Lecture 3 induced innate responses Flashcards
What is an example of innate immunity?
Infectious organism entering a wound in the skin. The organism must adhere and cross the epithelium to establish an infection. A local inflammatory/immune response may prevent this. If not it helps to contain the infection and delivers infectious agent to local lymph nodes.
What is a complement system?
Protein proenzyme cascade that consists of many proteins always present at a high concentration in our serum which can then become activated upon contact with pathogen surfaces. Initially it was found that these complement systems were activated by higher concentrations of immunoglobin.
How was the complement system discovered?
As a heat labile component of normal plasma that augments the opsonization and killing of bacteria by antibodies (classical pathway). Now it is known that activation can occur also in the absence of antibody (lectin and alternative pathways).
What is the location of the classical pathway?
Body fluids and tissues.
What are the complement inducers?
Pathogens
What is the structure of the first protein in the classical pathway?
Hexameric. C1. The head binds to constant regions of immunoglobins or directly to the pathogen surface. This causes a confirmational change in C1r, which then cleaves and activates C1s.
What does the classical pathway do?
Generate an active C3 convertase, which cleaves C3 into C3a (a peptide mediator of inflammation, phagocyte recruitment), C3b and [C4b] (bind covalently through a thioester bond to the pathogen surface: creates a permanent tag (opsonization).
What are the steps to the generation of C3 in the classical pathway?
Activated C1s cleaves C4 to C4a and C4b, which binds to the microbiol surface. C4b then binds C2 which is cleaved by C1s, to C2a and C2b forming the C4b2b complex. C42b is an active C3 convertase cleaving C3 to C3a and C3b, which binds to the microbiol surface or to the convertase itself. One molecule of C42b can cleave up to 1000 molecules of C3 to C3b. Many C3b molecules bind to the microbiol surface.
What do the formation of C3a and C5a lead to?
Peptide mediators of inflammation and phagocyte recruitment.
What do the small complement fragments C3a, C4a and C5a (anaphylatoxins) do?
Induce local inflammatory responses. When they are produced in large amounts they induce a generalized circulatory collapse (Anaphylactic shock).
What are the steps to anaphylactic shock?
Small component-cleavage products act on blood vessels to increase vascular permeability and cell adhesion molecules. Increased permeability allows increased fluid leakage from blood vessels and extravasation of immunoglobins and complement molecules. Migration of macrophages, polymorphonuclear leukocytes (PMNs) and lymphocytes is increased. Microbicidal activity of macrophages and PMNs is also increased.
What are the complement receptors?
Tag pathogens for phagocytosis. The complement proteins recognise and bind to the receptors leading to opsonization, inflammation etc.
What is CR1s function?
Promotes C3b and C4b decay. Stimulates phagocytosis. Red blood cell transport of immune complexes.
What is CR2s function?
Specifies C3d, iC3b, C3dg. Part of B-cell co-receptor. Epstein-Barr virus receptor.
What is CR3s and CR4s function?
Both specify iC3b and stimulates phagocytosis.
What is C5as function?
Binding of C5a activates G protein.
What is C3as function?
Binding of C3a activates G protein.
What are the steps in the terminal complement system?
C5b binds C6 and C7. C5b67 complexes bind to membrane via C7. C8 binds to the complex and inserts into the cell membrane. C9 molecules bind to the complex and polymerize. 10-16 molecules of C9 bind to form a pore in the membrane. This destroys the proton gradient across pathogen’s cell membrane.
What are deficiencies in C5-9 associated with?
Susceptibility to Neisseria (gohorrhea, meningitis).
Which two proteins regulate the complement system?
Properdin: A host plasma glycoprotein stabilises C3bBb (C3 convertase complex) on pathogen surfaces. Enhances complement activation by preventing breakdown of C3 convertase. Factor I: Another host plasma glycoprotein. Cleaves and inactivates C3b into iC3b (inactive C3b) to stop further complement activation.
How do host cells prevent self damage?
They express complementary regulatory proteins. CR1, Factor H, Membrane Cofactor protein MCP and Decay accelerating factor DCF all bind to C3b to displace Bb from C3bBb (C3 convertase). Factor I then cleaves C3b into iC3b which cannot activate complement further. On pathogens properdin stabilized C3bBb allowing the complement cascade to continue leading to opsonization of cell lysis.
What receptors do macrophages express for bacteria?
Mannose receptor, LPS receptor, glucan receptor, scavenger receptor. Bacteria binding to macrophage receptors initiate the release of cytokines and small lipid mediators of inflammation.
What is the general role of cytokines and chemokines?
Responsible for the induced innate response. Set up a site of inflammation and bring neutrophils and plasma proteins to the site of infection. Induce the expression of costimulatory molecules on macrophages and on dendritic cells which initiates adaptive immune responses.
What are cytokines?
Small proteins that are released by an activating stimulus and induced responses through binding to specific receptors, IL6 TNF and IFN. They have autocrine, paracrine and endocrine effects.
