Lecture 17 The Gastrointestinal System PT4 - Immune response Flashcards
Front: How are naïve B cells activated?
Back:
Naïve B cells express both IgM and IgD on their surface, acting as antigen receptors (BCR).
When an antigen binds to BCR, it triggers a signal transduction pathway via the associated signaling molecules Igα and Igβ.
The BCR complex is further activated in secondary lymphoid tissues (e.g., lymph nodes or spleen) when antigens are presented by follicular dendritic cells or other antigen-presenting cells.
Co-stimulatory signals from helper T cells (CD4⁺) are often required for full activation.
Antigen presentation and interaction with helper T cells promote B cell proliferation and differentiation into plasma cells and memory B cells.
Front: What are the steps in B cell activation by protein antigens?
Back:
Antigen Recognition: BCR binds to a native protein antigen, leading to receptor-mediated endocytosis.
Antigen Processing: The internalized antigen is processed and presented on MHC-II molecules.
T Cell Interaction: B cells present the processed antigen to cognate CD4⁺ T cells, activating them.
CD4⁺ T Cell Help: Activated T cells express CD40L and secrete cytokines, providing signals that promote B cell activation and differentiation.
B Cell Proliferation and Differentiation: B cells proliferate and differentiate into plasma cells (antibody secretion) or enter the germinal center for affinity maturation and isotype switching.
Front: Describe the germinal center reaction in B cell activation.
Back:
Formation: After B cell activation, some B cells migrate to germinal centers in lymph nodes or spleen.
Processes:
Somatic Hypermutation: BCR genes undergo mutations to increase the affinity of antibodies for the antigen.
Affinity Maturation: B cells with higher affinity receptors are selected for survival.
Isotype Switching: B cells switch from IgM/IgD to other isotypes (IgG, IgA, etc.), dictated by cytokines from helper T cells and CD40/CD40L interactions.
Outcome: Produces high-affinity memory B cells and long-lived plasma cells.
Front: What is isotype switching and how does it occur?
Back:
Definition: Isotype switching involves changing the constant region of the antibody (Fc region) without altering the antigen specificity.
Mechanism:
Triggered by CD40-CD40L interaction between B and T cells.
Cytokines (e.g., IL-4, TGF-β) determine the new isotype.
Activation-induced cytidine deaminase (AID) initiates recombination at switch (S) regions upstream of different constant genes, leading to a new antibody isotype.
Outcome: Enables different effector functions like IgG-mediated opsonization or IgA secretion in mucosal tissues.
Front: Explain the process of affinity maturation.
Back:
Occurs in: Germinal centers of secondary lymphoid organs.
Process:
B cells undergo somatic hypermutation in the variable regions of the BCR.
This creates a pool of B cells with varying affinities for the antigen.
B cells with higher affinity for the antigen are preferentially selected and survive.
Significance: Increases the quality of the antibody response, ensuring that the antibodies produced have a higher binding strength to the antigen.
Front: Compare T-dependent and T-independent antigens.
Back:
T-Dependent Antigens:
Require help from CD4⁺ T cells for B cell activation.
Lead to isotype switching, affinity maturation, and memory B cell formation.
Example: Protein antigens.
T-Independent Antigens:
Activate B cells without T cell help, usually through BCR cross-linking or PRR activation.
Mainly produce IgM with little or no class switching or memory.
Example: Polysaccharides, lipids.
Front: How do antibodies prevent infection and eradicate viruses?
Back:
Neutralization: Antibodies bind to pathogens/toxins, blocking their entry into host cells.
Opsonization: IgG antibodies enhance phagocytosis by tagging pathogens for macrophages and neutrophils.
Complement Activation: Antibodies (IgM, IgG) activate the complement system, leading to pathogen lysis.
Antibody-Dependent Cellular Cytotoxicity (ADCC): NK cells recognize antibody-coated target cells and induce apoptosis.
Front: What are the properties and effector functions of IgA and IgG?
Back:
IgA:
Found mainly in mucosal areas (gut, respiratory tract) and secretions (saliva, tears, breast milk).
Prevents pathogen adherence and invasion in mucosal tissues.
Exists as a dimer, facilitating mucosal transport.
IgG:
The most abundant antibody in circulation.
Performs opsonization, neutralization, and ADCC.
Can cross the placenta, providing passive immunity to the fetus.
Activates complement pathways.
IgG Subtypes: IgG1 (good for protein antigens), IgG3 (effective complement activator), etc.
