Lecture 25: Humoral Immunity II: Antibody Effector Functions

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Questions and Answers

Which characteristic is most likely to make an antigen a strong immunogen?

  • Simple, repeating structure.
  • High degree of foreignness. (correct)
  • Small molecular weight.
  • Originating from the host.

What is the primary function of class switch recombination (CSR)?

  • To change the antibody isotype, thus altering its effector function. (correct)
  • To enable B cells to respond to a wider variety of antigens.
  • To accelerate the rate of antibody production.
  • To increase the affinity of the antibody for its antigen.

Which of the following is NOT a major mechanism of antibody effector function?

  • Antibody-dependent cell cytotoxicity (ADCC)
  • Neutralization
  • Opsonization
  • Antigen Internalization (correct)

Which antibody isotype is MOST associated with allergic responses?

<p>IgE (A)</p> Signup and view all the answers

What is a key characteristic of haptens?

<p>They are small molecules that become immunogenic when bound to a carrier protein. (D)</p> Signup and view all the answers

Which factor is LEAST likely to affect the immunogenicity of an antigen?

<p>The color of the antigen. (B)</p> Signup and view all the answers

What is the primary role of circulating antibodies?

<p>To recognize and bind antigens, marking them for destruction. (A)</p> Signup and view all the answers

Where does class switch recombination (CSR) occur?

<p>In germinal centers of secondary lymphoid organs. (A)</p> Signup and view all the answers

Which enzyme is essential for the process of class switch recombination (CSR)?

<p>Activation-induced cytidine deaminase (AID) (B)</p> Signup and view all the answers

Following activation by antigen, what is the immediate fate of IgM and IgD produced within a B cell?

<p>They are secreted as antibodies. (C)</p> Signup and view all the answers

Which statement accurately describes the function of the secretory component associated with IgA?

<p>It facilitates IgA's transport across epithelial cells and protects it from degradation. (D)</p> Signup and view all the answers

Which antibody isotype is transported across the placenta to provide passive immunity to the developing fetus?

<p>IgG (C)</p> Signup and view all the answers

What is the primary mechanism by which IgA protects mucosal surfaces?

<p>By neutralizing pathogens, preventing their attachment to host cells. (B)</p> Signup and view all the answers

How does IgM initiate the classical pathway of complement activation?

<p>By recruiting C1q to IgM molecules bound to antigen on a pathogen surface. (A)</p> Signup and view all the answers

An individual is bitten by a venomous snake. Which therapeutic approach would MOST directly employ neutralization?

<p>Injecting anti-venom antibodies that bind to the snake venom toxins. (C)</p> Signup and view all the answers

What is the role of Fc receptors in antibody-mediated effector functions?

<p>They enable immune cells to bind to antibodies coating target cells or antigens. (C)</p> Signup and view all the answers

What is the correct order of events in the classical pathway of complement activation, beginning with antibody binding?

<p>C1q binding → C1r activation → C1s cleavage → C4 and C2 activation (D)</p> Signup and view all the answers

Which of the following is true regarding the transport of IgG across the placenta?

<p>It involves the FcRn receptor and is enhanced at acidic pH within endosomes. (D)</p> Signup and view all the answers

Which process BEST describes how antibodies contribute to the neutralization of a virus?

<p>Antibodies bind to viral surface proteins, preventing the virus from entering host cells. (D)</p> Signup and view all the answers

In antibody-dependent cell cytotoxicity (ADCC), which cell type is MOST critical for mediating the killing of target cells?

<p>Natural killer (NK) cells (C)</p> Signup and view all the answers

An individual with a genetic defect has a complete absence of Fc&RI (Fc epsilon receptor I). Which immune function would be MOST impaired in this individual?

<p>Response to parasitic worm infections. (C)</p> Signup and view all the answers

Which characteristic distinguishes IgA1 from IgA2?

<p>IgA1 is more susceptible to cleavage by bacterial proteases in the mucosa. (D)</p> Signup and view all the answers

After the classical C3 convertase (C4bC2a) is formed, what is its DIRECT enzymatic activity?

<p>It cleaves C3 into C3a and C3b. (D)</p> Signup and view all the answers

What is the MAIN role of C3b in complement activation?

<p>To opsonize pathogens, enhancing phagocytosis. (D)</p> Signup and view all the answers

How are immune complexes (ICs) removed from circulation?

