CD19 - CD19 molecule |Elisa - Clia - Antibody - Protein

Background

CD19 is a transmembrane glycoprotein primarily expressed on B cells, a subset of white blood cells responsible for producing antibodies and mediating humoral immunity. CD19 plays a crucial role in B-cell development, activation, and differentiation, making it a critical marker and regulator in the immune response. It is part of the immunoglobulin superfamily and serves as a coreceptor for the B-cell receptor (BCR), amplifying BCR-mediated signaling, which is essential for proper immune function.

CD19 is expressed throughout most stages of B-cell development, from the pro-B cell stage in the bone marrow to mature B cells in peripheral tissues. This widespread expression makes it a reliable marker for identifying B cells in research and clinical settings, and it is often targeted in therapeutic strategies aimed at modulating B-cell function, such as in CAR-T cell therapy for treating B-cell malignancies.

Alterations in CD19 expression or function have been implicated in various clinical conditions, including autoimmune diseases and B-cell cancers such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Therefore, understanding the structure and function of CD19 is critical for comprehending its role in both normal immune processes and pathological conditions.

Protein Structure

The CD19 molecule is a 95 kDa transmembrane glycoprotein composed of 556 amino acids. As part of the immunoglobulin superfamily, CD19 has a distinct domain structure that contributes to its function as a B-cell coreceptor.

Extracellular Domain:

• The extracellular domain of CD19 contains two immunoglobulin-like (Ig-like) domains at the N-terminus. These domains are critical for interactions with other coreceptors, such as CD21 (complement receptor 2), CD81 (a tetraspanin protein), and CD225 (interferon-induced transmembrane protein 1). These interactions facilitate the assembly of the CD19 complex, which enhances BCR signaling.
• The extracellular portion is glycosylated, which stabilizes the protein and may be involved in mediating interactions with other surface molecules or ligands.

Transmembrane Domain:

• The transmembrane domain of CD19 anchors the protein in the cell membrane and is involved in interactions with other membrane proteins. It contributes to the formation of the CD19/CD21/CD81 complex, which acts to amplify BCR signals. The transmembrane region is hydrophobic and spans the plasma membrane.

Cytoplasmic Tail:

• The cytoplasmic tail of CD19 is critical for signal transduction. It contains multiple tyrosine residues, which become phosphorylated upon activation of the BCR. These phosphorylated tyrosine residues serve as docking sites for downstream signaling molecules, particularly phosphatidylinositol 3-kinase (PI3K) and Lyn, a Src-family kinase. This phosphorylation cascade is essential for amplifying the signaling initiated by antigen binding to the BCR.
• The cytoplasmic domain is where CD19 exerts its main functional role, modulating intracellular signaling pathways that regulate B-cell activation, proliferation, and survival.

Overall, CD19 functions as a signal-amplifying coreceptor, linking the BCR to intracellular signaling pathways that promote robust immune responses. This structure enables CD19 to regulate the threshold for B-cell activation and tune immune responses.

Classification and Subtypes

CD19 is classified as part of the immunoglobulin superfamily, which includes proteins involved in immune recognition and response. It functions as a coreceptor with the B-cell receptor (BCR) and is a member of the CD19/CD21/CD81 complex, which amplifies BCR signaling upon antigen engagement. CD19 does not have subtypes but is part of a broader signaling network on B cells that includes interactions with several other surface molecules, such as CD21 (complement receptor 2), CD81, and CD225.

In terms of developmental expression, CD19 is expressed on B cells from the early pro-B cell stage through the mature B-cell stage, and it remains present on memory B cells. Importantly, it is lost during B-cell differentiation into plasma cells, which are responsible for antibody production.

Function and Biological Significance

CD19 serves as a central regulator of B-cell activation and function. It acts as a coreceptor for the B-cell receptor (BCR), which recognizes specific antigens. Upon antigen binding to the BCR, CD19 is phosphorylated, enhancing the signaling cascade initiated by the antigen-receptor interaction. The amplification of BCR signaling by CD19 lowers the activation threshold, allowing B cells to respond more effectively to antigens.