Front: What happens during the germinal center reaction?
Back:
Germinal centers are specialized areas in lymphoid tissues where B cells undergo intense proliferation and differentiation.
Processes Involved:
Massive Proliferation: Expansion of activated B cells.
Isotype Switching: B cells switch from producing IgM/IgD to other isotypes (IgG, IgA, etc.).
Somatic Hypermutation (SHM): Mutations occur in the variable region of the antibody gene, leading to affinity maturation.
Affinity Maturation: B cells with higher affinity for the antigen are selected and differentiate into memory B cells or long-lived plasma cells.
Interactions:
B cells interact with CD4⁺ T follicular helper (Tfh) cells and specialized follicular dendritic cells (FDCs) which present antigen for affinity testing.
Front: Describe the process of class switch recombination in B cells.
Back:
Initiation: CD40-CD40L interaction between B cells and helper T cells induces expression of Activation-Induced Cytidine Deaminase (AID) enzyme in B cells.
AID Function: Creates nicks in the DNA at switch (S) regions upstream of constant region genes.
Recombination:
DNA between targeted switch regions is removed, bringing a new constant region gene (e.g., IgG, IgE) next to the V(D)J region, altering the antibody’s isotype.
This changes the Fc region and thus the antibody’s effector function, but the antigen specificity remains unchanged.
Outcome: Allows B cells to produce different classes of antibodies (e.g., IgG for complement activation or IgA for mucosal immunity).
Front: How do cytokines influence isotype switching?
Back:
Cytokines from helper T cells determine the new antibody isotype by guiding AID activity at specific switch regions.
Examples:
IFN-γ induces switching to IgG subclasses, effective in opsonization and complement activation.
IL-4 promotes switching to IgE, important in defense against helminths and allergic responses.
TGF-β and other cytokines promote switching to IgA, which is crucial for mucosal immunity.
CD40-CD40L Interaction: Required for initiating the switch, ensuring the appropriate antibody response based on the immune context.
Front: What is somatic hypermutation and where does it occur?
Back:
Definition: SHM introduces point mutations in the variable region of the immunoglobulin gene.
Location: Occurs in the dark zone of the germinal center, where B cells are rapidly dividing.
Function: SHM increases the diversity of BCRs, allowing for selection of B cells that produce antibodies with higher affinity for the antigen.
Selection: B cells with high-affinity receptors receive survival signals from Tfh cells and differentiate into long-lived plasma cells or memory B cells.
Front: What is the difference between T-dependent and T-independent antigens?
Back:
T-Dependent Antigens:
Require help from CD4⁺ T cells for B cell activation.
Results in robust B cell responses, including isotype switching, affinity maturation, and memory B cell formation.
Example: Protein antigens.
T-Independent Antigens:
Do not require T cell help.
Primarily produce low-affinity IgM responses with minimal memory formation.
Example: Polysaccharides and lipopolysaccharides.
Front: Explain affinity maturation in B cells.
Back:
Occurs in the germinal center through somatic hypermutation.
Introduces random mutations in the variable region of the antibody gene.
B cells with mutations that increase affinity for the antigen are selected for survival.
These high-affinity B cells differentiate into long-lived memory B cells or plasma cells, which secrete high-affinity antibodies.
Front: How do antibodies help in preventing and controlling infections?
Back:
Neutralization: Antibodies bind to pathogens, blocking their entry into cells or neutralizing toxins.
Opsonization: IgG antibodies coat pathogens, enhancing phagocytosis by macrophages and neutrophils.
Complement Activation: IgM and IgG antibodies activate the classical complement pathway, leading to pathogen lysis.
ADCC (Antibody-Dependent Cellular Cytotoxicity): Antibodies bind to infected cells and attract NK cells to induce cell death.
Front: What are the properties and main functions of IgA and IgG?
Back:
IgA:
Found in mucosal tissues (gut, respiratory tract), secretions (saliva, breast milk).
Prevents microbial adherence to epithelial surfaces.
Exists as a dimer and is transported across epithelial barriers.
IgG:
Most abundant in serum, with subclasses (IgG1-4) having diverse roles.
Effective in opsonization, neutralization, and complement activation.
Crosses the placenta to provide passive immunity to the fetus.
Involved in ADCC through interactions with Fcγ receptors on NK cells.
Front: Describe the initial steps of the germinal center reaction.
Back:
Antigen Encounter: Naïve B cells recognize antigens in the B cell follicles of secondary lymphoid organs.