<p>They are captured by red blood cells via CR1 and transported to the spleen for removal by macrophages. (B)</p> Signup and view all the answers

Which statement is TRUE regarding fetal and neonatal immunity?

<p>IgG is transferred across the placenta, providing passive immunity to the fetus. (B)</p> Signup and view all the answers

Which cytokine involved in class switch recombination biases towards IgE and IgG4?

<p>IL-4 (D)</p> Signup and view all the answers

What is the implication of low molecular weight for a potential immunogen?

<p>Reduces its immunogenicity. (B)</p> Signup and view all the answers

How does the 'staple' form of IgM contribute to complement activation?

<p>It allows C1q to bind to the Fc portions of IgM. (C)</p> Signup and view all the answers

If C4bC2a is the classical C3 convertase, what is the alternative C3 convertase?

<p>C3bBb (A)</p> Signup and view all the answers

During an infection, an individual's B cells undergo class switching to produce IgE. What is the MOST likely effector function that will be enhanced by this switch?

<p>Killing of helminths (D)</p> Signup and view all the answers

What is the direct mechanism by which an antibody mediates neutralization?

<p>Blocking the pathogen's ability to bind to host cells or tissues (D)</p> Signup and view all the answers

Which factor primarily determines whether an antibody will promote inflammation or suppress it?

<p>Isotype. (D)</p> Signup and view all the answers

While studying the immune system, a researcher discovers a novel protein that, when bound to IgA, prevents its interaction with the polymeric immunoglobulin receptor (pIgR). What is the MOST likely consequence of this interaction?

<p>Reduced transport of IgA across mucosal epithelial cells (C)</p> Signup and view all the answers

Consider a scenario where a new bacterial strain has evolved a mechanism to cleave C3b into inactive fragments. What is the MOST likely immediate consequence of this bacterial adaptation within the host?

<p>Impaired opsonization and phagocytosis of the bacteria. (D)</p> Signup and view all the answers

A researcher is investigating a new drug that aims to modulate class switch recombination (CSR) to enhance the production of IgG3 in response to a specific viral infection. Which cellular interaction should the drug MOST directly target to achieve this outcome?

<p>Interactions between T follicular helper (TFH) cells and B cells in the germinal center. (C)</p> Signup and view all the answers

Which antibody isotype is MOST effective at neutralizing toxins in the bloodstream, and why?

<p>IgM, due to its pentameric structure, allowing for high avidity binding. (C)</p> Signup and view all the answers

A neonate is diagnosed with a genetic defect that impairs the function of the neonatal Fc receptor, FcRn. Which immunological consequence is MOST likely to occur in this infant?

<p>Reduced levels of passively acquired maternal IgG, resulting in increased susceptibility to infections. (D)</p> Signup and view all the answers

A researcher discovers that a particular antigen is able to activate the alternative pathway of complement, but is resistant to opsonization. Which modification of the antigen would MOST likely render it susceptible to opsonization?

<p>Modification to allow antibody binding, thereby enabling classical pathway activation. (A)</p> Signup and view all the answers

An experimental drug is designed to completely inhibit the function of C1q. What downstream effects would result from the use of this drug?

<p>Inhibition of the classical pathway of complement, but not the alternative or lectin pathways. (C)</p> Signup and view all the answers

Which of the following characteristics would render a molecule LEAST likely to be recognized as foreign by the immune system?

<p>Presence in multiple species (B)</p> Signup and view all the answers

Which event is LEAST likely to occur as a direct result of class switch recombination (CSR)?

<p>Alteration in V(D)J region sequence (C)</p> Signup and view all the answers

Which mechanism enables antibodies to prevent a pathogen from infecting cells?

<p>Neutralization (A)</p> Signup and view all the answers

If the gene encoding for AID (Activation-Induced Cytidine Deaminase) were non-functional, which process would be MOST directly impaired?

<p>The somatic hypermutation in the germinal center (C)</p> Signup and view all the answers

A patient with a respiratory infection is found to have high levels of IgD in their respiratory tract. This is MOST indicative which immunological process?

<p>A response to commensal or pathogenic bacteria in the respiratory system. (C)</p> Signup and view all the answers

A novel therapeutic approach aims to enhance the recruitment of immune complexes (ICs) to erythrocytes via the CR1 receptor, but unexpectedly leads to severe systemic inflammation. Which mechanism BEST explains this paradoxical outcome?

