Immunology Chapter: B Cell Development

Lymphocyte Development

• Hematopoietic stem cells give rise to multipotent progenitor cells.
• Common lymphoid progenitor cells differentiate into lymphocytes.
• Stromal cells and cytokines orchestrate this process.

Humoral Immunity

• B cells primarily target extracellular microbes and their products.
• Activated B cells differentiate into antibody-secreting plasma cells.
• Antibodies neutralize microbes, opsonize for phagocytosis, and activate complement.
• Antibody-dependent cellular cytotoxicity (ADCC) involves other cells like NK cells.

B Cell Subsets

• B-1 cells mature in the fetal liver and can self-renew.
• Follicular (B-2) B cells mature in the bone marrow.
• B-1 cells produce natural antibodies.

B Cell Receptor and Antibody Structure

• Mature B cells display BCRs on their surface.
• BCRs are composed of four polypeptide chains (two identical heavy chains and two identical light chains).
• Disulfide bonds join the chains.
• Variable and constant regions are present in both heavy and light chains.
• A transmembrane region anchors the BCR to the cell surface.

B Cell Receptors and Antibody Structure(2)

• The BCR complex interacts with CD79 (Igα + Igβ).
• This complex is essential for signaling during antigen-induced B cell activation.
• The components (Igα and Igβ) are analogous to CD3 and ζ chains found on T cells.

B Cell Development

• B cell development occurs in bone marrow.
• Stromal cells direct B cell development.
• V, J, and (in some cases) D gene segments undergo random somatic recombination during development to form a functional BCR.

B Cell Development (2)

• Early pro-B cells start with D-J rearrangement.
• Late pro-B cells continue with V-D-J rearrangement.
• Large pre-B cells check for functional heavy chains and compatible surrogate light chains.
• The pre-BCR is essential for survival and proliferation of B cells that pass these checkpoints.

Allelic Exclusion

• B cells should ideally only express one type of BCR.
• Expression of multiple BCRs could compromise immune response by preventing high-affinity binding and hindering the T-independent B cell response.
• B cells use allelic exclusion to prevent expressing differing BCR versions on the same cell, generating homogeneous BCRs.

Clinical Application: XLA

• X-linked agammaglobulinemia (XLA) is characterized by lack of B cells and low serum antibody levels.
• Mutations in the BTK gene which is critical in signaling from the pre-B cell receptor, cause the disease.

B Cell Development Checkpoints

• Early pro-B cell checkpoint involves heavy-chain gene rearrangements on two chromosomes.
• Late pro-B cell checkpoint involves checking for functional heavy chains and rearrangements on two chromosomes.
• Large pre-B cell checkpoint involves checking for functionality of heavy chains using surrogate light chain components.
• All these procedures have a high rate of apoptosis as non-productive rearrangements or inappropriate receptor pairing leads to programmed cell death to maintain a healthy immune response.

Allelic Exclusion- (2)

• Allelic exclusion restricts B cell receptor expression to a single type.
• This prevents the production of antibodies that bind multiple antigens inappropriately and thus leads to higher affinity and effective immune responses.

B Cell Diversity (Combinatorial)

• Combinatorial diversity arises from different combinations of V, D, and J gene segments.
• This process involves different combinations of heavy chain and light chain genes.
• Diversity in the immune system is essential to have vast repertoire of antibodies and receptors that bind a huge variety of antigens.

Junctional Diversity

• The addition or deletion of nucleotides during recombination at the junctions of V(D)J segments contributes to junctional diversity (N-nucleotides, P-nucleotides).

B Cell Diversity (Junctional)

• Junctional diversity involves modifications to the DNA segments during splicing.
• This results in variation of nucleic acids at the joining points of the V(D)J segments.
• The final result is an enormous range of antibody variations ready to bind to distinct antigens.

Large Pre-B Cell

• A critical step in B cell development is ensuring functional heavy chains and compatibility with surrogate light chains.
• Failure at this stage results in apoptosis.
• Note the similarity between this process and T cell development.

Allelic Exclusion (3)

• B cells have mechanisms restricting expression of one type of BCR to ensure uniformity.
• This prevents competing signals that could hinder an effective immune response.
• The ability of B cells to appropriately recognize antigen and generate an antibody with high affinity is an important part of maintaining the overall immune response.

B Cell Maturation

• Approximately 2.5 billion B cells enter daily development processes.
• The maturation pathway has intense competition within the lymphoid tissue.
• Most immature B cells don't reach the follicle and exit the pathway.
• Mature B cells last for ~100 days.

B Cell Development Summary

• B cell maturation is a multistage process with specific markers.
• Initial expression of CD19 and CD20 (progenitor B cell).
• Heavy chain and Pre-BCR activation (precursor B cell).
• Activation of the membrane-bound B cell receptor (immature B cell).
• Checkpoint stage to eliminate B cells with self-reacting BCR.

B Cell Activation

• B cell maturation is antigen-independent.
• B cell activation involves a complex process with T-independent and T-dependent stages.
• B-2 (follicular) B cells respond to T-dependent antigens.
• B-1 B cells respond primarily to T-independent antigens.

Follicular B Cell Migration

• Follicular B cells migrate between blood and lymphoid tissues, seeking an antigen.
• These cells are attracted to follicles by chemokines from dendritic cells.