Migration: Activated B cells migrate to the T cell zone (interfollicular region).
T Cell Help: B cells receive help from CD4⁺ T follicular helper (Tfh) cells via CD40L-CD40 interaction and cytokine signals.
==> Only after activation does the B cell enter the germinal center reaction.
1. SHM and Affinty Maturation
2. Isotype Switching: B cells undergo isotype switching, changing from IgM/IgD to other isotypes (IgG, IgA, etc.) depending on cytokine cues.
Proliferation: B cells proliferate in the outer B cell follicle, creating some early memory B cells and plasma cells with low-affinity receptors.
Front: What happens in the dark zone and light zone of the germinal center?
Back:
Dark Zone:
B cells proliferate rapidly and undergo somatic hypermutation (SHM).
SHM introduces mutations in the variable regions of the BCR to diversify antigen-binding capabilities.
Light Zone:
Contains FDCs presenting intact antigen and Tfh cells providing help.
B cells with high-affinity receptors for the antigen presented on FDCs are selected to survive and differentiate.
B cells presenting processed antigen to Tfh cells receive survival signals and undergo further selection.
Front: How does affinity maturation and selection occur in the germinal center?
Back:
Affinity Maturation: B cells in the dark zone undergo SHM, introducing random mutations in the variable region.
Selection in Light Zone:
B cells move to the light zone and compete for antigen on FDCs.
Those with high-affinity BCRs bind effectively and receive survival signals from Tfh cells.
Outcome: B cells with high-affinity receptors are selected to become long-lived plasma cells or memory B cells.
Front: What are the steps involved in isotype switching?
Back:
Initiation: Interaction between CD40 on B cells and CD40L on Tfh cells induces AID expression in B cells.
AID Activity: AID enzyme causes targeted DNA breaks at switch (S) regions preceding constant region genes (e.g., Cμ, Cγ, Cα).
Recombination:
DNA between selected switch regions is removed, bringing a new constant region next to the V(D)J segment.
Antigen specificity remains unchanged, but the antibody’s effector functions (e.g., IgG, IgA) are altered.
Outcome: B cells produce antibodies with new effector functions suited for different immune responses.
Front: How do plasma cells and memory B cells contribute to ongoing protection?
Back:
Plasma Cells:
Derived from activated B cells, they become long-lived, terminally differentiated cells that continuously produce high-affinity antibodies.
Reside in bone marrow or mucosal tissues and maintain antibody levels for extended periods.
Memory B Cells:
Do not secrete antibodies but have a membrane-bound BCR.
Circulate in the blood and reside in tissues, ready to respond rapidly upon re-exposure to the same antigen.
Can re-enter the germinal center reaction for further affinity maturation if needed.
Front: Compare memory B cells and plasma cells.
Back:
Memory B Cells:
Long-lived, express BCR on their surface.
Do not produce antibodies but rapidly proliferate upon antigen re-exposure.
Plasma Cells:
Secrete large quantities of antibodies.
Reside mainly in bone marrow, continuously producing antibodies for long-term immunity.
Common Origin: Both arise from activated B cells after germinal center reaction and provide long-lasting protection.
Front: What are T-independent antigens and how do they activate B cells?
Back:
Definition: Antigens that can activate B cells without T cell help.
Types: Polysaccharides, lipids, and nucleic acids.
Activation Mechanism: BCR cross-linking or activation of pattern recognition receptors (PRRs) on B cells.
Response:
Limited isotype switching (mainly IgM).
Little to no affinity maturation.
Short-lived plasma cells and limited memory B cell formation.
Role: Important in the immune response against encapsulated bacteria.
Front: How do T-dependent and T-independent antigens differ in terms of B cell activation?
Back:
T-Dependent Antigens:
Require CD4⁺ T cell help for B cell activation.
Lead to isotype switching, affinity maturation, and memory B cell formation.
T-Independent Antigens:
Directly activate B cells without T cell help.
Limited to producing IgM with little memory cell generation.
Response tends to be faster but less robust.
Front: What are the main processes affecting B cell development and function?
Back:
VDJ Recombination: Affects the variable region, generating diversity in antigen recognition.
Isotype Switching: Alters the constant region, changing antibody function without changing antigen specificity.
Somatic Hypermutation and Affinity Maturation: Affects the variable region, increasing affinity for specific antigens.
Plasma Cell Differentiation: Produces cells that continuously secrete antibodies.
