Podcast
Questions and Answers
Within the context of antibody-mediated complement activation via the classical pathway, which of the following statements most accurately describes the mechanistic role of the C1 complex subsequent to initial antibody binding?
Within the context of antibody-mediated complement activation via the classical pathway, which of the following statements most accurately describes the mechanistic role of the C1 complex subsequent to initial antibody binding?
- The C1 complex undergoes a conformational change that activates its serine protease subunits (C1r and C1s), which then cleave C4 and C2, leading to the formation of the C3 convertase (C4b2a). (correct)
- The C1 complex recruits Factor B and Factor D to the target cell surface, facilitating the assembly of the alternative pathway C3 convertase (C3bBb).
- The C1 complex directly cleaves C3 convertase into C3a and C3b, thereby initiating the downstream cascade leading to the formation of the membrane attack complex (MAC).
- The C1 complex binds directly to the pathogen surface, independent of antibody involvement, initiating the alternative complement pathway.
Class-switch recombination is a reversible process, allowing B cells to switch back to producing IgM or IgD antibodies after producing IgG, IgA, or IgE.
Class-switch recombination is a reversible process, allowing B cells to switch back to producing IgM or IgD antibodies after producing IgG, IgA, or IgE.
False (B)
Describe the biophysical and immunological significance of the J chain in the context of IgM and IgA antibody structures.
Describe the biophysical and immunological significance of the J chain in the context of IgM and IgA antibody structures.
The J chain facilitates the polymerization of IgM into pentameric structures and IgA into dimeric structures. It enhances avidity and mucosal transport, respectively.
In the context of antibody-dependent cellular cytotoxicity (ADCC), the critical interaction that triggers degranulation of the effector cell and subsequent target cell lysis involves the binding of the antibody's Fc region to the __________ receptor found on cells such as NK cells.
In the context of antibody-dependent cellular cytotoxicity (ADCC), the critical interaction that triggers degranulation of the effector cell and subsequent target cell lysis involves the binding of the antibody's Fc region to the __________ receptor found on cells such as NK cells.
Match each antibody isotype with its primary effector function or characteristic:
Match each antibody isotype with its primary effector function or characteristic:
Consider a scenario where a novel viral pathogen elicits an antibody response. Which of the following mechanisms would MOST effectively prevent the virus from entering host cells?
Consider a scenario where a novel viral pathogen elicits an antibody response. Which of the following mechanisms would MOST effectively prevent the virus from entering host cells?
The primary mechanism by which IgA antibodies protect mucosal surfaces is through complement activation, leading to lysis of pathogens.
The primary mechanism by which IgA antibodies protect mucosal surfaces is through complement activation, leading to lysis of pathogens.
Explain the molecular basis and immunological consequences of somatic hypermutation (SHM) in the context of affinity maturation.
Explain the molecular basis and immunological consequences of somatic hypermutation (SHM) in the context of affinity maturation.
In the context of IgE-mediated allergic reactions, the cross-linking of IgE antibodies bound to the FcεRI receptor on __________ triggers the release of histamine and other inflammatory mediators.
In the context of IgE-mediated allergic reactions, the cross-linking of IgE antibodies bound to the FcεRI receptor on __________ triggers the release of histamine and other inflammatory mediators.
Match the following therapeutic antibody modifications with their intended effects:
Match the following therapeutic antibody modifications with their intended effects:
Which of the following scenarios would MOST directly result in the activation of the classical complement pathway?
Which of the following scenarios would MOST directly result in the activation of the classical complement pathway?
Vaccines primarily rely on the induction of long-lived plasma cells in the bone marrow to provide immediate protection against subsequent infections.
Vaccines primarily rely on the induction of long-lived plasma cells in the bone marrow to provide immediate protection against subsequent infections.
Describe the key differences in the kinetics and characteristics of the primary versus secondary antibody responses.
Describe the key differences in the kinetics and characteristics of the primary versus secondary antibody responses.
The polymeric immunoglobulin receptor (pIgR) is essential for the transport of __________ across mucosal epithelial cells into the lumen.
The polymeric immunoglobulin receptor (pIgR) is essential for the transport of __________ across mucosal epithelial cells into the lumen.
