Podcast
Questions and Answers
Given a scenario where a patient presents with recurrent Neisseria infections but genetic testing reveals fully functional C5, C6, C7, and C8 proteins with appropriate serum concentrations, which of the following mechanisms could paradoxically account for the clinical presentation, assuming no other immune deficiencies are present?
Given a scenario where a patient presents with recurrent Neisseria infections but genetic testing reveals fully functional C5, C6, C7, and C8 proteins with appropriate serum concentrations, which of the following mechanisms could paradoxically account for the clinical presentation, assuming no other immune deficiencies are present?
- Expression of a variant form of CD59 (protectin) with enhanced binding affinity for C5b678 complexes, preventing their insertion into bacterial membranes. (correct)
- A gain-of-function mutation in factor B or factor D that leads to hyperactivation of the alternative pathway, resulting in rapid consumption of downstream complement components and impaired MAC formation.
- Polymorphism in the gene encoding the Neisseria porin protein that hinders the insertion of the MAC pore structure irrespective of complement activation.
- Presence of a naturally occurring autoantibody specifically inhibiting the catalytic activity of C9, thereby impeding MAC formation.
In the context of complement-mediated opsonization utilizing C3b, which of the following scenarios would MOST efficiently augment phagocytosis of a Gram-negative bacterium by macrophages?
In the context of complement-mediated opsonization utilizing C3b, which of the following scenarios would MOST efficiently augment phagocytosis of a Gram-negative bacterium by macrophages?
- Pre-treating the bacterium with a Fab fragment of an antibody specific to the O-antigen of LPS, followed by incubation with serum containing functional complement proteins under conditions of high ionic strength to minimize non-specific interactions.
- Blocking the active site of serum carboxypeptidase N (SCPN) with a competitive inhibitor to prevent the conversion of C3a into its des-Arg form, thereby increasing its chemotactic gradient for neutrophils.
- Genetically modifying the bacterium to express high levels of factor H on its surface, leading to localized inactivation of C3 convertase and reduced C3b deposition.
- Engaging both CR1 and CR3 receptors on the macrophage surface concurrently with ligands that activate the macrophage's TLR4 receptor, ensuring a robust inflammatory response. (correct)
Which of the following scenarios would MOST effectively mitigate the detrimental effects of anaphylatoxins (C3a and C5a) in a patient experiencing septic shock?
Which of the following scenarios would MOST effectively mitigate the detrimental effects of anaphylatoxins (C3a and C5a) in a patient experiencing septic shock?
- Utilizing a small molecule inhibitor that selectively blocks the C5a receptor (C5aR1) without affecting C3a receptor signaling, to preserve some level of immune cell recruitment. (correct)
- Employing recombinant carboxypeptidase N (CPN) to rapidly cleave the C-terminal arginine residue from C3a and C5a, rendering them inactive while avoiding off-target effects.
- Administering a fusion protein consisting of soluble CR1 linked to the Fc region of IgG to bind and neutralize both C3a and C5a.
- Engineering a catalytically inactive variant of MASP-2 conjugated to a targeting moiety specific for endothelial cells to inhibit the lectin pathway locally, thereby preventing systemic complement activation.
A researcher is investigating a novel therapeutic approach to prevent complement-mediated damage in a model of ischemia-reperfusion injury. Which of the following strategies would MOST effectively target ONLY the alternative pathway of complement activation, minimizing disruption of the classical and lectin pathways?
A researcher is investigating a novel therapeutic approach to prevent complement-mediated damage in a model of ischemia-reperfusion injury. Which of the following strategies would MOST effectively target ONLY the alternative pathway of complement activation, minimizing disruption of the classical and lectin pathways?
Consider a patient with a genetic mutation that results in a complete deficiency of C1q. Which of the following immunological abnormalities would be the MOST likely consequence of this deficiency?
Consider a patient with a genetic mutation that results in a complete deficiency of C1q. Which of the following immunological abnormalities would be the MOST likely consequence of this deficiency?
In the context of complement regulation, if a patient presents with a mutation leading to complete loss of function of Factor I, what would be the MOST immediate and direct consequence on the complement cascade?
In the context of complement regulation, if a patient presents with a mutation leading to complete loss of function of Factor I, what would be the MOST immediate and direct consequence on the complement cascade?
If a researcher aims to develop a novel therapeutic agent that specifically inhibits the anaphylatoxin activity of C5a without affecting its chemotactic properties, which of the following strategies would be MOST rational?
If a researcher aims to develop a novel therapeutic agent that specifically inhibits the anaphylatoxin activity of C5a without affecting its chemotactic properties, which of the following strategies would be MOST rational?
A research team discovers a novel bacterial pathogen that evades complement-mediated killing by secreting a protease that specifically cleaves C3a, rendering it inactive. Which of the following immunological consequences would be MOST likely to occur during infection with this pathogen?
A research team discovers a novel bacterial pathogen that evades complement-mediated killing by secreting a protease that specifically cleaves C3a, rendering it inactive. Which of the following immunological consequences would be MOST likely to occur during infection with this pathogen?
Consider a scenario where a patient has a mutation that results in a non-functional C6 protein. Which of the following infectious disease outcomes would be MOST specifically associated with this deficiency?
Consider a scenario where a patient has a mutation that results in a non-functional C6 protein. Which of the following infectious disease outcomes would be MOST specifically associated with this deficiency?
