CD33 molecule | Elisa - Clia - Antibody - Protein

Background

CD33, also known as Siglec-3 (Sialic acid-binding Ig-like lectin 3), is a transmembrane receptor expressed primarily on cells of myeloid lineage. It belongs to the immunoglobulin (Ig) superfamily and plays a significant role in the regulation of innate immunity. CD33 was first identified in the late 1980s as a marker on acute myeloid leukemia (AML) cells, making it a focal point for research in hematological malignancies. This glycoprotein is encoded by the CD33 gene located on chromosome 19q13.3. CD33 is involved in cellular signaling processes that modulate immune cell function and survival.

Protein Structure

CD33 is a type I transmembrane protein comprising several distinct domains:

Extracellular Domain:

• This domain contains two Ig-like regions: a V-set domain at the N-terminus followed by a C2-set domain.
• The V-set domain is responsible for binding sialic acid residues on glycoproteins and glycolipids, which is critical for its role in cell-cell interactions and signaling.
• Glycosylation sites within the extracellular domain enhance stability and ligand recognition.

Transmembrane Domain:

• The transmembrane region anchors CD33 in the cell membrane and spans approximately 20 hydrophobic amino acids.

Cytoplasmic Tail:

• The cytoplasmic tail contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are essential for signaling.
• Upon phosphorylation, ITIMs recruit SH2 domain-containing phosphatases (such as SHP-1 and SHP-2), leading to the attenuation of signaling pathways that promote cell activation.

Classification and Subtypes

CD33 is a member of the Siglec family, which are cell surface receptors that recognize sialic acid-containing glycoconjugates. Siglecs are classified based on their structure and function into two major groups:

• CD33-related Siglecs: Includes Siglec-5, -6, -7, -8, -9, -10, and others. These are primarily involved in the regulation of immune cell activity.
• Siglec-1, -2, and -4: These have distinct functions and structures compared to CD33-related Siglecs.

Function and Biological Significance

Immune Regulation:

• CD33 plays a critical role in modulating the immune response. By binding to sialylated ligands, it transmits inhibitory signals that dampen the activation of immune cells.
• This regulatory function helps maintain immune homeostasis and prevent overactive immune responses that could lead to autoimmunity.

Phagocytosis:

• CD33 is involved in the inhibition of phagocytosis. Its expression on macrophages and dendritic cells can modulate the engulfment of apoptotic cells and pathogens.
• Through its inhibitory signaling, CD33 reduces the production of pro-inflammatory cytokines and chemokines.

Hematopoiesis and Leukemia:

• CD33 is expressed on hematopoietic stem cells and myeloid progenitors. Its function in these cells includes regulating cell differentiation and survival.
• In acute myeloid leukemia (AML), CD33 is aberrantly expressed on leukemic blasts. Targeting CD33 with monoclonal antibodies (e.g., gemtuzumab ozogamicin) has been explored as a therapeutic strategy.

Neuroinflammation:

• Recent studies have implicated CD33 in the regulation of microglial activity in the central nervous system. It is thought to play a role in neuroinflammatory processes and is being investigated in the context of neurodegenerative diseases like Alzheimer’s.

Clinical Issues

Acute Myeloid Leukemia (AML):

• CD33 is a well-established target in AML therapy. Antibody-drug conjugates (ADCs) such as gemtuzumab ozogamicin have been developed to target CD33 on leukemic cells, delivering cytotoxic agents specifically to these cells.
• The effectiveness and safety of CD33-targeted therapies continue to be a major area of research, with efforts to improve the therapeutic index and reduce side effects.

Autoimmune Diseases:

• Dysregulation of CD33 signaling can contribute to autoimmune pathologies. Given its role in inhibiting immune responses, insufficient CD33 activity may lead to unchecked immune activation.
• Therapeutic modulation of CD33 activity, either through agonists to enhance its inhibitory function or antagonists to reduce it, is being explored for autoimmune disease treatment.

Neurodegenerative Disorders:

• CD33 has been linked to Alzheimer’s disease, where it is thought to influence the clearance of amyloid-beta plaques by microglia. Variants in the CD33 gene are associated with an increased risk of Alzheimer’s.
• Therapeutic strategies targeting CD33 in the brain aim to modulate microglial activity and improve the clearance of pathological proteins.

Summary

CD33 is a crucial regulator of immune cell function, playing significant roles in the modulation of phagocytosis, immune response, and hematopoiesis. Its structure, featuring an extracellular domain with sialic acid-binding capacity and a cytoplasmic tail with ITIM motifs, facilitates its inhibitory signaling functions. Clinically, CD33 is most notable for its expression in AML and its potential as a therapeutic target. Additionally, CD33's involvement in autoimmune diseases and neuroinflammation highlights its broader significance in health and disease. Ongoing research into CD33's mechanisms and therapeutic targeting continues to expand our understanding of its role in immune regulation and its potential in clinical applications.