Lecture 3 - Induced Innate Response Flashcards
What is Complement?
Heat-Labile Component of plasma/tissue which augments the opsonisation and killing of pathogens by antibodies
State the Three Pathways by which the Complement System can be Activated
- Classical Pathway (Antibody-Dependent)
- Lectin (MBL) Pathway
- Alternative Pathway (Amplification)
Define the Functions of the Two complement fragments produced from cleavage of C3:
(i) C3a
(ii) C3b
(i) C3a - Peptide Mediator of Inflammation (Phagocyte Recruitment)
(ii) C3b - Binds covalently to surface of pathogen via a thioester bond, producing a permanent tag (Opsonisation)
What are Anaphylatoxins? How can they work:
(i) Locally
(ii) Systemically
- Small Complement Fragments (C3a, C4a, C5a) that induce local inflammatory responses(i) Act on Blood Vessels to Increase Vascular Permeability and Expression of adhesion molecules(ii) Systemic Production induces generalised circulatory collapse (Anaphylatic Shock)
Explain why Opsonisation Improves Clearance of Pathogens
Phagocytes express complement receptors on their surface, which can recognise and bind to complement tags on pathogens to facilitate engulfment
Define the Membrane Attack Complex in terms of:
(i) Structure
(ii) Assembly
(iii) Function
(i) Pore-like structure formed from the Terminal Complement Components (C5-C9)
(ii) Polymerisation/Self-Assembly occurs as a result of a pro-enzyme cascade
(iii) Disrupts Proton Gradient across a pathogens cell membrane, Killing the microorganism
How is complement activation against Host cells prevented?
Host cells express Complement Regulatory Proteins (e.g., MCP), which are integral membrane proteins that cleave C3b to prevent complement activation
Define Cytokines (Give Two Examples). How can they act?
- Small proteins (25kDa) released by various cell types, which induce responses by binding to specific receptors
- E.g., TNFa, IL-6, IFN
- Autocrine, Paracrine and Endocrine Effects
Define Chemokines (Give Examples)
- Small Proteins which bind to GPCRs, and function mainly as Chemoattractants (Involved in Chemotaxis)
- E.g., CXCL9, CCL2
Compare Myelopoiesis in a:
(i) Local Infection
(ii) Systemic Infection
(i) Steady-state production of Neutrophils (Myelopoiesis) and Lymphocytes (Lymphopoiesis) in the Bone Marrow
(ii) Increased number of neutrophils are required, therefore emergency myelopoiesis occurs to help control spread of the pathogen.
* Due to Limited Supply of HSCs, this leads to decreased Lymphopoiesis
Describe the Liver Acute Phase Response
- IL-6 Produced at site of infection travels through the blood to the liver, where it activates hepatocytes to produce and secrete:
- C-Reactive Protein - opsonises pathogen by binding to phosphocholine on surface, also activates complement
- Mannose-Binding Lectin - opsonises pathogen by binding to mannose residues on bacterial surface
Describe TNFa in terms of:
(i) Production
(ii) Local Effects
(iii) Systemic Effects
(i) Macrophages in response to pathogens/cytokine activation
(ii) Inflammation and local clotting of blood vessels
(iii) Systemic Shock due to decreased blood volume and disseminated intravascular coagulation
Explain how Sepsis can occur
(Two Points)
- Due to Cytokines (e.g., TNFa) travelling from site of infection to liver, activating Kupffer Cells
- Due to direct contact between Kupffer Cells with circulating pathogens (i.e. Systemic Infection)
What are IFNs? Explain the Two-Cell System.
(2 Points)
- Antiviral Proteins produced in almost all cell types in response to infection
- Two-Cell System - infection of first cell triggers secretion of IFN, which generates an antiviral response in the second cell (ISGs)
How can Viral Infection be detected?
What does this Lead to?
(2 Points)
- Viral dsRNA is detected by TLR3, RIG-I or MDA5
- Activation of any receptor leads to phosphorylation of TFs IR3 and IR7, which are involved in expressing IFN
