CD33 is a protein found on the surface of certain cells in the human body. This protein plays a significant role in various biological processes, particularly those related to the immune system. Understanding CD33 helps shed light on how our bodies function and how certain diseases develop.
Understanding CD33: What It Is and Where It’s Found
CD33 is a type of receptor protein, a transmembrane receptor, spanning the cell membrane. It belongs to a family of proteins called sialic acid-binding immunoglobulin-like lectins, or Siglecs. These proteins are involved in cell signaling and recognition processes.
CD33 is predominantly found on the surface of myeloid cells, a type of white blood cell. These include monocytes, macrophages, dendritic cells, and granulocytes. CD33 is also expressed on early multi-lineage hematopoietic progenitors, myeloblasts, and monoblasts. It can also be present on some lymphoid cells.
The Normal Role of CD33 in the Body
In healthy individuals, CD33 functions as an inhibitory receptor, meaning it helps to regulate and dampen immune responses. It achieves this by binding to molecules containing sialic acid residues, found on other cells or pathogens. This binding triggers a signaling cascade within the cell.
Upon binding, the intracellular portion of CD33, which contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs), becomes phosphorylated. These phosphorylated ITIMs then act as docking sites for other proteins, such as SHP phosphatases. This interaction leads to a cascade that can inhibit cellular activities like phagocytosis, a process where immune cells engulf and clear debris or pathogens. This regulatory function helps maintain immune homeostasis, preventing overactive immune responses that could harm healthy tissues, autoimmune diseases, and chronic inflammation.
CD33’s Connection to Disease
CD33’s expression patterns and functional role link it to several diseases. It is widely recognized for its association with acute myeloid leukemia (AML), a cancer of the blood and bone marrow. In 85-90% of AML cases, CD33 is overexpressed on leukemic cells, specifically myeloblasts. This overexpression makes CD33 a distinguishing marker for AML and a potential target for treatment.
Beyond AML, CD33 has an emerging role in neurodegenerative diseases, particularly Alzheimer’s disease. Genome-wide association studies have identified variants of the CD33 gene as a risk factor for late-onset Alzheimer’s. In the brains of individuals with Alzheimer’s, increased levels of CD33 are observed, correlating with disease severity and the accumulation of amyloid plaques. CD33, primarily expressed on microglial cells—the brain’s immune cells—is thought to impair their ability to clear toxic beta-amyloid protein fragments, contributing to plaque formation. Conversely, a rare variant of CD33 is associated with a reduced risk of Alzheimer’s, possibly by enhancing microglial clearance of amyloid-beta.
How CD33 is Targeted in Medical Treatments
The presence of CD33 on the surface of certain cells makes it an attractive target for medical therapies, especially in cancer treatment. In acute myeloid leukemia (AML), CD33 serves as a target for antibody-drug conjugates (ADCs). One prominent example is gemtuzumab ozogamicin. This drug consists of a humanized anti-CD33 monoclonal antibody linked to a potent cytotoxic agent called calicheamicin.
When gemtuzumab ozogamicin is administered, the antibody portion recognizes and binds specifically to the CD33 antigen on leukemic cells. This binding triggers the internalization of the antibody-drug complex into the cell. Once inside the cell, the linker connecting the antibody to the calicheamicin is cleaved through acid hydrolysis, releasing the cytotoxic drug. The released calicheamicin then causes double-strand DNA breaks within the cancer cell, leading to cell cycle arrest and programmed cell death, or apoptosis. This targeted delivery minimizes damage to healthy cells that do not express CD33, thereby reducing systemic toxicity.
Research is also exploring CD33 as a therapeutic target in Alzheimer’s disease. Studies have investigated gene therapy approaches to reduce CD33 levels on microglial cells, aiming to enhance their ability to clear amyloid-beta plaques and reduce neuroinflammation. For instance, adeno-associated virus (AAV) vectors have been used to deliver artificial microRNAs designed to “knock down” CD33 expression. Early intervention with such gene therapies in mouse models of Alzheimer’s has shown promise in reducing amyloid-beta accumulation and neuroinflammation, suggesting CD33 modulation could be a future therapeutic strategy.