<p>Increased IC binding to erythrocytes saturates splenic macrophage Fc receptors, preventing IC clearance and promoting systemic deposition. (D)</p> Signup and view all the answers

A researcher engineers a novel immunotherapeutic fusion protein consisting of a target antigen linked to a modified Fc region that selectively binds to FcγRIIB with picomolar affinity. Contrary to expectations, in vivo administration exacerbates inflammation. What is the MOST likely reason for this outcome?

<p>The high-affinity binding to FcγRIIB prevents its normal inhibitory signaling, paradoxically leading to enhanced activation of inflammatory pathways. (A)</p> Signup and view all the answers

A patient presents with recurring parasitic worm infections despite producing high levels of IgE. Further investigation reveals a mutation in the gene encoding a key signaling molecule downstream of FcεRI in eosinophils. Which signaling defect would MOST likely explain this patient's susceptibility to parasitic infections?

<p>Reduced calcium influx, inhibiting the release of granule contents and cytotoxic mediators. (A)</p> Signup and view all the answers

A research team is developing a novel vaccine strategy that aims to elicit broadly neutralizing antibodies against a highly variable virus. They discover that including a specific adjuvant leads to a dramatic increase in the avidity of the resulting IgG antibodies, but also results in reduced somatic hypermutation. What is the MOST probable explanation for this observation?

<p>Increased antibody avidity enhances B cell receptor signaling, leading to accelerated B cell differentiation and reduced time for somatic hypermutation. (C)</p> Signup and view all the answers

A biotechnology company is designing a bispecific antibody to treat cancer. One arm binds to a tumor-associated antigen, while the other arm is designed to enhance ADCC. Which modification to the Fc region would MOST effectively augment NK cell-mediated cytotoxicity while minimizing complement activation?

<p>Increase the affinity for FcγRIIIA and incorporate mutations to prevent C1q binding. (A)</p> Signup and view all the answers

A researcher is investigating the role of IgA in preventing bacterial translocation across the intestinal epithelium. They discover a novel bacterial protease that specifically cleaves IgA2 within the hinge region. What is the MOST likely consequence of IgA2 cleavage in the context of intestinal immunity?

<p>Compromised IgA2 dimerization, leading to reduced avidity and impaired agglutination of bacteria, facilitating bacterial translocation. (C)</p> Signup and view all the answers

A neonate is diagnosed with a rare genetic defect that results in the complete absence of the neonatal Fc receptor (FcRn) in all tissues except the placenta, where its expression and function are normal. What is the MOST likely immunological consequence for this infant?

<p>Normal passive immunity in early infancy followed by severely impaired IgG homeostasis and increased susceptibility to infection later in infancy. (C)</p> Signup and view all the answers

A research scientist is investigating a novel strategy to enhance mucosal immunity against respiratory pathogens. They engineer a modified IgA antibody that exhibits enhanced binding to surfactant protein D (SP-D). What is the MOST likely outcome of this modification in the context of lung immunity?

<p>Enhanced IgA-mediated agglutination and clearance of pathogens in the alveolar space due to SP-D-mediated crosslinking. (A)</p> Signup and view all the answers

A patient with a history of recurrent bacterial infections is found to have normal levels of all antibody isotypes, but their IgM exhibits a significantly reduced capacity to activate the classical complement pathway. Further investigation reveals a mutation affecting the Cµ4 domain of IgM. Which functional consequence is MOST likely associated with this mutation?

<p>Impaired assembly of IgM into pentameric structures, reducing the avidity for C1q binding. (B)</p> Signup and view all the answers

A researcher discovers a novel viral evasion mechanism involving a virally encoded protein that specifically binds to C4b, preventing its association with C2a. Which step in the classical complement pathway is MOST directly inhibited by this viral protein?

<p>Formation of the classical C3 convertase. (C)</p> Signup and view all the answers

A clinician is treating a patient with a severe autoimmune disease characterized by the formation of pathogenic immune complexes. They decide to administer a high dose of intravenous immunoglobulin (IVIg) to modulate the immune response. Which Fc-mediated mechanism is MOST likely responsible for the therapeutic effect of IVIg in this context?

<p>Engagement of FcγRIIB receptors on B cells and antigen-presenting cells, delivering inhibitory signals that suppress B cell activation and autoantibody production. (C)</p> Signup and view all the answers

A researcher is studying the impact of glycosylation on the effector functions of IgG antibodies. They produce two versions of an IgG1 antibody, one with normal glycosylation and one with completely removed N-linked glycans from the Fc region. How would the removal of N-linked glycans from the Fc region of IgG1 MOST likely affect its effector functions?