Key functions of CD19 include:

B-cell Activation and Proliferation:

• CD19 amplifies signals from the BCR, ensuring that B cells can be activated by low levels of antigen. This enhanced sensitivity is critical for initiating immune responses, especially in secondary immune responses when memory B cells are activated.
• Through its association with signaling molecules like PI3K, CD19 promotes B-cell proliferation and differentiation, ensuring that the immune system can mount an effective response to pathogens.

Regulation of BCR Signaling:

• CD19, as part of the CD19/CD21/CD81 complex, interacts with complement-coated antigens via CD21, further enhancing the sensitivity of B cells to antigen recognition. This mechanism links the innate immune system (complement pathway) to adaptive immune responses.
• CD19 also helps regulate the balance between activating and inhibitory signals in B cells. By modulating the strength and duration of BCR signaling, CD19 ensures appropriate immune responses while preventing excessive activation that could lead to autoimmune disorders.

Role in B-cell Development:

• CD19 plays a role in early B-cell development by influencing precursor B-cell signaling and survival. The absence of CD19 disrupts normal B-cell maturation and can lead to immunodeficiencies.
• CD19 is also crucial for maintaining the germinal center reactions, where B cells undergo somatic hypermutation and class-switch recombination, processes essential for generating high-affinity antibodies.

Immune Memory:

• CD19 is expressed on memory B cells, which are responsible for rapid and robust antibody production upon re-exposure to previously encountered antigens. CD19 signaling in memory B cells helps maintain their long-term survival and readiness for secondary immune responses.

Clinical Issues

CD19 is associated with several clinical conditions, including B-cell malignancies, autoimmune diseases, and immunodeficiencies.

B-cell Malignancies:

• Overexpression or dysregulation of CD19 is a hallmark of many B-cell lymphomas and leukemias, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). The universal expression of CD19 on malignant B cells makes it an attractive target for therapies, including chimeric antigen receptor T-cell (CAR-T) therapy, which has shown remarkable success in treating B-cell cancers.
• CD19-targeted CAR-T therapy involves engineering patient T cells to express a receptor specific for CD19, enabling them to recognize and kill CD19-expressing malignant B cells. This therapy has revolutionized the treatment of relapsed or refractory B-cell malignancies, achieving high remission rates in many patients.

Autoimmune Diseases:

• CD19 dysregulation is implicated in autoimmune diseases, where B-cell hyperactivity leads to the production of autoantibodies. Elevated CD19 expression is observed in diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), suggesting a role in the pathogenesis of these conditions. Targeting CD19 in autoimmune diseases may help control aberrant B-cell activity and reduce autoantibody production.

Immunodeficiencies:

• Mutations or deletions in the CD19 gene can result in hypogammaglobulinemia or other immunodeficiencies characterized by impaired B-cell function and reduced antibody production. Such conditions make patients more susceptible to infections, as the immune system's ability to produce effective antibody responses is compromised.
• CD19-deficient patients often require immunoglobulin replacement therapy and other treatments to prevent recurrent infections.

Summary

CD19 is a vital molecule in the immune system, acting as a coreceptor for the B-cell receptor and amplifying signals necessary for B-cell activation, proliferation, and differentiation. Its expression on B cells from early development through to memory B cells makes it a key player in humoral immunity. CD19 is also a critical marker for B-cell malignancies and is the target of innovative therapies, such as CAR-T therapy, which has shown efficacy in treating refractory B-cell cancers.

Disruptions in CD19 function or expression are associated with various clinical conditions, including B-cell lymphomas, leukemias, autoimmune diseases, and immunodeficiencies. Its role in immune modulation and disease pathogenesis underscores its importance in both normal immune function and as a therapeutic target in disease settings. Understanding the structural and functional aspects of CD19 is essential for developing novel treatments for these conditions.