B Cell Ontogeny and Activation
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Questions and Answers

What is the primary function of the pre-BCR in B cell development?

  • Pre-BCR expression triggers the rearrangement of the light chain genes. (correct)
  • Pre-BCR signaling induces Btk activation, which promotes survival and proliferation of developing B cells. (correct)
  • The pre-BCR ensures that the heavy chain rearrangement is successful, leading to the formation of a complete BCR.
  • The pre-BCR binds to specific antigens, initiating an immune response.

What role does IL-7 play in B cell development?

  • IL-7 directly activates the pre-BCR, leading to B cell proliferation.
  • IL-7 is produced by bone marrow stromal cells and promotes survival of B cells during the early stages of development. (correct)
  • IL-7 is primarily involved in the negative selection of B cells in the spleen.
  • IL-7 induces the expression of RAG1 and RAG2, enzymes responsible for VDJ recombination.

What happens to a B cell that fails to successfully rearrange its heavy chain genes?

  • The B cell will enter a state of anergy, becoming unresponsive to antigens.
  • The B cell will continue to proliferate and differentiate into a mature B cell, but with a reduced capacity to produce antibodies.
  • The B cell will undergo apoptosis due to a loss of IL-7 signaling and insufficient survival signals. (correct)
  • The B cell will differentiate into a T cell instead, as heavy chain gene rearrangement is specific to B cells.

Which of the following is NOT a consequence of pre-BCR signaling?

<p>Binding of specific antigens to the pre-BCR receptor. (A)</p> Signup and view all the answers

What is the characteristic feature of an immature B cell?

<p>Expression of a fully assembled BCR containing both the heavy and light chains, IgM. (D)</p> Signup and view all the answers

Where do most immature B cells undergo negative selection?

<p>Spleen, in the T cell zone (PALS). (C)</p> Signup and view all the answers

What is the main function of Ig and Ig proteins expressed on immature B cells?

<p>They act as signal transducers, transmitting signals after antigen binding to the IgM. (A)</p> Signup and view all the answers

After successful light chain rearrangement, what does the developing B cell become known as?

<p>Immature B cell. (A)</p> Signup and view all the answers

What is X-linked Agammaglobulinemia (XLA) and how does it affect B cell development?

<p>XLA is a genetic defect in Btk, resulting in a deficiency of mature B cells and antibodies. (B)</p> Signup and view all the answers

What is the primary function of follicle-associated dendritic cells (FDC) in the spleen?

<p>FDCs provide BAFF, a cytokine that promotes survival and maturation of B cells. (A)</p> Signup and view all the answers

What is the fate of T1 transitional B cells that recognize self-antigens?

<p>They are eliminated through negative selection, preventing the development of autoimmune responses. (A)</p> Signup and view all the answers

What is the defining characteristic of a naive mature B cell?

<p>It has undergone successful heavy chain rearrangement, producing IgM. (A)</p> Signup and view all the answers

What happens to mature B cells in the spleen that do not interact with follicular dendritic cells (FDC)?

<p>They will undergo apoptosis and be eliminated. (A)</p> Signup and view all the answers

What is the main difference between marginal zone B cells and naive mature B cells?

<p>Marginal zone B cells are specialized for responding to blood-borne antigens. (C)</p> Signup and view all the answers

What is the primary function of Btk in B cell development?

<p>Btk promotes survival, proliferation, and maturation of B cells following pre-BCR signaling. (B)</p> Signup and view all the answers

Which of the following is NOT a characteristic of immature B cells? (Select all that apply)

<p>Exposure to self-antigens for negative selection. (A), Ability to produce antibodies. (B), Expression of the pre-BCR. (C)</p> Signup and view all the answers

Which of the following enzymes is NOT directly involved in the immunoglobulin gene rearrangements during B lymphocyte ontogeny?

<p>Caspase-3 (A)</p> Signup and view all the answers

What is the primary function of the checkpoint mechanisms during B cell ontogeny?

<p>Prevent the development of self-reactive B cells (C)</p> Signup and view all the answers

Which of the following molecules is NOT involved in the signaling pathway leading to clonal proliferation of B cells?

<p>IL-10 (C)</p> Signup and view all the answers

During B cell ontogeny, what is the main reason for the generation of immense diversity in immunoglobulin receptors?