<p>Reduced complement activation and impaired binding to Fcγ receptors. (B)</p> Signup and view all the answers

A pharmaceutical company is developing a novel therapeutic antibody that targets a cytokine involved in allergic inflammation. They aim to minimize the risk of off-target effects mediated by Fc receptor interactions. Which modification to the Fc region of the antibody would BEST achieve this goal?

<p>Introduce mutations in the Fc region that selectively disrupt binding to all Fcγ receptors while preserving structural integrity. (D)</p> Signup and view all the answers

A researcher is investigating the mechanisms underlying the development of food allergies. They hypothesize that impaired IgA production in the gut leads to increased sensitization to food antigens. Which experimental approach would BEST test this hypothesis in a mouse model?

<p>Deleting the gene encoding the polymeric immunoglobulin receptor (pIgR) in intestinal epithelial cells and assess the development of food allergies. (A)</p> Signup and view all the answers

A patient with a history of severe asthma experiences a life-threatening exacerbation triggered by exposure to a specific allergen. Despite aggressive bronchodilator therapy, their airway inflammation persists. Which antibody-mediated mechanism is MOST likely contributing to the persistent airway inflammation in this patient?

<p>IgE-mediated crosslinking of FcεRI receptors on mast cells and basophils, leading to the release of histamine and other inflammatory mediators. (C)</p> Signup and view all the answers

A researcher is investigating the influence of different cytokines on class switch recombination (CSR). They stimulate B cells with anti-CD40 and IL-4, but also add a novel compound that inhibits the activity of STAT6. What is the MOST likely consequence of STAT6 inhibition on CSR in these stimulated B cells?

<p>Selective inhibition of CSR to IgE and IgG4 due to impaired expression of germline transcripts for these isotypes. (B)</p> Signup and view all the answers

A researcher discovers that a particular antigen, while possessing high molecular weight and chemical complexity, fails to elicit a strong antibody response in vivo. Further analysis reveals that the antigen is rapidly degraded in the endosomes of antigen-presenting cells. Which strategy would MOST effectively enhance the immunogenicity of this antigen?

<p>Conjugating the antigen to a carrier protein that is resistant to enzymatic degradation. (A)</p> Signup and view all the answers

A biotech company is developing a novel therapeutic antibody to neutralize a soluble inflammatory mediator. To optimize its pharmacokinetic properties, they aim to engineer the antibody to maximize its interaction with FcRn. Which strategy would MOST effectively increase FcRn binding affinity while minimizing the risk of inducing unwanted effector functions?

<p>Selecting for variants with increased affinity for FcRn at acidic pH but reduced affinity for Fcγ receptors at neutral pH. (A)</p> Signup and view all the answers

A patient is diagnosed with a rare genetic deficiency in activation-induced cytidine deaminase (AID) specifically affecting somatic hypermutation in B cells, but not class switch recombination. Which downstream effect would MOST likely be observed in this individual?

<p>Severely impaired affinity maturation and limited antibody diversity despite normal isotype distribution. (A)</p> Signup and view all the answers

A research team discovers a novel bacterial pathogen that expresses a surface protein with high affinity for polymeric immunoglobulin receptor (pIgR). What is the MOST likely functional consequence of this interaction for the host's immune response?

<p>Impaired recruitment of IgA to the mucosal surface due to competitive inhibition of IgA binding to pIgR. (D)</p> Signup and view all the answers

A researcher is investigating mechanisms of immune evasion employed by a newly discovered virus. They identify a viral protein that selectively inhibits the formation of the alternative C3 convertase (C3bBb). How would this viral protein MOST directly affect the host's immune response?

<p>Impaired opsonization of the virus, reducing uptake by phagocytes. (C)</p> Signup and view all the answers

While investigating a new vaccine adjuvant, a researcher discovers it induces robust IgG responses, but the resulting antibodies exhibit unusually short half-lives in vivo. Further analysis reveals the adjuvant promotes aberrant glycosylation of the IgG Fc region. Which specific glycosylation change would MOST likely explain the reduced IgG half-life?

<p>Aberrant mannosylation, leading to enhanced uptake by mannose receptors on macrophages. (A)</p> Signup and view all the answers

A patient is treated successfully for a venomous snake bite with antivenom containing neutralizing antibodies. However, several weeks later, the patient develops serum sickness, characterized by fever, joint pain, and glomerulonephritis. Which mechanism is MOST likely responsible for the development of serum sickness in this patient?

