CD19

Detailed Information

CD19 is a 95 kDa transmembrane glycoprotein that is a critical member of the immunoglobulin (Ig) superfamily. Comprising 15 exons and codes for a protein of 556 amino acids, encoded by the 7.41 kb CD19 gene found on the short arm of chromosome 16 (16p11.2 The CD19 gene is uncommon in that its proximal promoter lacks a TATA box and has a quite short 5' untranslated region. Especially, the main transcription sites are located within 50 base pairs of the initiation codon, which is necessary for the correct production of this important protein.

Comprising a single transmembrane domain, an extracellular N-terminus, and a cytoplasmic C-terminus, CD19 is structurally classed as a type I transmembrane protein. Within its extracellular domain, CD19 has two C2-type Ig-like domains split by a short helical non-Ig region perhaps including disulfide connections. Its stability and purpose also depend critically on N-linked glycosylation sites, which it has. Highly conserved, the cytoplasmic domain consists of 242 amino acids including multiple tyrosine residues necessary for its signaling capability. Three important tyrosine residues—Y391, Y482, and Y513—among them are very important for the biological activities of CD19. Studies have shown that swapping phenylalanine for tyrosine at sites Y482 and Y513 causes the suppression of phosphorylation of additional tyrosine residues, therefore influencing the general signaling pathways.

Kinetics of CD19 Expression

CD19 was first identified as the B4 antigen in human B lymphocytes through the application of anti-B4 monoclonal antibodies. Specifically expressed in both normal and neoplastic B cells as well as in follicular dendritic cells is this protein. A pivotal step in B cell development, CD19 surface expression starts during B cell lymphopoiesis around the time of immunoglobulin gene rearrangement. Pax5, a transcription factor necessary for appropriate expression of CD19, controls this expression; in fact, investigations have shown that Pax5 knockout mice halt lymphoid progenitors at the pro-B cell stage.

The surface density of CD19 is carefully controlled during B cell growth and maturation. With somewhat greater levels seen in B1 cells than in B2 (typical B) cells, CD19 expression in mature B cells is thrice higher than in immature B cells. Crucially, CD19 is one of the most consistent surface indicators for B cells; it is expressed throughout the pre-B cell stage through to final differentiation into plasma cells.

Physiological Functions of CD19

CD19 plays a pivotal role in establishing intrinsic B cell signaling thresholds, modulating both B cell receptor (BCR)-dependent and -independent signaling pathways. Its impact reaches both antigen-independent development and immunoglobulin-induced B cell activation, so it is essential for eliciting the best immune response. Working in tandem with the BCR and other surface molecules, CD19 helps different downstream protein kinases be recruited and bound. These include phosphatidylinositol 3-kinase (PI3K), Ras family proteins, Abl, Bruton's tyrosine kinase (Btk), and adaptor molecules Vav and Grb2 in addition to Src family kinases Lyn and Fyn.

Figure 1. Dependency of mature murine b cell survival on BCR and BAFF-R signaling. (Hobeika E, et al., 2015)

More recently, studies stressing its function in regulating tyrosine phosphorylation and Akt kinase signaling pathways have underlined the need for CD19 for ideal MHC class II-mediated signaling. By changing inherent and receptor-induced signals, the complex created by CD19 together with complement receptor CD21, tetraspanin CD81, and other surface proteins lowers the threshold for receptor-dependent signaling. This role establishes CD19 as a fundamental co-receptor for BCR signal transduction.

Using PI3K and downstream Akt kinases, CD19 improves BCR-induced signaling upon BCR activation, hence facilitating B cell proliferation. Moreover, the CD19/CD21 complex has an independent binding capacity to the activated complement component C3d. Tyrosine phosphorylated CD19 may interact with co-localized kinases to control BCR signaling, therefore facilitating the translocation of the complex into membrane "lipid rafts." Studies have shown, notably, that while CD19 does not need CD21 for signal transduction, the binding of C3d to CD21 may activate the CD19/CD21 signaling complex, hence increasing B cell activation.

Part of the tetraspanin web, CD81 acts as a chaperone protein, giving components engaged in different signal transduction pathways docking sites. Normal levels of CD21 and BCR expression notwithstanding, CD81 is essential for CD19 expression; in CD21-deficient animals, CD19 expression was found to be about 30–50% of that in wild-type mice. Moreover, CD19 and CD38 interact and co-localize in lipid rafts to constitute part of the B cell signaling system. In vivo experiments revealed that total B cell signaling and CD19 expression were lowered in CD81 deficient cells.

It is thought that CD19 functions two-fold in B cell activation. First, it serves as an adapter protein, drawing cytoplasmic signaling proteins to the membrane. Experimental data indicates that BCR ligation phosphorizes the tyrosine residues of CD19, which helps to attract cytosolic proteins with the SH2 domain. Second, in colliding with the BCR, CD19 serves as a signaling component for the CD19/CD21 complex. Using BCR-CD19/CD21 colliding, antigens carrying complement increase B cell activation, therefore amplifying this interaction.

Apart from its vital functions in immunological signaling, CD19 also controls the growth of bone marrow. CD19 affects BCR signals, therefore altering B cell development from early differentiation events in the bone marrow to later maturation stages in the spleen, even if its activities on bone marrow cells are not essential. By interacting with components of the pre-BCR, CD19 can modulate signal thresholds independent of the BCR, hence maybe influencing the transition from early pre-B to tiny resting pre-B cells in the bone marrow.

Advances in CD19 Targeting Immunotherapy

Beyond its basic biological roles, CD19 is becoming a major target for immunotherapy, especially for hematological malignancies. For many B cell malignancies, recent advances in therapeutic methods aiming at CD19 have fundamentally changed therapy modalities. For Obexelimab, a new medication aiming at treating adult relapse multiple sclerosis, Zenas, for instance, got implicit clinical trial permission from China's National Medical Products Administration (NMPA) on September 9, 2024. This marks a major turning point in extending the therapeutic uses of CD19 beyond conventional hematological malignancies.

Merck said on August 9, 2024, that it had paid $1.3 billion to acquire the CD3×CD19 bispecific antibody pipeline CN 201 from Tongrun Biotechnology, therefore demonstrating a significant commitment to creative antibody-based treatments. The growing curiosity for bispecific antibodies emphasizes how flexible and therapeutically powerful CD19-targeted therapies are. Emphasizing the progress of CD19-targeted treatments, the NMPA earlier, on February 28, 2024, authorized AstraZeneca's CD19 bispecific antibody AZD0486 for treating relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).