<p>Random recombination of variable, diversity, and joining gene segments (C)</p> Signup and view all the answers

Which of the following stages of B cell development is characterized by the expression of both IgM and IgD on the cell surface?

<p>Mature B cell (D)</p> Signup and view all the answers

Which of the following statements accurately describes the role of follicular dendritic cells (FDC) in antigen (Ag) presentation?

<p>FDC capture, concentrate, and slowly release Ags, preserving them intact for long periods, and display these Ags to B cells. (B)</p> Signup and view all the answers

Which of the following is TRUE regarding the role of complement proteins in B cell activation?

<p>Complement fragments, such as iC3b and C3d, can bind to the B cell co-receptor (CR2) and enhance BCR signaling. (D)</p> Signup and view all the answers

What is the role of the B cell co-receptor, composed of CD21 (CR2), CD19, and CD81, in B cell activation?

<p>The co-receptor provides a second signal that amplifies BCR signaling, increasing the sensitivity to antigen. (D)</p> Signup and view all the answers

What is the significance of BCR crosslinking during B cell activation?

<p>Crosslinking of BCRs by multimeric antigens initiates a signal that activates the B cell. (D)</p> Signup and view all the answers

Which of the following is NOT a characteristic of B-1 B cells?

<p>B-1 B cells produce a diverse repertoire of antibodies, including IgM, IgG, and IgA. (D)</p> Signup and view all the answers

Which of these statements accurately describes the difference between follicular B cells (FOB) and marginal zone B cells (MZB)?

<p>FOB require T cell help for activation, while MZBs are T-independent. (C)</p> Signup and view all the answers

What is the primary role of Src kinases in the intracellular signaling pathways triggered by BCR engagement?

<p>Src kinases are responsible for phosphorylating ITAMs on the cytoplasmic tails of Igα and Igβ. (C)</p> Signup and view all the answers

Which of the following accurately describes the role of Syk in B cell signaling?

<p>Syk binds to phosphorylated ITAMs and activates downstream signaling pathways, similar to ZAP-70 in T cells. (B)</p> Signup and view all the answers

What is the significance of the extensive dendrite surface area of FDC?

<p>The dendrites facilitate the capture and display of a large number of Ags. (C)</p> Signup and view all the answers

Which of the following is a consequence of a deficiency in functional B cell co-receptor components, such as CD19 or CD81?

<p>Low levels of serum antibodies. (C)</p> Signup and view all the answers

Which of the following statements accurately describes the role of macrophages in the subcapsular sinus of lymph nodes in antigen presentation?

<p>Macrophages in the subcapsular sinus primarily release antigens for uptake by follicular dendritic cells (FDC). (B), Macrophages in the subcapsular sinus primarily capture and process large antigens. (D)</p> Signup and view all the answers

Which of the following statements BEST describes the role of BCR signaling in the activation of a B cell?

<p>BCR engagement triggers a signaling cascade that culminates in gene activation. (C)</p> Signup and view all the answers

Why is it important for FDC to express both CR1 and CR2 on their surface?

<p>CR1 and CR2 allow FDC to capture antigens from both the afferent lymphatics and from dendritic cells. (A)</p> Signup and view all the answers

What is the significance of the slow release of antigens by FDC?

<p>Slow release of antigens allows FDC to regulate the intensity of B cell activation. (B), Slow release of antigens allows FDC to maintain a steady supply of antigens for B cell activation. (C)</p> Signup and view all the answers

Which of these statements accurately describes the relationship between B cells and T cells in the development of a humoral immune response?

<p>T cells provide help to B cells for activation and differentiation into antibody-producing cells. (B)</p> Signup and view all the answers

Which of the following statements is CORRECT regarding the difference between T-dependent and T-independent antigen responses?

<p>T-dependent responses require the interaction of B cell with T cell help, while T-independent responses do not. (B)</p> Signup and view all the answers

Flashcards

B cell ontogeny

The development process of B lymphocytes from precursor cells in the bone marrow.

Immunoglobulin gene rearrangement

The process by which B cells modify their immunoglobulin genes to produce diverse antibodies.

Checkpoint mechanisms in B cells

Regulatory steps in B cell development ensuring functional and non-auto-reactive cells.

Clonal proliferation

The process in which selected B cells rapidly divide to produce many identical cells after activation.