<p>Formation of immune complexes containing the antivenom antibodies and residual snake venom antigens, depositing in tissues and activating complement. (D)</p> Signup and view all the answers

A researcher is investigating the role of Fc receptors in regulating macrophage activation. They discover that ligation of a specific Fc receptor on macrophages by IgG immune complexes triggers the production of IL-10, an immunosuppressive cytokine. Which class of Fc receptor is MOST likely mediating this effect?

<p>Inhibitory Fcγ receptors, such as FcγRIIB, which dampen macrophage activation and promote immune tolerance. (C)</p> Signup and view all the answers

A researcher aims to develop a novel therapeutic strategy for treating autoimmune hemolytic anemia, an autoantibody-mediated disease where red blood cells (RBCs) are targeted for destruction. Which approach is MOST likely to be effective in reducing RBC destruction while minimizing systemic immunosuppression?

<p>Engineering a modified IgG Fc region that selectively binds to inhibitory FcγRIIB receptors on macrophages and B cells. (C)</p> Signup and view all the answers

During an investigation of a novel immune deficiency, a researcher discovers that a patient's B cells are capable of initiating class switch recombination (CSR), but unable to complete the process efficiently. Genomic analysis reveals a mutation affecting the non-homologous end joining (NHEJ) pathway specifically within B cells. Which aspect of CSR is MOST likely impaired in this patient?

<p>Rejoining of DNA strands following switch region excision, resulting in circular DNA formation. (D)</p> Signup and view all the answers

A researcher is developing a vaccine against a highly glycosylated virus. The vaccine elicits a strong IgG response, but the resulting antibodies exhibit poor neutralizing activity against the native virus. Which factor is MOST likely contributing to the reduced neutralizing potency of the antibodies?

<p>The antibodies bind to the glycan moieties but do not block the virus's interaction with its cellular receptor. (D)</p> Signup and view all the answers

A study reveals that a particular adjuvant skews the isotype profile towards IgG2 in mice. This adjuvant causes enhanced signaling through which receptor on B cells?

<p>TLR (Toll-like receptor) (C)</p> Signup and view all the answers

A newborn has significantly reduced levels of IgG but normal levels of IgM and IgA. Which condition would MOST likely explain this observation?

<p>Defect in the neonatal Fc receptor (FcRn) (A)</p> Signup and view all the answers

A novel drug is designed to enhance the presentation of antigens on MHC class II molecules by B cells. The drug MOST likely targets what aspect of B cell function?

<p>Disrupts lysosomal degradation pathways within the B cell. (D)</p> Signup and view all the answers

A research team discovers a novel immunodeficiency characterized by impaired somatic hypermutation and class switch recombination, but with normal germinal center formation. Comprehensive analysis reveals a specific defect in the glycosylation pathway within B cells, leading to the production of aberrant N-glycans on the activation-induced cytidine deaminase (AID) enzyme. Which consequence is MOST likely resulting from the altered glycosylation of AID?

<p>Reduced protein stability and accelerated degradation of AID within the germinal center B cells. (D)</p> Signup and view all the answers

A hypothetical biopharmaceutical company is engineering a novel, multi-specific antibody construct. One arm binds to a tumor-specific antigen, while a second arm is designed to directly activate the alternative pathway of complement. To optimize the therapeutic efficacy while minimizing systemic inflammatory side effects, which of these design considerations is MOST critical?

<p>Utilizing a modified Fab region that binds to properdin, thereby stabilizing the alternative pathway C3 convertase exclusively in the tumor microenvironment. (D)</p> Signup and view all the answers

A research team aims to develop a novel vaccine against a highly variable viral pathogen. They engineer a virus-like particle (VLP) displaying conserved viral epitopes and administer it with different adjuvants. Unexpectedly, they observe that an adjuvant known to potently activate dendritic cells leads to significantly lower avidity of the resulting IgG antibodies compared to an adjuvant that induces weaker DC activation. Which mechanism is the MOST probable explanation for this observation?

<p>Potent DC activation results in rapid B cell differentiation into short-lived plasma cells, bypassing the germinal center reaction necessary for affinity maturation. (B)</p> Signup and view all the answers

A research group is investigating the role of different IgA subclasses in maintaining intestinal homeostasis. They discover a novel commensal bacterial species that secretes a highly specific protease that cleaves IgA1, but not IgA2, within the hinge region. What is the MOST likely long-term consequence of this proteolytic activity on the host's intestinal immunity?