A patient with a suspected complement deficiency undergoes a series of functional assays. The results indicate normal activity of the classical and lectin pathways, but significantly reduced activity of the alternative pathway. Further analysis reveals normal levels of C3, Factor B, and Factor D. Which of the following deficiencies would MOST likely explain these findings?
A patient with a suspected complement deficiency undergoes a series of functional assays. The results indicate normal activity of the classical and lectin pathways, but significantly reduced activity of the alternative pathway. Further analysis reveals normal levels of C3, Factor B, and Factor D. Which of the following deficiencies would MOST likely explain these findings?
Flashcards
Complement System
Complement System
Enhances the innate immune response and triggers adaptive immunity via a cascade of protein activations.
Complement Activation Pathways
Complement Activation Pathways
Classical pathway: Initiated by antigen-antibody binding, linking innate and adaptive immunity. Lectin pathway: Activated by mannose-binding lectin on gram-negative bacteria. Alternative pathway: Triggered by spontaneous C3 hydrolysis.
Opsonization (via C3b)
Opsonization (via C3b)
Tags bacteria for phagocytosis, enhancing recognition and engulfment by phagocytic cells.
Anaphylatoxins (C3a, C5a)
Anaphylatoxins (C3a, C5a)
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Membrane Attack Complex (MAC)
Membrane Attack Complex (MAC)
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Chemotaxis
Chemotaxis
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Degranulation
Degranulation
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Granules
Granules
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C5-C8 Deficiency
C5-C8 Deficiency
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C1, C2, C3 and C4 Deficiency
C1, C2, C3 and C4 Deficiency
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Study Notes
- The complement system enhances the innate immune response and aids in activating the adaptive immune response.
- Proteins of this system are made in the liver and released into the blood.
- Inflammatory stimuli trigger the activation of complement proteins in a cascade.
Complement Activation Pathways
- Activation occurs through three pathways, each leading to the activation of complement protein C3.
Classical Pathway
- Triggered by antigen binding to antibodies, serving as a bridge between innate and adaptive immunity.
- C3 is split into C3a and C3b.
- C3b coats the bacterial cell wall (opsonization), marking it for phagocytosis.
- Macrophages use a specific receptor to bind C3b, securing the microbe for engulfment.
- C3a recruits inflammatory cells like neutrophils, macrophages, and dendritic cells.
- It acts as an anaphylatoxin, causing smooth muscle contraction, histamine release from mast cells, and increased vascular permeability
- C3b amplifies the complement system by generating more C3, and cleaves C5 into C5a and C5b.
- C5b combines with C6, C7, C8, and C9 to form the membrane attack complex (MAC), leading to bacterial cell lysis.
Lectin Pathway
- Activated when mannose-binding lectin attaches to carbohydrates on gram-negative bacteria surfaces.
- This pathway activates the classical pathway without needing antibodies, and is part of the innate immune response.
Alternative Pathway
- Triggered by spontaneous C3 hydrolysis.
- Requires binding to factors B and D, starting a cascade similar to the other two pathways.
Membrane Attack Complex (MAC)
- All three pathways converge to form MAC, a protein complex that creates a pore in the bacterial cell membrane, particularly in gram-negative bacteria, leading to its destruction.
Chemotaxis
- Chemotaxins establish a chemical gradient recognized by immune cells through specific receptors.
- Neutrophils, for example, have receptors for C5a and IL-8, and move towards higher concentrations of the chemotaxin.
- Intracellular signaling pathways facilitate this movement by reorganizing the cytoskeleton, promoting cell migration.
Role of Complement Fragments
- C5a and C3a act as chemotaxins, attracting neutrophils, eosinophils, monocytes, and macrophages to inflammation sites.
- C5a and C3a are anaphylatoxins, inducing basophils and mast cells to degranulate, releasing histamine and heparin.
- This causes smooth muscle contraction, bronchial constriction, and increased vascular permeability.
Anaphylatoxins
- Small protein fragments (C3a, C4a, and C5a) are generated during complement system activation, acting as pro-inflammatory mediators.
- They recruit and activate immune cells, amplifying inflammation.
Mast Cell and Basophil Activation
- Anaphylatoxins stimulate mast cells and basophils to release inflammatory mediators like histamine, which increases blood vessel permeability and smooth muscle contraction.
Degranulation
- A process where immune cells release granules containing pre-formed bioactive molecules into the extracellular environment.
- Critical in the immune response, especially against infections and in modulating inflammation.
Granules
- Small vesicles within cells containing pre-formed bioactive molecules.
- These molecules are released during degranulation and are essential for various immune and inflammatory functions.
Deficiencies in Complement Proteins
- Lack of C1, C2, C3, or C4 can result in a lupus-like illness, chronic renal disease, and repeated infections.
- Deficiencies in C5, C6, C7, or C8 lead to recurrent Neisseria infections, increasing the risk of gonorrhea or meningitis.
- C9 deficiency appears to cause no significant issues, as C5-C8 can still lyse bacteria without it.
Recap of Complement Pathways
- Classical: Initiated by an antibody bound to a pathogen.
- Lectin: Initiated by mannose-binding lectin protein binding to mannose.
- Alternative: Continuously active due to ongoing C3 cleavage into C3a and C3b.
- All three pathways result in MAC formation, C3a and C5a acting as chemotaxins and anaphylatoxins, and C3b serving as an opsonin.
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Description
The complement system enhances the innate immune response and aids in activating the adaptive immune response. Activation occurs through three pathways, each leading to the activation of complement protein C3. C3b coats the bacterial cell wall marking it for phagocytosis. C3a recruits inflammatory cells.
