localization of B cells in lymphoid organs and inflamed tissues, CD22 further influences immune function and disease progression.

Figure 2. CD22 structure and signaling pathway. CD22 molecule is a transmembrane protein from SIGLEC (Sialic acid-binding immunoglobulin-type lectins) family. It has three parts: (i) V-type Ig domain with sia-binding site, (ii) C1-type Ig domain, (iii) C2-type Ig domain. The CD22 intracellular region contains ITIMs (Immunoreceptor tyrosine-based inhibitory motifs). The tyrosine residues of the ITIMs become phosphorylated with the ligand binding, which leads to activation of SHP-1 (Src homology region 2 domain-containing phosphatase-1), SHP-2 (Src homology region 2 domain-containing phosphatase-2), SHIP-1 ((Src homology region 2 domain-containing inositol 5′ polyphosphatase-1). These phosphatases act as negative regulators for down-streaming signaling from B-cell receptors. (Aujla et al., 2019)

CD22 and Disease Pathogenesis

B Cell Malignancies

CD22 is highly expressed on mature and precursor B cells, making it a valuable biomarker and therapeutic target for B cell malignancies. In conditions such as B cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin's lymphoma (NHL), CD22 expression remains intact, providing an avenue for targeted therapies.

Autoimmune Diseases

CD22 dysfunction has been implicated in autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Reduced CD22 expression or function leads to hyperactive B cells and autoantibody production, exacerbating disease pathology. Strategies to enhance CD22 signaling or restore its inhibitory effects are being explored as potential therapeutic approaches.

CD22 and Infections

While CD22 plays a role in the regulation of several B cell functions, its involvement in protection against viral infections remains uncertain. Studies have shown that CD22^-/- mice infected with lymphocytic choriomeningitis virus, vesicular stomatitis virus, or Staphylococcus aureus show no difference in survival compared to wild-type (WT) mice. However, CD22 deficiency has been associated with increased susceptibility to West Nile virus (WNV) and accelerated progression of murine AIDS (MAIDS) caused by murine leukemia virus. In CD22^-/- mice, the onset of splenomegaly and lymphadenopathy is more rapid, occurring within four weeks of infection.

CD22 as a Drug Target

Antibody-Drug Conjugates (ADCs)

• Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) designed to target CD22-expressing B cell malignancies. It consists of a humanized anti-CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. Upon binding to CD22, Inotuzumab Ozogamicin is internalized, leading to the release of calicheamicin, which induces DNA damage and apoptosis in malignant B cells. This targeted approach has shown significant efficacy in treating relapsed or refractory B-ALL and NHL.

CAR-T Cell Therapy

CD22-directed chimeric antigen receptor (CAR) T-cell therapy has shown promise, particularly in CD19-negative relapsed B-cell malignancies, expanding treatment options for B-cell leukemia and lymphoma.

In summary, by exploiting CD22's ability to regulate BCR signaling and its selective expression on B cells, CD22-targeting drugs offer precision therapy for B-cell cancers and autoimmune diseases, minimizing off-target effects and improving therapeutic efficacy.

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References

1. Aujla A, Aujla R, Liu D. Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Biomark Res. 2019;7(1):9.
2. Clark EA, Giltiay NV. CD22: a regulator of innate and adaptive b cell responses and autoimmunity. Front Immunol. 2018;9. doi:10.3389/fimmu.2018.02235
3. Ereño-Orbea J, Sicard T, Cui H, et al. Molecular basis of human CD22 function and therapeutic targeting. Nat Commun. 2017;8(1):764. doi:10.1038/s41467-017-00836-6