<p>Increased susceptibility to systemic infections due to enhanced translocation of bacterial antigens across the compromised epithelial barrier. (B)</p> Signup and view all the answers

A researcher is studying the impact of passive immunization on the development of autoimmune disease in a mouse model. They transfer IgG antibodies specific for a self-antigen known to drive disease pathogenesis. Surprisingly, they observe a transient amelioration of disease followed by a significant disease exacerbation. Which Fc-mediated mechanism is MOST likely responsible for the observed disease exacerbation?

<p>Formation of large immune complexes leading to complement-mediated tissue damage and enhanced antigen presentation. (D)</p> Signup and view all the answers

Flashcards

Immunogens

Substances that elicit an immune response, typically foreign, high in weight, chemically complex, and degradable.

Class Switch Recombination (CSR)

Permits B cells to switch antibody isotype, enabling specific effector functions against pathogens.

Major Antibody Effector Mechanisms

Neutralization, opsonization, and antibody-dependent cell cytotoxicity (ADCC).

IgM

Protects against a range of infections

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IgD

Most effective against infections in the respiratory tract.

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Chemical Nature of Antigens

Proteins, polysaccharides, nucleic acids, and lipids

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Hapten

A low molecular-weight compound that induces an immune response only when attached to a carrier molecule (protein).

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Four Requirements for Immunogenicity

Foreignness, high molecular weight, chemical complexity, and degradability.

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Circulating Antibodies (Abs)

Soluble glycoproteins that bind antigens, promoting killing/removal of immune complexes.

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Class switch recombination

Enables specific effector functions in response to pathogens

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IgM

Binds strongly to pathogens with multiple repetitive epitopes.

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AID

Activation of CD40 on GC B cells

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Neutralization (of microbes)

Enables pathogen attachment prevention to host tissues for colonization.

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molecules that bind Ags on microbe surface

IgA and specific IgG molecules

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Opsonization

Enhanced phagocytosis of antibody-coated microbes

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Antibody-Dependent Cell Cytotoxicity (ADCC)

Killing of antibody-bound target cells by NK cells.

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FcyRIII

Expressed by NK cells

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ADCC

Activation of degranulation of the eosinophils and destruction of the worm

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Dark Pink

Constitutive expression of an Fc receptor by a cell

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IgG Antibodies

Involves Neutralization, Opsonization, Complement activation, and ADCC

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IgG1

Most common in serum and can cross placenta.

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Activation of complement

C1q must crosslink with surface bound IgG molecules

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IgG antigen-binding sites

Forms stable immune complexes which, if not removed, can cause vasculitis

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Red blood cells

Express CR1 and can capture IC in the blood

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Babies

Low IgG levels leave them prone to infection

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Breast Milk

Delivers IgA and 10% IgG/IgM to protect mucosal surfaces.

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FcRn

Promoted by acidic pH; stabilizes the antibody and enables delivery in and out of cells

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J Chain

It Provides structural stabiliity and aids translocation

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Mucosal translocation of IgA

IgA protects surfaces of the mucosal epithelia

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IgM

First Ig synthesized by B cells and complement activation

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IgE function

Immunity to parasites. Can cause Allergic responses

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IgD

Exists on the B cell surface functioning as an antigen receptor

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Exogenous Antigens

Antigens entering from the environment

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Endogenous Antigens

Antigens generated within the cells of the host

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too high a does is as bed as too low

Tolerance

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IgA

Secreted into mucus, tears, saliva

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Vast Majority of Immunogens

Protein; they may be pure proteins or they may be glycoproteins or lipoproteins and are usually very good immunogens

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Polysaccharides

These are Pure polysaccharides and lipopolysaccharides that are good immunogens

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Nucleic Acids

Usually poorly immunogenic, however they may become immunogenic when single stranded or when complexed with proteins

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Lipids

These are generally non-immunogenic, although they may be haptens.

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Dosage of an Antigen

Activate sufficient numbers of lymphocytes.

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TFH cells signal B cells.

CD4+ T cells provide the cytokine signal that drives isotype switching.

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Antibody effector function

Activation of the classical pathway of complement by C1q

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Antibody mediated Opsonization

Facilitates phagocytosis via binding to Fc receptors on phagocytes.

