Questions and Answers
What are TI-1 antigens?
Typically bacterial cell-wall components that bind to innate immunity PRRs on B cells.
What are TI-2 antigens?
Polymeric protein antigens and capsular polysaccharides that crosslink many mIgM BCRs.
Which type of B cells are T-independent?
What types of antibodies do B-1B and marginal zone B cells primarily produce?
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Negative signaling through CD22 is necessary to amplify BCR signaling.
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How does negative signaling through CD22 regulate B cell activation?
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B-2 B cells are T dependent and need a __________ for activation.
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What are the functions of B cells?
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What is the clonal selection hypothesis?
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What are the two different types of B cell responses?
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How does the B cell bind antigen at the start of a T-dependent B-cell response?
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What demonstrated the need for T cell help in generating an antibody response?
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Where do naive B cells encounter antigens?
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What is the role of follicular dendritic cells (FDCs)?
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What happens when the BCR recognizes its cognate antigen?
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How are B cells activated?
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Are all antigens processed the same way?
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What are the two different ways antigens are processed?
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What occurs after BCR-mediated endocytosis?
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How can a B cell find and bind to a T cell specific for the same antigen?
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What happens when the B cell enters the lymph node?
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After stimulation, into what two things do primary B cells differentiate?
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What is affinity maturation?
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What do activated B cells initiate in addition to differentiating into plasma cells?
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What are the two zones in the germinal center?
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What are B cells in the dark zone referred to as?
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What is somatic hypermutation and where does it occur?
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What is the role of follicular dendritic cells (FDCs) in germinal centers?
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How do activated B cells transition within the germinal center?
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What happens to B cells when they enter the dark zone?
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What is long-term humoral immunity?
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What is class switch recombination (CSR)?
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What influence cytokines have on CSR?
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How does somatic hypermutation lead to increased antibody affinity?
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Why do memory B cells provide a rapid response to secondary infection?
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Study Notes
B-Cell Function
- B cells generate plasma cells that secrete antibodies, which neutralize pathogens like viruses and bacteria.
- Antibodies have identical antigen-binding sites to B-cell surface receptors.
- Activation of B cells necessitates assistance from T helper cells.
Clonal Selection Hypothesis
- Immature B lymphocytes possess immunoglobulin (Ig) receptors with identical specificity.
- On encountering an antigen, B cells mature and replicate in lymphoid organs, forming clones that produce the same antibodies.
- Post immune response, memory B cells remain for enhanced secondary responses.
- Self-reactive B cells are eliminated during development.
B-Cell Response Types
- T-dependent (TD) Response: Requires CD4+ helper T cells and is generated by protein antigens.
- T-independent (TI) Response: Elicited by multivalent or polymerized antigens without T-cell help, involving TI-1 and TI-2 antigens.
Initiation of T-Dependent B-Cell Response
- B cells bind antigens via Ig receptors, initiating internalization and processing through MHC class II molecules.
- T helper cells provide activation signals through CD40-CD40L interactions and cytokine release.
B-Cell Activation Evidence
- Adoptive transfer experiments in irradiated mice showed that both bone marrow and thymus-derived cells are needed for an antibody response.
Activation Site of B Cells
- Naïve B cells encounter antigens in lymph nodes and spleen, migrating to lymphoid follicles.
- B cells can be activated by antigens or recirculate when not stimulated.
Role of Follicular Dendritic Cells (FDCs)
- FDCs present antigen-antibody complexes to B cells, helping in selection and differentiation in germinal centers.
Antigen Recognition and BCR Clustering
- BCR engagement leads to receptor clustering and formation of an immunological synapse, crucial for activation.
B-Cell Activation Mechanism
- Antigen binding to BCR initiates a signal transduction cascade involving tyrosine phosphorylation and formation of a signalsome.
- Activation results in transcription of survival, proliferation, and differentiation factors, including the transition to antibody-secreting cells.
Antigen Processing Methods
- Two pathways: exogenous and endogenous; involve endocytosis and presentation via MHC class II molecules.
Chemokine Influence on B-Cell Migration
- B cells express chemokine receptors guiding their movement to lymph node areas with T cells and antigens.
Differentiation Outcomes of B Cells
- Activated B cells differentiate into either plasma cells or form germinal centers.
- Transcription factors such as IRF-4 and Bcl-6 determine the fate of B cells.
Affinity Maturation Process
- Initial antibody production begins with IgM, transitioning to higher-affinity IgG during antigen encounters.
- Localized foci form where affinity maturation occurs, leading to protective immunity.