Match each antibody isotype with its relative concentration in serum:
Match each antibody isotype with its relative concentration in serum:
Which of the following statements BEST describes the role of Fc receptors in antibody effector functions?
Which of the following statements BEST describes the role of Fc receptors in antibody effector functions?
IgM antibodies are capable of crossing the placenta and providing passive immunity to the fetus.
IgM antibodies are capable of crossing the placenta and providing passive immunity to the fetus.
Discuss the role of antibody glycosylation in modulating Fc receptor binding and subsequent effector functions.
Discuss the role of antibody glycosylation in modulating Fc receptor binding and subsequent effector functions.
Antibodies neutralize toxins and pathogens by binding to them and preventing their interaction with host cell receptors; this process is termed __________.
Antibodies neutralize toxins and pathogens by binding to them and preventing their interaction with host cell receptors; this process is termed __________.
Match each effector function with the antibody isotype most associated with it:
Match each effector function with the antibody isotype most associated with it:
A patient with a genetic deficiency in AID (activation-induced cytidine deaminase) would MOST likely exhibit which of the following immunological defects?
A patient with a genetic deficiency in AID (activation-induced cytidine deaminase) would MOST likely exhibit which of the following immunological defects?
The process of opsonization enhances phagocytosis by directly activating the phagocyte to engulf the target, regardless of antibody involvement.
The process of opsonization enhances phagocytosis by directly activating the phagocyte to engulf the target, regardless of antibody involvement.
Explain the role of FcRn (neonatal Fc receptor) in regulating IgG levels and its implications for therapeutic antibody half-life.
Explain the role of FcRn (neonatal Fc receptor) in regulating IgG levels and its implications for therapeutic antibody half-life.
The rapid and heightened antibody response observed upon secondary exposure to an antigen is primarily attributed to the activation of __________ cells.
The rapid and heightened antibody response observed upon secondary exposure to an antigen is primarily attributed to the activation of __________ cells.
Which of the following mechanisms represents the MOST immediate effector function of antibodies upon encountering a circulating virus?
Which of the following mechanisms represents the MOST immediate effector function of antibodies upon encountering a circulating virus?
Flashcards
Neutralization (antibodies)
Neutralization (antibodies)
Antibodies binding to a virus to stop it from entering cells.
Opsonization
Opsonization
A process where antibodies coat a pathogen to promote phagocytosis.
Complement-Dependent Lysis (CDC)
Complement-Dependent Lysis (CDC)
Antibodies activate the complement system to lyse pathogens.
Antibody-Dependent Cellular Cytotoxicity (ADCC)
Antibody-Dependent Cellular Cytotoxicity (ADCC)
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Antibody-Dependent Phagocytosis (ADP)
Antibody-Dependent Phagocytosis (ADP)
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Class-Switch Recombination
Class-Switch Recombination
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IgM
IgM
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IgG
IgG
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IgA
IgA
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IgE
IgE
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Secondary Antibody Response
Secondary Antibody Response
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Memory B Cells
Memory B Cells
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Long-Lived Plasma Cells
Long-Lived Plasma Cells
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Virus Neutralization
Virus Neutralization
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Study Notes
- Antibodies recognize pathogens, then trigger effector functions.
- Effector functions include Neutralization, Complement-dependent lysis (CDC), Opsonisation and antibody-dependent cellular cytotoxicity (ADCC), and Opsonisation and antibody-dependent-phagocytosis (ADP).
Neutralization
- Antibodies bind to viruses, stopping viruses from entering cells.
- Neutralization typically occurs by binding to the part of the virus that binds to the host cell receptor.
- Antibodies can neutralize bacteria and their toxins.
- Neutralizing antibodies bind viruses and prevent them from entering cells.
- Vaccines provide protection through neutralizing antibodies.
- Examples of vaccine protection from neutralizing antibodies include Smallpox (1796), Yellow Fever (1933), Polio myelitis (1955, 1958), Combination MMR (1980), Hepatitis B Subunit (1980s), Hepatitis B Sag recombinant subunits (1990s), HPV vaccine for cervical cancer (2005), Rotavirus vaccine in Africa (2009), Ebola virus (2015), Dengue vaccine (2015), and SARS-CoV-2 vaccines (2020).
