B cells, or B lymphocytes, are essential components of the adaptive immune system, responsible for producing antibodies that neutralize pathogens. They arise from stem cells in the bone marrow and develop through a series of stages, resulting in various subtypes with distinct functions. These include short-lived plasmablasts that respond rapidly to infections, and long-lived memory B cells that provide immunity by “remembering” pathogens from past infections. In addition to antibody production, B cells play a key role as antigen-presenting cells (APCs), activating T cells to generate a robust immune response. Advances in understanding B cell biology have highlighted their significance in autoimmune diseases and led to the development of innovative B cell-targeted therapies.
B Cell Development and Maturation
The development of B cells begins with multipotent progenitor cells (MPPs) in the bone marrow. MPPs differentiate into the common lymphoid precursor (CLP), which leads to the B cell lineage. Throughout B cell development, specific signaling molecules and transcription factors (such as PU.1, E2A, and PAX5) are essential for guiding the progression from progenitor stages to fully developed B cells.
A critical step in B cell development is the generation of a functional B cell receptor (BCR). B cells undergo recombination of the immunoglobulin (Ig) gene segments, creating a diverse range of BCRs capable of recognizing unique antigens. Initially, recombination occurs in the heavy chain genes (D-J joining), followed by the assembly of the light chain genes. This process involves proteins like terminal deoxynucleotidyl transferase (TdT) and recombinase-activating genes 1 and 2 (RAG1/2), which promote the diversity of BCRs.
Following successful BCR assembly, B cells proceed through a sequence of developmental stages marked by the expression of IgM on the cell surface. Immature B cells then exit the bone marrow and enter the peripheral bloodstream as transitional B cells, where they undergo further maturation into either circulating or non-circulating B cell subsets.
Subtypes of Mature B Cells and Their Functional Roles
Upon reaching maturity, B cells differentiate into specialized subsets with distinct roles in the immune response:
Follicular (FO) B Cells: Predominantly located in lymph nodes, FO B cells are central to generating high-affinity antibody responses in germinal centers (GCs).
Marginal Zone (MZ) B Cells: Found mainly in the spleen, MZ B cells respond rapidly to blood-borne antigens and are crucial for initiating immune responses to encapsulated bacteria.
Memory B Cells: These cells “remember” previous infections and are capable of mounting a quick and robust response upon re-exposure to the same pathogen.
Plasma Cells: Derived from activated B cells, plasma cells secrete large amounts of antibodies into the bloodstream, conferring immediate immunity against pathogens.
B Cell Activation: T Cell-Dependent and Independent Pathways
B cells can be activated via two main pathways: T cell-dependent and T cell-independent, depending on the type of antigen encountered.
Therapeutic Targeting of B Cells in Disease
Due to their involvement in immune regulation, B cells are implicated in a range of autoimmune diseases and cancers. Aberrant B cell activity contributes to the pathogenesis of conditions like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Therapies that target specific B cell markers or pathways aim to mitigate these pathological immune responses.
Monoclonal antibodies targeting surface markers are among the most successful therapies for B cell-mediated diseases:
CD20: Rituximab, a chimeric anti-CD20 antibody, was the first B cell-targeting therapeutic. It depletes CD20-positive B cells, helping treat B cell lymphomas and autoimmune diseases. Variants of Rituximab, such as Ofatumumab and Ocrelizumab, are designed for more specific disease profiles.
CD19: Targeted by MEDI-551, an affinity-optimized monoclonal antibody, CD19 is expressed on plasmablasts and some plasma cells. MEDI-551 induces antibody-dependent cellular cytotoxicity (ADCC), efficiently depleting pathogenic B cells in lymphoid tissues.
CD22: Epratuzimab, a monoclonal antibody targeting CD22, triggers modest ADCC and can modulate B cell receptor signaling, offering an approach for autoimmune disease management.
Inhibiting B Cell Survival Factors
Targeting the B lymphocyte stimulator (BLyS) has proven effective in treating B cell diseases. BLyS promotes B cell survival, and its neutralization induces apoptosis in B cells. Belimumab, an anti-BLyS antibody, is approved for SLE treatment, while Atacicept, a TACI-Ig fusion protein, binds both BLyS and APRIL to inhibit B cell maturation.
Modulating B Cell-T Cell Interactions and Intracellular Functions
Therapies that disrupt B cell-T cell interactions are also being investigated. Monoclonal antibodies that block CD40L prevent T cell-mediated B cell activation, though early trials showed platelet aggregation risks. Modified formats, such as the CD40L Fab fragment CDP7657, minimize these risks and are under investigation for SLE treatment.
References:
Akkaya, M., Kwak, K., & Pierce, S. K. (2019). B cell memory: building two walls of protection against pathogens. Nature Reviews Immunology, 20(4), 229–238. https://doi.org/10.1038/s41577-019-0244-2
