T-Independent B Cell Responses

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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?

Marginal B cells

B-2B cells

B-1B cells

Both A and C (correct)

What types of antibodies do B-1B and marginal zone B cells primarily produce?

Relatively low-affinity, primarily IgM antibodies. Signup and view all the answers

Negative signaling through CD22 is necessary to amplify BCR signaling.

False Signup and view all the answers

How does negative signaling through CD22 regulate B cell activation?

Phosphorylation of ITIMs on CD22 recruits SHP-1 tyrosine phosphatase, which dephosphorylates neighboring signaling complexes. Signup and view all the answers

B-2 B cells are T dependent and need a __________ for activation.

helper T cell Signup and view all the answers

What are the functions of B cells?

The function of a B cell is to give rise to plasma cells that secrete antibodies capable of binding to an organism or molecule that poses a threat to the host. Signup and view all the answers

What is the clonal selection hypothesis?

Immature B lymphocytes bear immunoglobulin receptors on their cell surfaces. On antigen stimulation, the B cell will mature and replicate. Signup and view all the answers

What are the two different types of B cell responses?

T-dependent (TD) response and T-independent (TI) response. Signup and view all the answers

How does the B cell bind antigen at the start of a T-dependent B-cell response?

The B cell binds antigen via its Ig receptors. Signup and view all the answers

What demonstrated the need for T cell help in generating an antibody response?

Adoptive transfer experiments. Signup and view all the answers

Where do naive B cells encounter antigens?

In the lymph nodes. Signup and view all the answers

What is the role of follicular dendritic cells (FDCs)?

FDCs serve as antigen concentration sites for future selection and differentiation. Signup and view all the answers

What happens when the BCR recognizes its cognate antigen?

The receptors on the B-cell membrane cluster and form an immunological synapse. Signup and view all the answers

How are B cells activated?

Antigen binding to the B-cell receptor activates a signal transduction cascade. Signup and view all the answers

Are all antigens processed the same way?

False Signup and view all the answers

What are the two different ways antigens are processed?

Through the exogenous pathway and the endogenous pathway. Signup and view all the answers

What occurs after BCR-mediated endocytosis?

Peptides are loaded onto MHC class II molecules and returned to the B-cell surface. Signup and view all the answers

How can a B cell find and bind to a T cell specific for the same antigen?

B cells are highly motile and respond to chemokine signals. Signup and view all the answers

What happens when the B cell enters the lymph node?

The B-cell chemokine receptor CXCR5 helps migrate B cells to the follicles. Signup and view all the answers

After stimulation, into what two things do primary B cells differentiate?

Plasma cells or germinal centers. Signup and view all the answers

What is affinity maturation?

It is a process that leads to the production of antibodies that bind the antigen with higher affinity. Signup and view all the answers

What do activated B cells initiate in addition to differentiating into plasma cells?

germinal center response Signup and view all the answers

What are the two zones in the germinal center?

Dark zone and light zone Signup and view all the answers

What are B cells in the dark zone referred to as?

centroblasts Signup and view all the answers

What is somatic hypermutation and where does it occur?

A process of rapid mutation in B cells that occurs in the dark zone. Signup and view all the answers

What is the role of follicular dendritic cells (FDCs) in germinal centers?

Provide survival signals to B cells. Signup and view all the answers

How do activated B cells transition within the germinal center?

They move from the dark zone to the light zone. Signup and view all the answers

What happens to B cells when they enter the dark zone?

They lose expression of MHC class II molecules. Signup and view all the answers

What is long-term humoral immunity?

The production of antigen-specific antibodies by long-lived plasma cells. Signup and view all the answers

What is class switch recombination (CSR)?

The process allowing B cells to switch from IgM to other antibody classes. Signup and view all the answers

What influence cytokines have on CSR?

They induce transcription over targeted switch regions. Signup and view all the answers

How does somatic hypermutation lead to increased antibody affinity?

Through the introduction of random mutations in the immunoglobulin genes. Signup and view all the answers

Why do memory B cells provide a rapid response to secondary infection?

They have lower activation thresholds and higher signaling molecules. Signup and view all the answers

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.