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First step of IgG-mediated complement activation

IgG molecules bind to antigen on bacterial surface

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IgG4 Characteristics

Promotes opsonization, ADCC, and cross placenta.

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Neutralization

Substances prevent microbe attachment and the infectious process.

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Study Notes

  • Immunogens are antigens that trigger an immune response
  • The most effective antigens are foreign, high in weight, chemically complex, and degradable

Categories of Antigens

  • Antigens entering the body from the environment: inhaled macromolecules (e.g., cat hair proteins causing asthma), ingested macromolecules (e.g., shellfish proteins causing allergy), and molecules introduced beneath the skin (e.g., splinter, vaccine).
  • Antigens are generated within the host's cells
    • Autoantigens - Self-antigens
    • Alloantigens - Tissue-specific antigens present in some individuals. Ex: ABO, HLA
    • Intracellular pathogens include viruses, intracellular bacteria, and parasites
    • Endogenous antigens are included in this group

Chemical Nature of Antigens

  • Proteins are the most common immunogens and are generally very good for this purpose
  • Polysaccharides, specifically pure and lipopolysaccharides, make good immunogens
  • Nucleic acids are typically poor immunogens, but may become immunogenic when single-stranded or complexed with proteins
  • Lipids are generally non-immunogenic, but may act as haptens

Haptens

  • Haptens are low molecular-weight compounds
  • Haptens induce an immune response only when bound to a carrier molecule, usually a protein
  • The carrier protein has a unique antigenic structure different from the hapten
  • The immune response targets both the hapten and the carrier protein

Immunogenicity Requirements

  • Immune cells that don't recognize self survive development and training, leading to foreignness
  • The molecular weight of 100 kDa or more is best, molecules under 10 kDa are typically poorly immunogenic in this respect
  • Proteins are the best immunogens because they are so complex
  • Antigen presentation is necessary and critical

Immunogenicity Affecting Factors

  • Failure to activate enough lymphocytes can come from poor dosage of antigen
  • Repeated doses (boosters) of antigen are important
  • MHC molecules and the antigen binding or not plays a role
  • Parental administration is favored for Route of administration ("around the gut")
  • Subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and oral GI are also routes

Role of Antibodies (Abs)

  • Antibodies promote the activation of effector mechanisms and removal of the immune complex
  • Soluble glycoproteins recognize and bind antigens
  • Function as membrane-bound surface Ag receptors on B lymphocytes that plays a role in differentiation
  • B cells can alter their antibody isotype via class switch recombination (CSR) to incorporate specific effector functions against pathogens

Surface Ig and Secreted Ig

  • Five antibody isotypes exist, produced by B cells, each designated by a different H chain (μ, δ, γ, ε, α)
  • IgM and IgD, are expressed on the surface of B cells due to BCR gene rearrangements.
  • After encountering an antigen, new IgM and IgD is produced within the differentiated B cell and secreted as antibodies
  • The newly produced IgM and IgD lack transmembrane domains, restricting them to the cell membrane
    • IgM provides protection against various infections, and is produced in large amounts
    • IgD is most effective in the respiratory tract and produces in small amounts

Isotype Switching

  • IgM is secreted early against pathogens
  • Monomeric sIgM or BCR
  • Secreted IgM exhibits 10 binding sites
  • There are limits with IgM’s bulk, low affinity and the reduced capacity to recruit host effector mechanisms
  • In order to access the additional effector mechanisms IgM must be changed to another form while retaining it's Ag-specificity
  • Class switch recombination (CSR) or isotype switching, DNA recombination of the rearranged V region with another H chain gene occurs to facilitate this.
  • Cytokines drive class switching. IFN-γ, IL-4 > TGF-β
  • Class switch recombination tailors the Ig response to specific groups of infectious agents

CSR in B Cells

  • CSR occurs after engagement with TFH cells in GC B cells and centrocytes, cytokines, and AID are produced
  • Likely follows affinity maturation
  • DC produces IL-12 to program TFH cells to secrete IFN-γ and lead isotype switching through engagement of GC B cells

AID converts cytosines into uracils

  • AID targets cytosines in the Sµ and Sy1 switch regions for deamination to uracil in this example.
  • Uracil lacking a base is removed by uracil-DNA-glycosylase
  • A nick results in the DNA strand after APE1 (endonuclease) excises the abasic nucleotide
  • Circular DNA contains Cµ, Cs, and Cγ3
  • DNA repair now aligns the V region (not altered) with the C region
  • All classes of Ig are made in two forms: Surface Ig or BCR, Secreted antibody

Immunoglobulin Isotype Functions

  • Isotype effector mechanisms include neutralization, opsonization, and antibody-dependent cell cytotoxicity (ADCC)
  • Unique effector functions are exhibited by IgG1-3 (IFN-γ), IgA (TGF-β), IgE, IgG4 (IL-4), and IgM (IL-2, IL-4, IL-5)
  • Fc receptors mediate most antibody effector activities, their function, and the cells involved in the processes must also be in balance.