B Cell Activation Signaling 1

• B cells are initially activated when their BCRs bind to antigens.
• Receptor aggregation is a signal for activation-related proliferation.
• Signal 1 involves antigen binding to BCR followed by receptor crosslinking.

B Cell Activation Signal 2

• Activated B cells need a second signal (from helper T cells) for full activation and differentiation.
• This second signal involves interactions between BCR and CD19/CD21 receptor complexes

B-2 (Follicular) vs. B-1 B cells

• B-2 cells primarily respond to T-dependent antigens.
• B-1 cells react primarily to T-independent antigens.
• B-1 response is in mucosal tissues, and peritoneal cavity. B-2 is in the follicles of the lymph nodes and the spleen.
• B-1 cells produce antibodies quickly upon antigen exposure (like IgM), while B-2 cells differentiate and develop a more diverse repertoire.

B Cell Activation, Follicular B Cell Migration

• The process entails B cells' interaction with antigen, causing its migration to lymphoid tissue follicles.
• Follicular cells' attraction to the follicles is governed by B cell-specific chemokines produced by follicular dendritic cells (FDCs).
• If unactivated, B cells leave, guided by S1P gradient.

B Cell Activation: Antigen Presentation

• Follicular B cells function as antigen-presenting cells for T helper cells, activating an immune response.
• B cells present antigens to T helper cells (if they're not already activated by a dendritic cell).

B Cell Activation: Linked Recognition

• T cells involved in activation can respond to antigens the B cell processed.
• This process is a critical check to ensure tolerance of self-antigens.
• Helper T cells need to recognize the same antigen presented by B cells to activate immune response.

B Cell Activation: B-2 Follicular B cell Activation

• Follicular B cells are initially stimulated by antigen binding to the BCR.
• Receptor aggregation, induced by antigen binding and crosslinking is required for subsequent signaling to initiate proliferation in the B cell.

B Cell Differentiation- Ex. Germinal Center Reaction

• Activated B cells mature into plasma cells or memory cells depending on the specific differentiation pathway.
• A subset of follicular B cells rapidly differentiate into plasma cells which then produce antibodies located outside of follicles.
• Short-lived plasma cells generate low affinity IgM antibodies, and memory B cells are created for later immune responses.

B Cell Differentiation: Isotype Switching

• Isotype switching allows antibody switching to different classes of antibodies (like IgM to IgG).
• This is regulated via helper T cell interactions with B cells through cytokines influencing the class switch recombination.

B Cell Differentiation: Affinity Maturation

• Affinity maturation is an important mechanism that elevates antibody binding affinity.
• Mutations in the variable regions of the antibody (heavy and light chains) happen to give the highest binding affinity that is necessary for the antigen.

B Cell Differentiation: After Affinity Maturation

• Proliferating B cells undergo affinity maturation mutations after the first round of differentiation.
• This leads to the production of B cells with increased antigen binding affinity and subsequently the creation of memory B cells and plasma cells.
• The high-affinity B cells, along with memory cells are able to quickly respond if the antigen is encountered again.

B Cell Differentiation: After Affinity Maturation(2)

• Follicular B cells interact with follicular dendritic cells (FDCs) which present the specific antigen.
• Follicular B cells bind an antigen with the highest possible affinity with their BCR, which activates them and leads them through further differentiation/maturation.
• Follicular B cells with a low affinity will likely undergo apoptosis.

B Cell Differentiation: Exit from Lymphoid Tissue

• High-affinity follicular B cells exit the lymphoid tissue and differentiate into plasma cells (produce antibodies) or memory B cells (crucial in subsequent encounters).
• Some long-lived plasma cells migrate to the bone marrow, producing antibody against the specific antigen for months or even years.
• Circulating memory cells provide rapid response upon a second encounter with the same antigen.

B Cell Differentiation: Plasma Cells

• Plasma cells have a critical role in maintaining antibody production against antigens.
• Plasma cells are mostly committed to antibody synthesis and loss of other functions/pathways that aren't directly antibody production-related.

B Cell Differentiation: Memory B Cells

• Memory B cells are responsible for rapid responses upon re-encountering a pathogen.
• Memory B cells have significantly quicker response times, as they possess a high affinity BCR against the specific antigen.

B-1 B Cell Activation

• B-1 B cells play a crucial role in the rapid antibody response against T-independent antigens.
• These cells are present in mucosal tissues, like the peritoneal and pleural cavities where they are ready for immediate response against antigens.
• B-1 B cells act as a first line of defense, responding directly to antigens with a quick, IgM-mediated antibody response.

B-1 B Cell Activation (2)

• These B cells are key to rapid antibody production against simple antigens.
• The speed of response of B-1 cells helps fight pathogens in mucosal sites quickly and effectively.
• Multivalent antigen binding efficiently triggers B-1 activation.

Summary of B Cell Development

• B cells arise from hematopoietic stem cells in bone marrow.
• B cell development involves series of steps and check-points to ensure pathogen-specific immunity and self-tolerance.
• Development of memory cells allows for rapid secondary responses to the antigens.
• The pathway involves RAG rearrangements.
• Affinity maturation and class switching increase the complexity and effectiveness of the antibody response.

Test your understanding of the crucial steps in B cell development, from their primary functions to the roles of specific genes and proteins. This quiz covers key concepts related to B cell receptors, lymphocyte maturation, and associated genetic conditions such as X-linked agammaglobulinemia. Prepare to dive deep into the fundamental aspects of immunology!