Memory B Cell Formation: Generates long-lived cells that respond rapidly to antigen re-exposure.
Front: What are the main functions of antibodies in the immune response?
Back:
Neutralization: Antibodies bind to pathogens and toxins, preventing their interaction with host cells.
Opsonization: Antibodies coat microbes, enhancing their recognition and phagocytosis by macrophages and neutrophils.
Complement Activation: IgM and IgG activate the classical complement pathway, resulting in lysis of pathogens.
Antibody-Dependent Cellular Cytotoxicity (ADCC): NK cells recognize and kill antibody-coated target cells.
Interaction with Fc Receptors: Fc regions of antibodies bind to specific receptors on immune cells, dictating effector functions like phagocytosis and cytokine release.
Front: What are the different antibody isotypes and their main effector functions?
Back:
IgG:
Neutralization of microbes and toxins.
Opsonization for phagocytosis.
Activation of classical complement pathway.
ADCC via NK cells.
Transfer of maternal immunity across the placenta.
IgM:
Primary antibody response.
Potent activator of the classical complement pathway.
IgA:
Mucosal immunity: neutralizes pathogens at mucosal surfaces (e.g., respiratory and gastrointestinal tracts).
Secreted into breast milk to protect infants.
IgE:
Defense against helminths.
Mediates allergic reactions by binding to mast cells and basophils, causing degranulation.
Front: How does IgA provide protection at mucosal sites?
Back:
IgA is produced in mucosal-associated lymphoid tissues (e.g., Peyer’s patches) and secreted as a dimer with a joining (J) chain.
Actively transported across epithelial cells via the poly-Ig receptor and released into the lumen with the secretory component.
Neutralizes pathogens and toxins at mucosal surfaces, preventing entry and colonization.
Present in saliva, tears, and breast milk, contributing to local immunity and protecting infants.
Front: Describe the transport and secretion of IgA at mucosal sites.
Back:
IgA is synthesized as a dimer in plasma cells.
Binds to the poly-Ig receptor on the basolateral surface of epithelial cells.
Internalized into vesicles and transported across the epithelial cell.
Proteolytic cleavage of the receptor releases IgA into the lumen with a portion of the receptor called the secretory component, protecting IgA from degradation.
Front: How do antibodies assist in preventing and controlling viral infections?
Back:
IgA:
Neutralizes viruses at mucosal sites, blocking their entry and preventing infection.
IgG:
Neutralizes viruses in blood and tissues, preventing their spread.
Mediates ADCC: NK cells destroy infected cells coated with IgG.
Opsonization of virions enhances their clearance by phagocytes.
Front: What is antibody neutralization and how does it work?
Back:
Neutralization is the process by which antibodies bind to pathogens or toxins, preventing them from interacting with host cells.
Mechanism:
Antibodies block the entry of pathogens through epithelial barriers.
Bind to receptors on pathogens, inhibiting their ability to infect host cells.
Neutralize toxins by preventing them from binding to cellular receptors.
Key Isotypes: IgA (mucosal surfaces) and IgG (systemic circulation).
Importance in Vaccination: Neutralizing antibodies are often the goal of vaccine development, as they can prevent infection or toxin-mediated disease.
Front: How do IgA and IgG differ in their roles during viral infections?
Back:
IgA:
Primarily acts at mucosal surfaces (e.g., respiratory and gastrointestinal tracts) to prevent viral entry and colonization.
First line of defense against inhaled and ingested pathogens.
IgG:
Neutralizes viruses in blood and tissues, providing systemic protection.
Mediates ADCC and opsonization, enhancing the clearance of infected cells and virions.
Can cross the placenta, providing passive immunity to the fetus.
Front: How do antibodies mediate opsonization and promote phagocytosis?
Back:
Opsonization is the process by which antibodies coat the surface of a pathogen, making it more recognizable to phagocytic cells like macrophages and neutrophils.
Mechanism:
Fc regions of bound antibodies bind to Fc receptors on phagocytes, triggering engulfment of the pathogen.
Enhances the efficiency of phagocytosis, leading to quicker clearance of the pathogen.
IgG is the primary antibody involved in opsonization due to its high affinity for Fcγ receptors on phagocytic cells.
Front: What is ADCC and which cells are involved?
Back:
ADCC is a mechanism by which immune cells kill antibody-coated target cells.
Mechanism:
Antibodies (mainly IgG) bind to antigens on the surface of target cells.
Fc regions of the antibodies are recognized by Fcγ receptors on NK cells.