Germinal Center Dynamics
- Germinal centers within follicles involve two zones:
- Dark Zone: Proliferating B cells (centroblasts).
- Light Zone: B cells and FDCs interact (centrocytes).
- B cells migrate between zones based on cytokine signaling and receptor modifications.### Germinal Centers and Somatic Hypermutation
- Germinal centers are initiated by rapid B cell division in response to antigen stimulation, growing to approximately 10,000 cells within days.
- Somatic hypermutation occurs in dark zones, leading to high mutation rates in B cell receptors, enhancing antibody affinity.
- In light zones, high-affinity mutated B cells interact with T follicular helper (TFH) cells and follicular dendritic cells (FDCs) for selection.
- Activated B cells can differentiate into IgM+ memory cells, plasma cells, or return to germinal centers for further mutations.
Maintenance and Selection in Germinal Centers
- B cells require survival signals from TFH cells and FDCs, which present antigens for extended periods.
- FDCs capture antigens through various mechanisms, aiding in continuous selection of high-affinity B cells.
- As B cells transition between dark and light zones, they continuously test their affinity for specific antigens.
Affinity Testing Mechanism
- In the dark zone, B cells lose MHC class II expression and must re-seek antigens when reentering the light zone.
- B cells with higher affinity receptors can bind to antigens more effectively, leading to B cell survival and T cell help.
Somatic Hypermutation Process
- Somatic hypermutation leads to random point mutations in rearranged immunoglobulin heavy and light chains.
- Activation-induced deaminase (AID) mediates the mutation by converting deoxycytidine into deoxyuridine, facilitating subsequent mutations.
AID Functionality
- AID introduces uridine-guanosine mismatches, repaired by multiple pathways, each potentially introducing mutations.
- Repair mechanisms can either correct the lesion or create mutations by substituting nucleotides adjacent to the mismatched base.
Targeting Mutational Hotspots
- Mutational hotspots are specific regions within antibody variable regions that AID frequently targets for mutations.
- The frequency of mutations is significantly higher in complementarity-determining regions (CDRs) compared to the rest of the antibodies.
Class Switching Recombination (CSR)
- CSR allows B cells to switch from producing IgM to other antibodies (e.g., IgG) through DNA recombination mechanisms.
- AID plays a key role in inducing double-strand breaks at switch regions, facilitating the recombination of antibody classes.
- CSR occurs in both germinal centers and primary foci, allowing quicker immune responses than somatic hypermutation.
Cytokine Role in Antibody Class Selection
- Cytokines influence which switch regions undergo recombination; different cytokines modify transcription factors that dictate switch region activity.
- B cells need additional costimulatory signals (e.g., from CD40) alongside cytokines to engage in CSR.
Long-term Humoral Immunity
- Long-lived plasma cells, established in niches like bone marrow, produce antibodies without further antigen resimulation, contributing to long-lasting immunity.
- Interaction between TFH cells and B cells initiates plasma cell differentiation around 10 days after antigen exposure.
B Cell Memory and Response to Infections
- Memory B cells respond swiftly to secondary infections due to reduced activation thresholds and enhanced signaling interaction molecules.
- Some memory B cells can proliferate with innate stimulus alone, unlike naïve B cells, which typically require T cell help.
Temporal Differences in Memory Responses
- High-affinity IgG memory cells respond early but are limited in extent, while IgM+ memory cells re-enter germinal centers for affinity maturation when antigen concentrations decline.
- IgM memory cells act as a fail-safe mechanism to maintain immune responses against lingering antigens.
T-Independent B Cell Responses
- T-independent responses generated by B-1 and marginal zone (MZ) B cells primarily yield low-affinity IgM antibodies.
- TI-1 antigens activate B cells through innate immune receptors, while TI-2 antigens require strong cross-linking of B cell receptors (BCRs) for activation.
T Dependent and T Independent B Cells
- B-1B cells and marginal zone B cells are categorized as T-independent, while B-2 B cells require T cell help for activation.
Regulation of B Cell Signaling
- Negative signaling through CD22 and FcγRIIb (CD32) ensures proper cessation of B cell activation following antigen clearance.
- SHP-1 phosphatase dephosphorylates signaling components, inhibiting unnecessary BCR signaling.
- Certain B cells, like CD5+ B cells, can secrete IL-10, acting as negative regulators to further modulate the immune response.
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Description
Explore the concepts of T-independent B cell responses and the role of TI-1 and TI-2 antigens in activating B cells without helper T cells. Understand the differences between T-independent and T-dependent activation mechanisms. Discover key examples and implications in immunology.