6.1 B cell development in bone marrow
2 min read•july 25, 2024
B cell development in the bone marrow is a complex process that shapes our immune system. It starts with stem cells and ends with mature B cells ready to fight infections. Along the way, these cells undergo genetic changes and face several checkpoints to ensure they're functional and not harmful.
The bone marrow provides a nurturing environment for B cells to grow. Stromal cells and various proteins guide the developing B cells through each stage. The process involves rearranging genes to create unique antibodies, while also making sure these antibodies won't attack our own body.
B Cell Development in Bone Marrow
Stages of B cell development
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- Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood cell types including lymphocytes
- Common lymphoid progenitor (CLP) commits to lymphoid lineage producing B and T cells
- initiates immunoglobulin gene rearrangement starting with heavy chain D-J joining
- expresses pre-B cell receptor triggering proliferation and light chain rearrangement
- displays complete on surface undergoes for self-reactivity
- co-expresses IgM and ready to exit bone marrow and enter circulation
Role of stromal cells and cytokines
- Stromal cells create supportive microenvironment secreting growth factors and
- CXCL12 (SDF-1) guides B cell precursors to bone marrow niches
- Stem cell factor (SCF) promotes early progenitor survival and division
- Interleukin-7 (IL-7) crucial for pro-B and pre-B cell survival and proliferation
- Flt3 ligand supports early B cell development by activating Flt3 receptor
- BAFF and APRIL promote survival of immature and transitional B cells in bone marrow and periphery
V(D)J recombination process
- D-J joining occurs in heavy chain locus during pro-B cell stage
- V-DJ joining follows in heavy chain during pre-B cell stage
- V-J joining happens in light chain locus at immature B cell stage
- RAG1 and RAG2 enzymes create double-strand breaks at specific recombination signal sequences (RSS)
- Non-homologous end joining (NHEJ) repairs breaks adding nucleotides for junctional diversity
- Process generates vast array of unique B cell receptors (BCRs)
Checkpoints for functional B cells
- Pre-BCR checkpoint tests successful heavy chain rearrangement triggers light chain rearrangement
- Central tolerance checkpoint eliminates or edits self-reactive immature B cells (clonal deletion, receptor editing, anergy)
- ensures BCR can recognize self-MHC molecules for antigen presentation
- Transitional B cell checkpoint further screens against autoreactivity in periphery
- Receptor editing allows rearrangement of alternative light chains to rescue potentially autoreactive B cells
- Allelic exclusion ensures expression of single BCR specificity per cell maintaining clonal selection principle
Key Terms to Review (21)
Antibody production: Antibody production is the process by which B cells, a type of white blood cell, create antibodies in response to antigens, which are foreign substances like pathogens. This process is crucial for the adaptive immune response, allowing the body to recognize and neutralize specific threats. Understanding how antibody production occurs involves knowledge about where B cells develop, their maturation processes, and how vaccinations can stimulate this production to enhance immunity against diseases.
B-cell receptor (BCR): The B-cell receptor (BCR) is a membrane-bound immunoglobulin that serves as the primary antigen receptor on B cells. It plays a crucial role in the activation and differentiation of B cells upon binding to specific antigens, leading to antibody production and an adaptive immune response. The BCR also consists of associated signaling proteins that transmit activation signals into the cell, ensuring a robust immune response against pathogens.
Bone marrow microenvironment: The bone marrow microenvironment refers to the specialized niche within the bone marrow that supports the development and differentiation of hematopoietic stem cells into various blood cell lineages, including B cells. This microenvironment is composed of a complex network of extracellular matrix components, stromal cells, and signaling molecules that interact with developing B cells, guiding their maturation and functional capabilities.
Cd19: CD19 is a pan-B-cell marker that plays a crucial role in B cell development, activation, and differentiation. It is primarily expressed on B cells from the early stages of development in the bone marrow through to mature B cells. CD19 acts as a co-receptor that enhances the signaling capabilities of the B cell receptor (BCR), facilitating effective immune responses.
Cytokines: Cytokines are small signaling proteins that are crucial for cell communication in the immune system. They play an essential role in mediating and regulating immunity, inflammation, and hematopoiesis, linking innate and adaptive immune responses.
E2a: e2a (E2A transcription factor) is a basic helix-loop-helix (bHLH) protein that plays a crucial role in the early development of B cells in the bone marrow. It is essential for the transition from pro-B cells to pre-B cells, facilitating the rearrangement of immunoglobulin genes, which is vital for the production of functional antibodies.