- Antibodies to HIV envelope proteins can block binding to human CD4.
- SARS-CoV2 antibodies to the spike protein can block binding to human ACE2.
Antibody-Mediated Complement Activation
- C1q binding sites are exposed once the antibody binds to the target.
- Classical complement pathway (C3 activation) is activated by the biding of antibodies.
- Eventually leads to the formation of C9 pore, killing target cell.
Antibody-Dependent Cellular Cytotoxicity
- Infected cells or tumors are targeted based on mAb therapy.
- Killing cell must carry the correct Fc receptor for the Ig subclass.
- IgG binds to FcyR, IgA binds to FcaR, and IgE binds to FceR.
Antibody-Dependent Phagocytosis
- Bacteria, viruses, and cells (tumors) are targeted.
- Macrophages or neutrophils perform phagocytosis via Fc receptors
Class-Switch Recombination
- Class-switch recombination allows antibodies to change format.
- All B cells initially produce IgM and IgD BCR.
- Class switch involves deleting the IgM/D CONSTANT region genes from the DNA and switching to IgG, IgA, or IgE.
Antibody Structure and Function
- The "scoop" of the ice cream represents the part of the antibody that recognizes the pathogen.
- The "cone" represents the constant region/FC, which determines the "effector" functions.
- Ig class-switching alters the BCR/antibody, mediated by AID and is irreversible.
- Different antibody constant regions lead to diverse functions and locations.
Antibody Classes
- There are different antibody constant regions.
- Diverse antibody structures equal diverse function/location.
- The main antibody types are IgG, IgM, IgA, IgE and IgD
IgM
- IgM is the first responder after infection occurs.
- Forms stable hexamers or pentamers held together with J "joining chain".
- IgM has low affinity but high avidity.
- Effectively activates complement.
IgG
- IgG provides specialized security.
- IgG has high affinity for antigen (post SHM).
- It is abundant and widely distributed, making up 75% of the antibodies in the blood.
- This antibody penetrates tissues and crosses the placenta.
- IgG is effective for neutralization.
- There are four subclasses: IgG1, IgG2, IgG3, and IgG4.
- These differ in activation of complement and binding to Fcy receptors, resulting in different effector functions.
- IgG1 and IgG3 are pro-inflammatory, while IgG4, not so much.
- Most therapeutic antibodies are IgG, which can be fine-tuned by Fc engineering.
IgA
- IgA is a local task force.
- Has High affinity for antigen post germinal centre and SHM.
- It can be a monomer or dimer joined by a J chain.
- IgA is dominant in mucosa tissues and effectively secreted to patrol mucosal surfaces.
- A J chain is needed for mucosal transport via the Polymeric Ig Receptor (pIgR).
- IgA neutralizes pathogenic bacteria while helping commensals in the gut.
- It triggers ADCC by cells expressing the Fca receptor.
IgE
- IgE is involved in triggering detox or allergic reactions.
- It protects from toxins in food, venoms, and large parasites, but also causes allergy.
- The amount of IgE in serum is very low, and it does not neutralize.
- IgE binds to Fcε receptor on mast cells and basophils.
- Cross-linking of IgE on mast cells by antigen leads to a rapid release of histamine, leading to coughing, sneezing, vomiting, and cleansing surfaces from toxins and parasites.
Antibody Preparation
- Antibody production by memory B cells and high affinity antibody occurs within 4-5 days.
- This is not the 2 weeks it takes in primary responses.
- This is why vaccines work.
- High affinity, switched isotypes, happen in secondary response
- Low affinity, mainly IgM, happen in primary response
Serological and Cellular Memory
- Primary infection induces B cell and serological memory.
- Naive B cells are part of the primary response, and memory B cells are part of the secondary response
Summary
- Antibodies directly neutralize pathogens; uses Fc portion to activate complement and attract killer cells and phagocytes.
- Class switch recombination diversifies antibody effector functions to match pathogens and location.
- Primary infection induces B cell and serological memory.
- The above is the basis of vaccine efficacy.
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