Chapter 6: The Development of B Lymphocytes

Chapter Contents

  • The development of B cells in the bone marrow

    • 6-1 B-cell development in the bone marrow proceeds through several stages

    • 6-2 B-cell development is stimulated by bone marrow stromal cells

    • 6-3 Rearrangement of the immunoglobulin heavy-chain genes occurs in pro-B cells

    • 6-4 The pre-B-cell receptor monitors the quality of immunoglobulin heavy chains

    • 6-5 Rearrangement of the light-chain loci occurs in pre-B cells

    • 6-6 B cells encounter two checkpoints during their development in the bone marrow

    • 6-7 A program of protein expression underlies the stages of B-cell development

    • 6-8 Many B-cell tumors have chromosomal translocations involving immunoglobulin genes

    • 6-9 B cells expressing the cell-surface protein CD5 have a distinctive repertoire of receptors

  • Selection and further development of the B-cell repertoire

    • 6-10 The immature B-cell population is purged of cells bearing self-reactive B-cell receptors

    • 6-11 The antigen receptors of autoreactive immature B cells can be modified by receptor editing

    • 6-12 Immature B cells that recognize monovalent self antigens are made nonresponsive

    • 6-13 Maturation and survival of B cells occurs in lymphoid follicles

    • 6-14 Encounter with antigen leads to the differentiation of activated B cells into plasma cells and memory B cells

    • 6-15 Different types of B-cell tumor reflect B cells at different stages of development

B Cell Circulation Facts

  • Tens of billions of B cells generated each day in the bone marrow; only 50% survive.

  • Bone marrow: primary lymphoid tissue.

  • Lymph nodes, spleen, and Peyer’s patches: secondary lymphoid tissue.

  • Development of a B cell requires a unique B Cell Receptor (BCR), which is an immunoglobulin (Ig) molecule (monomeric IgM and IgD).

The Development of B Cells in the Bone Marrow

6-1 B-cell Development in the Bone Marrow Proceeds Through Several Stages

  • Hematopoietic stem cell (HSC): expresses CD34.

  • Other progenitor cells: each has distinctive markers on the surface.

  • Pro-B cell: This stage marks the birth of a B cell.

  • CD: Cluster of differentiation; markers used to group immune cell types.

6-2 B-cell Development is Stimulated by Bone Marrow Stromal Cells

  • Stromal cells (non-lymphoid): Help the B cells differentiate.

    • Function through:

    • Using adhesion molecules that maintain contact.

    • Releasing growth factors (e.g., stem cell factor (SCF) and IL-7) to facilitate B cell development.

  • Eventually, the B cell exits the bone marrow as an immature naïve B cell, maturing in secondary lymphoid tissue.

6-3 Rearrangement of the Immunoglobulin Heavy-chain Genes Occurs in Pro-B Cells

  • Pro-B cells initiate immunoglobulin heavy chain rearrangements.

6-4 The Pre-B-cell Receptor Monitors Quality of Immunoglobulin Heavy Chains

  • Surrogate light chain (sLC): A placeholder for the heavy chain.

  • The combination of sLC and heavy chain forms the pre-B cell receptor (pre-BCR).

    • Low amounts of pre-BCR present on the cell surface; its assembly indicates B cell survival.

  • Allelic exclusion: Assembling of pre-BCR signals cessation of rearrangement of the other heavy chain (VpreB and λ5 form the sLC).

6-5 Rearrangement of the Light-chain Loci Occurs in Pre-B Cells

  • Rearrangement Mechanism: One rearrangement event required (VJ).

    • Several attempts often occur to create a properly assembled gene; multiple VJ pairings can be utilized.

    • With 4 light chain genes and multifactorial attempts, the success rate is approximately 85%.

  • Each large pre-B cell leads to around 100 small pre-B cells, each featuring a different light chain but sharing the same heavy chain.

6-6 B Cells Encounter Two Checkpoints During Development in the Bone Marrow

  1. Pre-B cell receptor.

  2. B cell receptor.

6-7 A Program of Protein Expression Underlies the Stages of B-cell Development

  • Growth factors and receptors are initially expressed.

  • RAG proteins: On-off expression occurs twice during development.

  • Igα and Igβ are consistently on until the B cell becomes a plasma cell, at which point expression ceases.

  • The Ig locus is compacted in all cells except B cells, allowing transcription of immunoglobulin genes.

6-8 Many B-cell Tumors Have Chromosomal Translocations Involving Immunoglobulin Genes

  • Cancers develop partially randomly due to genetic errata.