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Differentiation of B cells

The process where activated B cells become plasma cells or memory B cells, tailored for immune response.

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B Cell Receptor (BCR)

A membrane-bound immunoglobulin on B cells that binds to antigens.

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Bone Marrow (BM) Stromal Cells

Supportive cells in the bone marrow that help retain B cell precursors.

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IL-7 Role

A cytokine produced by stromal cells that promotes B cell survival and differentiation.

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Apoptosis Blockade

Mechanisms that prevent programmed cell death to allow B cells to develop.

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Pro-B Cells

Early B cell precursors that undergo heavy chain gene rearrangement.

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Pre-B Cell

A B cell stage expressing the pre-BCR that drives cell proliferation.

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X-linked Agammaglobulinemia (XLA)

An immunodeficiency disease caused by mutant Btk, reducing mature B cell production.

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L Chain Rearrangement

The process where light chain genes are rearranged, crucial for BCR formation.

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Immature B Cell

B cell expressing IgM on its surface, still developing in the spleen.

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Negative Selection

A process where self-reactive B cells are eliminated to prevent autoimmune responses.

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Transitional B Cells

Intermediate B cells (T1 and T2) that mature in the spleen.

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Follicular DC (FDC)

Cells in the spleen aiding in the maturation of naïve B cells.

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Mature B Cells

Fully developed B cells ready to respond to antigens.

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Marginal Zone B Cells

B cells positioned in the marginal zone of the spleen, crucial for quick antigen response.

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BCR Gene Rearrangement

The genetic process that assembles the B cell receptor for antigen recognition.

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Antigen (Ag) Entry to LN

Small Ags enter lymph nodes (LN) via afferent lymphatic vessels; large Ags are captured by macrophages or dendritic cells.

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Follicular Dendritic Cells (FDC)

FDC capture, concentrate, and slowly release Ags for B cell recognition.

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BCR Activation

B cell receptor (BCR) engagement with an Ag epitope leads to B cell activation.

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Crosslinking in BCR

Multiple BCRs engaging multimeric Ags promote clustering and signaling for B cell activation.

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BCR Signaling Molecules

Igα and Igβ are signaling components of BCR that contain ITAMs for activating pathways.

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ITAM Phosphorylation

Src kinases phosphorylate ITAMs on Igα and Igβ, enabling B cell activation signaling.

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Co-receptor in B cell Activation

B cell co-receptor includes CR2, CD19, and CD81, enhancing BCR signaling upon Ag binding.

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CR2 Function

CR2 (CD21) recognizes iC3b and C3d fragments, aiding BCR signaling during Ag encounter.

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Role of Src Kinases

Src kinases enhance B cell signaling by phosphorylating proteins like CD19.

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B-1 B Cells

B-1 B cells arise early, produce only IgM, and do not require T cell help.

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B-2 B Cells

B-2 B cells develop in bone marrow; they need T cell help and produce various Ig isotypes.

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B cell Memory

Follicular B cells generate memory B cells, while B-1 B and marginal zone B cells have limited memory.

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B cell Isotype Switching

B-2 B cells can produce different Ig isotypes upon activation, allowing for diverse immune responses.

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Study Notes

B Cell Ontogeny and Activation

  • B cell development occurs on the surface of bone marrow stromal cells
  • SDF-1 (stromal cell-derived factor 1 or CXCL12) retains stem cells and lymphoid progenitors at the surface of bone marrow stromal cells
  • Cells receiving stimulatory signals are programmed for apoptosis
  • To continue through the process, a mechanism must block apoptosis
  • The process of lymphocyte development results in antigen receptor expression
  • B cell receptor (BCR) - displays light and heavy chains, Igα, Igβ, and ITAM signaling
  • T cell receptors (TCR) - displays CD3 subunits, αβ and ITAMS signaling
  • Immunoglobulin gene rearrangements are linked to B lymphocyte ontogeny
  • B cell ontogeny involves checkpoint mechanisms, enzymes, and molecules at each stage.
  • Clonal proliferation and differentiation processes are key aspects of B cell development.

Learning Objectives

  • Recognize how immunoglobulin gene rearrangements tie to B lymphocyte ontogeny.
  • Identify steps in B cell ontogeny, including checkpoint mechanisms, enzymes, and molecules at each stage.
  • Understand clonal proliferation and differentiation processes.

