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What is the main characteristic difference between T-independent and T-dependent antigens?
What is the main characteristic difference between T-independent and T-dependent antigens?
What is the role of memory B cells in the humoral immune response?
What is the role of memory B cells in the humoral immune response?
What mechanism allows for isotype switching in B cells?
What mechanism allows for isotype switching in B cells?
Which cytokine is primarily involved in promoting the differentiation of B cells into plasma cells during the initial response?
Which cytokine is primarily involved in promoting the differentiation of B cells into plasma cells during the initial response?
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What distinguishes the secondary immune response from the primary immune response?
What distinguishes the secondary immune response from the primary immune response?
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What is necessary for B cell activation in the presence of T-dependent antigens?
What is necessary for B cell activation in the presence of T-dependent antigens?
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Why do plasma cells generated during the immune response have a limited lifespan?
Why do plasma cells generated during the immune response have a limited lifespan?
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What is the primary characteristic of T-independent antigens in terms of B cell activation?
What is the primary characteristic of T-independent antigens in terms of B cell activation?
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Which of the following statements accurately describes T-dependent antigens?
Which of the following statements accurately describes T-dependent antigens?
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What distinguishes long-lived plasma cells from other B cells after activation?
What distinguishes long-lived plasma cells from other B cells after activation?
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Isotype switching allows B cells to change from producing which of the following antibodies?
Isotype switching allows B cells to change from producing which of the following antibodies?
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During the primary immune response, which is true of the initial B cell activation?
During the primary immune response, which is true of the initial B cell activation?
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What is the outcome of affinity maturation during the immune response?
What is the outcome of affinity maturation during the immune response?
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Where do T-dependent B cell activations occur primarily?
Where do T-dependent B cell activations occur primarily?
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What is a characteristic of marginal zone B cells?
What is a characteristic of marginal zone B cells?
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Which of the following best describes the antibody response observed in a secondary immune response?
Which of the following best describes the antibody response observed in a secondary immune response?
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What is the primary outcome of T-dependent B cell activation?
What is the primary outcome of T-dependent B cell activation?
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In the germinal centers, which process is critical for the formation of high-affinity antibodies?
In the germinal centers, which process is critical for the formation of high-affinity antibodies?
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Which of the following statements regarding memory B cells is correct?
Which of the following statements regarding memory B cells is correct?
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What defines isotype switching in B cells during a T-dependent immune response?
What defines isotype switching in B cells during a T-dependent immune response?
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What is the role of follicular dendritic cells in the germinal center?
What is the role of follicular dendritic cells in the germinal center?
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How do T-independent antigens primarily differ from T-dependent antigens in B cell activation?
How do T-independent antigens primarily differ from T-dependent antigens in B cell activation?
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What is a key trigger for isotype switching in B cells?
What is a key trigger for isotype switching in B cells?
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What occurs during the primary immune response in comparison to the secondary immune response?
What occurs during the primary immune response in comparison to the secondary immune response?
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What is the role of activation-induced deaminase (AID) in B cell activation?
What is the role of activation-induced deaminase (AID) in B cell activation?
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Study Notes
Humoral Immunity
- Humoral immunity is a branch of the adaptive immune system
- Involves antibodies produced by B cells
- Antibodies circulate in bodily fluids like blood and lymph, targeting and neutralizing pathogens.
B Cell Recap
- B cells develop in bone marrow (also in birds, rabbits, and pigs)
- Three stages of development:
- Maturation: Immunocompetent B cells develop in bone marrow
- Activation: Contact with antigen triggers activation
- Differentiation: B cells differentiate into plasma cells (for antibody production) and memory B cells
- Sites of Development: Bone marrow, Bursa of Fabricus (birds), Peyer's Patches (other mammals).
- B cells activated by external antigens in lymph node and by blood-borne antigens in the spleen.
- Plasma cells secrete immunoglobulins specific to antigens.
B Cell Receptors
- B cells have 200,000-500,000 identical BCRs per cell
- BCRs are composed of two heavy chains and two light chains
- BCRs include soluble forms (antibodies), antibodies bind to specific antigens
- BCRs include Ig-a and Ig-b (CD79a & CD79b) glycoprotein heterodimers that help transduce activation signals.
- Longer tails called ITAMs (immunoreceptor tyrosine-based activation motifs) extend into the cell to signal.
B Cell Activation
- Driven by the presence of antigen (multivalent antigen - repeated epitopes)
- Naive B cells that don't encounter antigen die within a few weeks
- T-independent antigens can directly activate B cells without helper T cells (weak response).
- T-independent antigens include mitogenic antigens and cross-linking antigens
- T-dependent antigens require helper T-cell activation for a stronger response.
- A short-lived plasma cell response, no memory.
- The B cells that act independently are called Marginal Zone B cells (secondary lymphoid organs) or B-1 cells (mucosal tissues & peritoneal cavity)
B Cell Activation (T-Cell Dependent)
- Has helper T-cell support (occurs in secondary lymphoid organs)
- One activated B cell can activate up to 5000 antibody-secreting cells.
- Each antibody-secreting cell can produce 2000 antibodies per second.