  • High recombination and mutation rates elevate the chances of errors, compounded by the natural ability to self-renew, leading to cancer.

  • Chromosome Translocation: An accidental fusion of different chromosomes.

    • Example: MYC proto-oncogene disruption leads to Burkitt’s lymphoma due to its role in the cell cycle regulation.

6-9 B cells Expressing Cell-surface Protein CD5 Have a Distinctive Repertoire of Receptors

  • B-1 Cells: An atypical B cell subset formed early in embryonic development.

    • Characterized by the presence of CD5 surface protein.

    • Antibody diversity is limited; receptors are semi-specific or polyspecific.

  • B-1 cells are produced in the embryonic bone marrow, ceasing in adults; however, they persist in lymphoid tissue and can self-renew.

Selection and Further Development of the B-cell Repertoire

6-10 Isolation of Self-Reactive B-cell Receptors

  • Goal: Eliminate self-reactive B cells.

  • Mechanism: B cells binding to self-antigen in bone marrow and periphery either die or remain inactive.

  • Self-antigens: Multivalent and present on stromal and hematopoietic stem cells in bone marrow; self-reactive B cells are retained and can modify their BCR.

  • Result: Only non-self-reactive immature B cells exit the bone marrow, fulfilling the negative selection aspect of development.

6-11 Receptor Editing in Autoreactive Immature B Cells

  • Receptor Editing Steps:

    1. Self-reactive B cells reduce IgM BCR levels while maintaining RAG protein expression.

    2. They undergo light-chain rearrangement to generate a new BCR, leading to two outcomes:

    • New BCR is not self-reactive → further development.

    • New BCR remains self-reactive → Rearrangement continues until attempts are exhausted.

    1. Clonal deletion occurs; self-reactive B cells are subjected to apoptosis and are cleared by macrophages.

  • Conclusion: Receptor editing aids self-tolerance in B cells.

6-12 Immature B Cells and Monovalent Self Antigens

  • Immature B cells may bind to monovalent and soluble self-antigens in the bone marrow, leading to an anergic state.

  • Anergic state characterized by: low receptor expression and cytoplasmic low levels.

  • Anergic cells have a brief lifespan (~5 days) post-entrance into periphery.

6-13 Maturation and Survival of B Cells in Lymphoid Follicles

  • B cells traverse blood, lymph vessels, and secondary lymphoid tissue.

  • Enter lymph nodes via a homing mechanism related to extravasation: through high endothelial venules (HEV). Stromal and dendritic cells secrete chemokines; naïve B cells bind through specific receptors.

  • B cells acquire maturity in primary lymphoid follicles, influenced by Follicular Dendritic Cells (FDCs) and BAFF (B-Cell Activating Factor).

  • Competition: Entry into primary follicles extends lifespan; most immature B cells fail to enter and perish—anergic B cells are trapped in T cell areas.

6-14 Activation and Differentiation Post-Antigen Encounter

  • When antigen binding occurs:

    • Antigen-specific B cells retain within the T cell area.

    • CD4 T cells assist in B cell activation, leading to:

      • Direct transformation to plasma cells (secreting IgM).

      • Plasma cells, being highly specialized, undergo extensive protein synthesis and secretion while losing MHC II and BCR expression.

    • Co-migration of corresponding T and B cell pairs forms primary follicles that evolve into secondary lymphoid structures featuring germinal centers, fostering affinity maturation and proliferation.

    • Germinal center B cells evolve into medullary cords, spleen, or bone marrow as plasma cells, secreting high-affinity antibodies; some become long-lived memory B cells capable of rapid response upon antigen recognition.

6-15 B-cell Tumors Correspond to Different Stages of Development

  • Various types of B-cell tumors exhibit properties reflecting their developmental stage:

    • Location within the body

    • Morphology of the cells

    • Surface receptor expressions

Summaries and Diagrams

Summary of B Cell Development Stages

  • Main stages include:

    • Stem cells (CD34)

    • Early Pro-B cell (D-J rearranging)

    • Late Pro-B cell (V-DJ rearranging)

    • Large Pre-B cell (producing μ heavy chain; proliferation)

    • Small Pre-B cell (V-J rearranging)

    • Immature B cell (expressing μ and kappa (к) or lambda (λ) light chains on cell surface)

Figures Referred:

  1. The development phases of B cells

  2. Heavy Chain Rearrangement Process

  3. The Checkpoints During Development

  4. Life Cycle of Immature B Cells

  5. B-Cell Receptor Changes

  6. Receptor Editing Process