CD20 is a protein found on the surface of B lymphocytes, which are a type of white blood cell in the immune system. Understanding CD20’s presence and behavior on these cells has become relevant in medical contexts.
What is the CD20 Gene and Protein?
CD20 refers to both a gene, MS4A1, and the protein it produces. The MS4A1 gene is located on chromosome 11 at 11q12.2, spanning approximately 16,000 base pairs and consisting of eight exons. It produces at least three different mRNA transcripts, all translating into an identical full-length CD20 protein.
The CD20 protein is a non-glycosylated phosphoprotein with a molecular weight ranging from 33 to 37 kDa. It is a transmembrane protein with four hydrophobic transmembrane domains, one intracellular domain, and two extracellular loops. Both the amino and carboxyl termini of the protein are located within the cytoplasm. CD20 is present on the surface of B cells from their early pre-B cell stage of development through to mature B cells, but its expression is lost on terminally differentiated plasma cells and hematopoietic stem cells. It often exists on the cell surface as homodimeric and homotetrameric oligomers, associating with other cell-surface and cytoplasmic proteins involved in signal transduction, such as CD53, CD81, and CD82.
Role of CD20 in B-Cell Function
The CD20 protein plays a part in the normal functioning of B cells within the adaptive immune system. It contributes to B-cell activation, proliferation, and differentiation. CD20 influences intracellular calcium levels, possibly by acting as a calcium channel or being directly involved in calcium flux across the plasma membrane, a process important for B-cell signaling.
CD20 forms connections with the B-cell receptor (BCR) complex, a key receptor on B cells. This interaction can amplify BCR signaling, activating intracellular kinases such as Lyn, Syk, and ERK, and playing a role in B-cell activation and antibody production when exposed to antigens. CD20’s presence is linked to these signaling pathways, contributing to the initiation of B-cell responses and the overall humoral immune response.
CD20 in Disease Development
The consistent presence of CD20 on certain B cells makes it a significant marker and target in various diseases. It plays a role in the development and progression of B-cell lymphomas, such as non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Almost all B-cell NHLs are CD20-positive, although rare CD20-negative subtypes exist.
CD20 is also expressed on malignant B cells in chronic lymphocytic leukemia (CLL). Lower levels of CD20 are typically seen in CLL cases compared to other B-cell non-Hodgkin lymphomas. Furthermore, CD20 is implicated in certain autoimmune diseases where B cells contribute to the disease process, such as rheumatoid arthritis (RA) and multiple sclerosis (MS). In these conditions, pathogenic B cells expressing CD20 contribute to immune dysregulation through autoantibody production or by activating autoreactive T cells.
Targeting CD20 for Treatment
The widespread and consistent expression of CD20 on diseased B cells makes it an effective target for therapeutic interventions. Monoclonal antibodies (mAbs) are a primary form of CD20-targeting therapy. Rituximab, approved in 1997, was the first anti-CD20 monoclonal antibody used clinically for B-cell malignancies and autoimmune diseases. Since then, other anti-CD20 antibodies like obinutuzumab and ofatumumab have been developed, offering enhanced cytotoxic capabilities.
These antibodies work through several mechanisms to eliminate CD20-positive B cells. One mechanism is antibody-dependent cell-mediated cytotoxicity (ADCC), where the antibody binds to CD20 on the target cell, marking it for destruction by immune effector cells like natural killer (NK) cells, macrophages, and neutrophils. Another mechanism is complement-dependent cytotoxicity (CDC), where the antibody binding activates the complement system, leading to lysis of the targeted B cell. Additionally, anti-CD20 antibodies can directly induce apoptosis, or programmed cell death, in B cells.
These therapies have significantly improved outcomes in treating B-cell lymphomas, CLL, rheumatoid arthritis, and multiple sclerosis.