Germinal Centers: Germinal centers are specialized structures within secondary lymphoid organs, like lymph nodes and spleen, where B cells undergo proliferation, selection, and differentiation in response to antigen stimulation. They play a critical role in the adaptive immune response by facilitating the processes of B cell activation, affinity maturation, and antibody class switching, ensuring the generation of high-affinity antibodies tailored to effectively combat pathogens.
Humoral Immunity: Humoral immunity is a vital component of the immune system that involves the production of antibodies by B cells to identify and neutralize pathogens like bacteria and viruses. This type of immunity is crucial for recognizing foreign antigens and facilitating their elimination through various mechanisms, connecting deeply with other immune functions such as T cell activation and the development of vaccines.
IgD: IgD is a class of immunoglobulin that plays a crucial role in the immune system, primarily found on the surface of immature B cells and involved in their activation. While its exact function remains less understood than other antibody classes, it is believed to be important for B cell receptor signaling and may play a role in respiratory immune defense. Understanding IgD helps clarify the development and diversity of antibodies and how B cells mature and undergo class switching.
IgM: IgM, or Immunoglobulin M, is the largest antibody isotype in terms of size and is the first antibody produced during an immune response. It plays a critical role in the early stages of immunity, particularly in responding to pathogens before the body has fully developed a specific immune response, making it key in both antibody diversity and class switching.
Immature b cell: An immature B cell is a precursor stage in B cell development, occurring in the bone marrow, characterized by the expression of surface immunoglobulin (IgM) and the absence of fully functional receptors for antigens. This stage is crucial for ensuring that B cells have the proper receptors to recognize a diverse range of pathogens while undergoing a selection process to eliminate self-reactive cells.
Mature B cell: A mature B cell is a fully developed B lymphocyte that has successfully undergone the processes of maturation in the bone marrow and is now capable of producing specific antibodies. These cells play a crucial role in the adaptive immune response, as they are responsible for recognizing antigens and generating immune responses tailored to those specific threats.
Memory B cells: Memory B cells are long-lived immune cells that arise after an initial infection or vaccination, enabling a faster and stronger antibody response upon re-exposure to the same pathogen. These specialized cells are crucial for adaptive immunity, as they provide lasting protection and immunological memory.
Negative Selection: Negative selection is a critical process in the immune system where developing immune cells that strongly recognize self-antigens are eliminated to prevent autoimmunity. This mechanism ensures that only those cells with the appropriate affinity for foreign antigens and tolerance to self-antigens survive, maintaining the body's immune balance and preventing harmful responses.
Pax5: Pax5 is a transcription factor crucial for B cell development, primarily acting to regulate the expression of genes necessary for B cell lineage commitment and maturation. It is essential during various stages of B cell development in the bone marrow, influencing processes such as immunoglobulin gene rearrangement and maintaining B cell identity.
Plasma Cells: Plasma cells are specialized B cells that produce large quantities of antibodies, playing a crucial role in the immune response. They are formed from activated B cells following exposure to antigens, and their primary function is to secrete antibodies that target specific pathogens, helping to neutralize infections and promote clearance.
Positive Selection: Positive selection is a critical process during the development of immune cells, particularly T cells and B cells, where cells that successfully recognize self-MHC (Major Histocompatibility Complex) molecules are allowed to survive and mature, while those that do not are eliminated. This ensures that only immune cells capable of recognizing foreign antigens presented by MHC molecules remain functional, thereby contributing to effective immune responses.
Pre-B cell: A pre-B cell is an early stage in B cell development characterized by the successful rearrangement of immunoglobulin heavy chain genes and the expression of a pre-B cell receptor on its surface. This stage is crucial as it marks the transition from pro-B cells to immature B cells, allowing for further maturation and selection processes in the bone marrow.
Pro-b cell: A pro-b cell is an early stage of B cell development in the bone marrow, characterized by the rearrangement of immunoglobulin heavy chain genes. This stage marks a critical transition in B cell maturation, where the cell prepares to produce functional antibodies and undergoes selection processes to ensure proper immune response capability.
Stromal cell interactions: Stromal cell interactions refer to the essential communication and functional relationships between immune cells and the non-hematopoietic cells in the bone marrow microenvironment. These interactions are critical for the proper development and maturation of B cells, as they provide necessary signals, support, and a niche for these cells during their growth and differentiation processes.
V(d)j recombination: v(d)j recombination is a crucial process in the immune system that generates diverse receptors for B cells and T cells by rearranging gene segments known as variable (V), diversity (D), and joining (J) segments. This process occurs primarily in the primary lymphoid organs, enabling the generation of a vast array of antibodies and T cell receptors that can recognize various antigens, which is essential for effective immune responses.