NK cells release cytotoxic granules, inducing apoptosis in the target cell.
Significance: ADCC is crucial in eliminating virally infected cells and tumor cells.
Front: How do antibodies activate the complement system?
Back:
Initiation: IgM and certain subclasses of IgG (e.g., IgG1, IgG3) bind to antigens on pathogen surfaces.
Complement Binding: C1q binds to the Fc region of these antibodies, initiating the classical complement pathway.
Results:
Formation of the membrane attack complex (MAC), leading to pathogen lysis.
Generation of opsonins (e.g., C3b) that enhance phagocytosis.
Production of inflammatory mediators (e.g., C5a) that recruit immune cells to the site of infection.
Front: What is the advantage of B cells requiring T cell help for activation?
Back:
Enhanced Specificity and Regulation: T cell help ensures that B cells are activated only when the immune system has verified the antigen’s presence, preventing inappropriate activation.
Memory Formation: T-dependent (TD) B cell activation leads to robust memory B cell and plasma cell formation.
Isotype Switching and Affinity Maturation: Interaction with T cells allows for isotype switching (e.g., from IgM to IgG) and somatic hypermutation, resulting in higher affinity antibodies and specialized effector functions.
Front: How do T-dependent and T-independent antigens influence vaccine design?
Back:
T-Dependent (TD) Antigen Vaccines:
Require the involvement of T cells, leading to the generation of high-affinity, long-lasting antibodies and immunological memory.
Example: Protein-based vaccines, such as those for diphtheria and tetanus.
T-Independent (TI) Antigen Vaccines:
Activate B cells without T cell help, usually inducing low-affinity IgM responses with limited memory formation.
Used for polysaccharide-based vaccines against bacteria like Streptococcus pneumoniae.
Conjugate Vaccines: Combine TI antigens with protein carriers to convert them into TD responses, enhancing efficacy and memory response.
Front: Why do we produce more IgA than any other type of antibody?
Back:
Mucosal Defense: IgA is specialized for protecting mucosal surfaces, which are the primary entry points for many pathogens.
Wide Distribution: Found in high concentrations in secretions like saliva, tears, breast milk, and mucus, providing a first line of defense.
Continuous Exposure: Mucosal surfaces are continuously exposed to external antigens, necessitating a high production of IgA to maintain local immunity.
Front: What is an advantage of ADCC in the immune response?
Back:
Targeted Destruction of Infected Cells: ADCC enables NK cells to recognize and kill infected or abnormal cells coated with antibodies, limiting the spread of infection.
No Need for Phagocytosis: ADCC allows for the destruction of larger target cells (e.g., virus-infected or cancer cells) that cannot be phagocytosed easily.
Cross-Talk Between Humoral and Cellular Immunity: ADCC bridges antibody-mediated recognition with cell-mediated killing, enhancing the efficiency of the immune response.
Front: Why are higher affinity antibodies generated during the secondary antibody response?
Back:
Affinity Maturation: Repeated exposure to the same antigen leads to additional rounds of somatic hypermutation and selection in the germinal center.
Selection for High Affinity B Cells: B cells with the highest affinity for the antigen are preferentially selected to proliferate and differentiate into plasma cells and memory B cells.
Improved Pathogen Neutralization: Higher affinity antibodies bind more effectively to the antigen, leading to more efficient pathogen neutralization and clearance.
What is an advantage of having
B cells needing T cell help?
Advantage of B cells needing T cell help: It enhances regulation, ensures B cell activation is appropriate, and facilitates processes like isotype switching and affinity maturation.
How will TD vs TI antigens
influence vaccine design?
T-dependent (TD) vs. T-independent (TI) Antigens in Vaccine Design: TD antigens generate long-lasting memory and high-affinity antibodies, making them ideal for vaccines. TI antigens usually require conjugation to proteins for better vaccine efficacy.
Why do you think we produce
more IgA that any other type of
antibody?
More IgA Production: IgA is the primary antibody at mucosal sites, which are major entry points for pathogens, necessitating high production levels.
What is an advantage of ADCC?
Advantage of ADCC: It enables targeted killing of antibody-coated cells without the need for phagocytosis, making it effective against large or intracellular pathogens.
Why are higher affinity
antibodies generated during the
secondary antibody response?
Higher Affinity Antibodies in Secondary Response: Repeated antigen exposure leads to additional rounds of affinity maturation, selecting B cells with higher affinity, resulting in more effective immune responses.