Neutralization

  • The first step in successful microbial infection attaches to host tissues and colonizes
  • Microbe-produced antibodies commonly target ligands used to bind host cell receptors.
  • Antibodies prevent microbe attachment = neutralization
  • Example-influenzas
  • Virus binds to surface glycoproteins of respiratory epithelia, using hemagglutinin or H
  • Vaccine generated IgG is in the mucus of the tract, and binds to prevent the virus or bacteria from attaching

Toxins Neutralizing

  • Toxins are the main mechanism for pathogenesis, vaccines can generate antibodies to bind the toxins that produce disease
  • Vaccinated antibodies don't stop colonization from attaching

Opsonization

  • IgA and specific IgG molecules bind Ags on the microbe surface
  • Fc receptors on phagocytic cells bind the Fc regions of the antibodies
  • Fc receptor ligation promotes phagocytic uptake and digestion
  • Enhanced phagocytosis of the microbe via the coating of antibody = opsonization

Complement Activation

  • IgG1-3 (+IgM) can activate the classical pathway of complement.
  • IgG and IgM activate the classical pathway.
  • IgM is the first antibody produced and complement activation is the primary effector mechanism
  • C1q binding activates C1r which causes cleavage and activation of C1s.

Antibody-Dependent Cell Cytotoxicity (ADCC)

  • NK cells express Fc gamma receptor III (FcyRIII)
  • FcyRIII of NK cells can bind to Fc regions of antibodies (IgG1 or IgG3) attached to an Ag on target cells
  • Antibody directed cell killing is known as antibody-dependent cell cytotoxicity

IgE and parasitic worms

  • The IL-4-helminths production of IgE is what causes the immune response against helminths
  • Eosinophils attach to the Fc region of IgE
  • Degranulation of the eosinophils are carried out after a number of Fc&RI attachments along worm
  • IgE is driven against parasitic worms and eosinophils attack

Soluble Antigen Removal

  • IgG antigen-binding sites have higher affinity than IgM → stable immune complexes (IC)
  • IC form when antibody binds soluble Ag
  • Activation of the classical pathway → C3b deposition on the Ag → phagocytes take up and remove these IC from the body
  • IC can develop during the course of an immune response, if this occurs they develop and must be removed to prevent build-up in small blood vessels and kidney glomeruli

Fetal and Neonatal Immunity

  • IgG passes the placenta efficiently, newborns typically have adult-level IgG
  • Before birth, the baby begins IgM production but between birth to 12 months the antibody levels are deficient: high infection risk
  • Antibodies can be provided through breast milk to protect mucosal surfaces from infection
  • Breast milk has 90% IgA (IgG and IgM comprise the remaining 10%)

IgG1/IgG3-4 Fetal Immunity

  • With the Fc receptor neonatal (FcRn) in the blood, IgG stabilizes interaction
  • There must be an acidic pH is what promotes association of neonatal FC’s

Mucosal Immunity

  • The surfaces of the mucosal epithelia are protected by IgA
  • IgA is secreted to get IgA to the apical region, in the MALT from IgA-secreting PC on the basolateral.
  • Receptors on epithelia bind J chain
    • Secretory Piece is important
  • IgA then associates with mucins via mucins

Fc receptor expression

  • Constitutive expression of an Fc receptor by a cell is denoted by dark pink and "+"; inducible expression is denoted by lighter pink and (+)

IgG

  • IgG is the most common serum Ig
  • IgG1 and IgG3 cross the placenta.
  • IgG is opsonization (IgG1, IgG3 best)

IgA

  • IgA1 and IgA2 are secreted into mucus
  • IgA exists in dimer form and are important in mucosal immunity. IgA is effective at neutralization.

IgE

  • IgE mediates immunity to parasites
  • IgE drives allergic reactions and response

  • IgM is effective at complement activation and agglutination.

  • Basophils eliminates bacteria via binding mlgD on the B cell surface

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