B Cell Receptor (BCR)

  • BCR recognition includes light and heavy chains, Igα, Igβ, and ITAM signaling components
  • These components are crucial to the function of the B cell.

B Cell Development

  • B cell development occurs on bone marrow stromal cells
  • Early pro-B, Late pro-B, Pre-B, Immature B, mature B
  • IL7 produced by BM stromal cells promotes survival signals
  • Failure to successfully rearrange H chains reduces IL-7 receptors and leads to cell death
  • Pre-BCR formation is vital for IL-7 signaling
  • Successful D-J and V-DJ, VDJ rearrangement
  • Pre-B cells express pre-BCR
  • Pre-BCR signaling drives proliferation of large pre-B cells
  • B cell receptors (BCR) engagement triggers signaling and B cell activation events.

B Cell Activation Outcomes

  • Outcome 1: Antigen binding and cross-linking of membrane Ig result in clonal expansion (proliferation) and anti-apoptotic factors.
  • Outcome 2: Increased antigen presentation (MHC I and II, B7).
  • Outcome 3: Increased production of cytokine receptors (IL-2R, IL-4R, IL-5R, IL-21R).
  • Outcome 4: Increased expression of CCR7 and decreased expression of CXCR5.

B Cell Co-receptor Signaling

  • B cell co-receptor components (CR2, CD19, CD81) are required for B cell activation
  • CR2 recognizes iC3b and C3d fragments of complement
  • CD19 and CD81 signal and aggregate to form B-cell co-receptor (BCR).
  • Src kinases (like Lyn) phosphorylate cytoplasmic tails of CD19
  • P-CD19 enhances signaling pathways associated with BCR crosslinking
  • Co-receptor activation boosts BCR signaling by 10,000 times
  • Deficiency in co-receptor components leads to reduced antibody production, inadequate isotype switching, and impaired responses to infections and vaccinations

FDC and Antigen Presentation

  • Follicular dendritic cells (FDCs) store and display intact antigens for extended periods.
  • Ags are captured by FDCs and preserved for months or years on the cell surface.
  • This process allows for continued B cell activation and maturation.

B-1 and B-2 B Cells

  • B-1 cells: Develop from fetal liver progenitors and reside in peritoneal and pleural cavities
  • Do not need T cell help
  • Produce primarily IgM antibody
  • Recognize carbohydrate epitopes
  • B-2 cells: Develop from bone marrow progenitors
  • Found in secondary lymphoid tissues (lymph nodes, spleen)
  • Produce different antibody isotypes (IgM, IgG, IgA, IgD, IgE)
    • Requires T cell help to produce isotypes beyond IgM
    • Respond to protein antigens
    • Undergo class switching for isotype diversity

Final outcomes after FOB BCR Recognition of Ags

  • Outcomes of FOB BCR recognition include clonal expansion (proliferation)
  • ↑ Antigen presentation (MHC I/II, B7)
  • ↑ Cytokine receptors (IL-2R, IL-4R, IL-5R, IL-21R).
  • ↑ Expression CCR7, ↓ Expression CXCR5.

B Cell Maturation

  • Immature B cells leave the bone marrow, traveling to the spleen and migrating into the T cell zone of the white pulp (PALS)
  • The immature B cells mature into T1 transitional B cells.
  • T1 transitional cells undergo negative selection
  • Those that survive become T2 transitional B-cells
  • T2 transitional B cells migrate into the follicle and interact with follicular dendritic cells (FDCs)
  • The interaction with FDCs completes the maturation process and transforms the T2 cells into naïve (mature) B cells.
  • Marginal zone B cells develop from T2 transitional B cells
  • Marginal zone B cells are critical for generating rapid IgM responses directed towards blood-borne antigens

X-linked Agammaglobulinemia (XLA)

  • XLA is an X-linked disease caused by a mutant version of BTK
  • Mutant BTK results in a lack of mature B cells
  • Patients are at high risk of infections, and lifelong immunoglobulin (Ig) replacement therapy is necessary for survival.

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Lec 13: B Cell Ontogeny and Activation (Medical Immunology COM5850) PDF

Description

Explore the intricate process of B cell development and activation. This quiz delves into the mechanisms involved, including immunoglobulin gene rearrangements and the regulatory checkpoints essential for successful B lymphocyte ontogeny. Test your knowledge on the key aspects of B cell biology.

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