- Isotype switching: Changes from IgM to more durable, high-affinity IgG, IgA, or IgE
- Affinity maturation: B cells producing high-affinity antibodies dominate the response
- Long-lived plasma cells & memory B cells. Mediated by Follicular B cells (B-2 cells)
Humoral Response (Primary)
- Characterized by a lag phase caused by:
- Clonal selection: selecting the B-cell with the highest antigen specificity
- Clonal expansion: creating many identical B cells
- Differentiation: producing plasma and memory cells to produce antibodies
- Mostly IgM and IgG in primary reaction.
- Characterized by low antibody level and IgM dominance.
Humoral Response (Secondary)
- Memory B cells stimulated by subsequent antigen contact.
- Dependent on the existence of memory B and helper T cells
- Stronger, faster, and lasts longer
- Higher affinity antibodies; instant response.
- Higher levels of IgG than IgM.
Co-stimulation of B cells
- B cells require a two-factor signal to activate from helper T cells.
- Signal 1: helper TCR and MHC class 2 from B cell.
- Signal 2: CD40-CD40L induces B7 and CD28.
- Cytokines are released
Humoral Immunity (General)
- Antigen arrives in secondary lymphoid organ.
- B cell recognition of antigen triggers initial response.
- BCR binds to antigen initiating intracellular signaling
- B cells then present antigen in MHC class II molecules to helper T cells
- Helper T cells activate B-cells, further differentiating and proliferating to become plasma cells.
- Short-lived plasma cells produce antibodies immediately
- Activated B and T cells migrate into follicles forming germinal centers where differentiation continues.
- A germinal center is composed of the dark and light zones.
- Somatic mutation, isotype switching, and affinity maturation in the light zone
Germinal Centers
- Within follicles of secondary lymphoid tissues.
- Basal dark zone and light zone are present.
- Proliferating B cells in the dark zone.
- Follicular dendritic cells and follicular helper T cells in the light zone to cause somatic mutation, affinity maturation, and isotype switching.
- High affinity antibody-secreting cells and memory cells exit the germinal center
Isotype Switching
- Involve genetic alterations in the immunoglobulin heavy-chain loci
Affinity Maturation
- Occurs by somatic hypermutation through point mutations, deletions, and insertion of Ig genes.
- Selection of high-affinity B-cells to create better binders and neutralizers via high-affinity antibody production.
Clonal Selection
- B cells binding antigens in germinal centers survive.
- B cells with low affinity to foreign antigens are eliminated via clonal deletion.
Plasma Cell Differentiation
- Short-lived plasma cells result from T-independent responses during extra-follicular response.
- Long-lived plasma cells are generated by T-dependent responses in germinal centers. -These produce antibodies for decades after antigen removal.
Memory B Cells
- Generated during germinal center reaction, or in T-independent responses.
- Mostly during T-dependent responses.
- Make rapid response to subsequent antigen encounters
- Long-lived due to anti-apoptotic BCL-2.
- Remain in lymphoid organs, some circulate.
Antibodies (General)
- Antibody functions include neutralization, opsonization, ADCC, and complement activation.
Antibody Structure
- Composed of 4 polypeptide chains: 2 heavy chains and 2 light chains.
- Determined by isotypes (alpha, gamma, delta, epsilon, and mu), and subtypes that differ slightly.
- Connected by disulfide bonds and non-covalently hydrogen and hydrophobic bonds.
- Variable and constant regions.
- Fragment antigen-binding region (Fab) - antigen binding
- Fragment crystallizable region (Fc) - antibody interactions
Antibody Functions
- Neutralization, opsonization, ADCC (antibody-dependent cellular cytotoxicity), and complement activation.
Immunoglobulin Classes
- Each class has a unique amino acid sequence in the constant region of the heavy and light chains
- IgG, IgM, IgA, IgE, and IgD
IgM
- First immunoglobulin synthesized in newborns.
- Most effective complement activator.
- Structurally, its five subunits are joined by joining chains.
IgA
- Dominates in body secretions (milk, tears, mucus)
- Protects from pathogens that enter vulnerable mucosal portals.
IgE
- Small amounts in serum; allergic reactions, and parasite immunity.
IgD
- Found on the surface of B cells; not much biological function.
Anitgenic Determinants on Ig
- Isotypic: Species-specific constant regions of heavy and light chains
- Allotypic: Differences in amino acids within the same Ig class within a species
- Idiotypic: Differences in the variable regions; unique to individual antigens
Methods of Determining Antibody Structure
- Digested Ig with enzyme papain into Fab and Fc regions
- Cleaved above the disulfide bond.
- Digested Ig with enzyme Pepsin into an Fab complex, and a partial Fc, and cleaved below the disulfide bond.
Other notes:
- B and T cell differentiation, maturation, and activation occur in different areas of lymphoid organs (liver, spleen, lymph nodes).
- Some processes that occur in a T-dependent B cell activation include antibody secretion, isotype switching, affinity maturation, and memory cell formation.
- B cells require a two-factor signal for activation.
- Multiple factors act on B cells prior to their differentiation into plasma cells.
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