Topic 2: Innate Immunity Flashcards
1
Q
How do cells of the innate immune system target pathogens?
A
- They recognize structures on pathogens called Pathogen Associated Molecular Patterns (PAMPs) e.g. double stranded RNA, LPS, bacteria flagellin
- These PAMPs are ideal targets as they are common to many pathogens but not mammalian cells
2
Q
How do innate immune cells recognise PAMPs?
A
- Innate immune cells recognise PAMPs via receptors called Pattern Recognition receptors (PRRs)
- They faciliate an immune response against that pathogen
- Many different families including toll-like receptors (TLRs), NOD-like receptors and RIG-like receptors
3
Q
What is a Toll-like receptor?
A
- A TLR is a type of PRR present on/within innate immune cells
- TLRs bind PAMPs as a dimer (hetero or homodimer) and become activated
4
Q
What are the TLR families and where are they found?
A
TLR1/TLR2: - heterodimer; found on cell membrane - recognises bacterial and fungal structures TLR2/TLR6: - heterodimer; found on cell membrane - recognises bacterial and fungal structures TLR3: - homodimer; found in endosome - recognises dsRNA TLR4: - homodimer; found on cell membrane - recognises LPS TLR5: - homodimer; found on cell membrane - recognises flagellin TLR7: - homodimer; found in endoome - recognises ssRNA from viruses TLR8: - homodimer; found in endosome - recognises ssRNA from viruses TLR9: - homodimer; found in endosome -recognises DNA that is unmethylated TLR 10: - homodimer; found on cell membrane - recognises bacterial structures
5
Q
What is the process of phagocytosis?
A
- Recognition of PAMPs by PRRs on phagocytic cells e.g. macrophages and neutrophils
- Ingestion of pathogen into cell by surrounding pathogen with extensions of the plasma membrane
- Ingested pathogen is surrounded by membrane internally making a phagosome
- Fusion of phagosome with another intracellular compartment- the lysosome making a phagolysosome
- The pathogen is broken down within the phagolysosome
6
Q
What is the complement pathway? What are its 3 roles?
A
- A soluble component of the innate immune response comprised of ~30 proteins produced by the liver
Roles:
1. Opsonisation of pathogens: coating pathogens in complement molecules (C3b) to attract phagocytic cells to phagocytose them
2. Inflammation: attract further leukocytes to the site of the pathogen (C3a)
3. Directly kill pathogens: by forming pores in pathogen membrane (C5 etc)
7
Q
What are the 3 pathways for initiating the complement activation pathway?
A
- Alternative pathway: triggered when some complement proteins are activated on microbial surfaces and are not controlled (as complement regulatory proteins are not present on microbes).
- Classical pathway: triggered by the binding of antibodies that bind to microbes or other antigens. Component of humoral immunity.
- Lectin pathway: is activated when a carbohydrate-binding plasma protein mannose binding lectin (MBL) which binds to surface glycoproteins of microbes and activates proteins of the classical pathway. Initiated by microbial product in the absence of antibodies therefore part of the innate immune response.
8
Q
Describe the complement pathway:
A
- Activation of the complement pathway via 1 of 3 pathways: alternative, classical or lectin
- Leads to the generation of C3 convertase
- C3 convertase cleaves C3 into C3a and C3b
- C3a causes inflammation attracting leukocytes
- C3b coats the surface of the pathogen opsonising it for phagocytosis
- C3b activates the late stage events of the complement pathway in which C5 convertase is formed
- C5 convertase cleaves C5 to C5a (inflammation) and C5b which contributes to the formation of the membrane attack complex
- The membrane attack complex (made up for C9, C5b etc.) causes the cell to lyse
9
Q
What is the inflammasome?
A
- A pro-inflammatory protein complex that is formed after the stimulation of intracellular NOD-like receptors by DAMPs and PAMPs
- The inflammasome promotes the inflammation and destruction of damaged/infected self cells
- The presence of intracellular factors (e.g. bacteria products, viral DNA etc) causes the inflammasome to assemble (NOD-like receptor, adaptor and caspase-1)
- This assembly cleaves caspase-1 into its active form
- Innate signals cause the production of pro-IL-1B
- Caspase-1 cleaves pro-IL-1B to IL-1B (its active form)
- IL-1B is secreted from the cell causing acute inflammation
10
Q
What is a DAMP?
A
- A DAMP is a damage associated molecular pattern that are created by dead/dying cells and are recognised by receptors on innate immune cells stimulating innate immune responses.
11
Q
What is a natural killer cell?
A
- An innate immune cell that develops from the lymphoid progenitor cells
- They detect and killl damaged/stressed self-cells be releasing toxic granules onto their surfaces
- They can also respond to signals from infected macrophages to active the macrophage to become a more effective killer by secreting IFN-y
- NK cells target cells not expressing MHC I (a self-MHC marker) which is an inhibitory receptor for the NK
12
Q
What is a cytokine?
A
- A soluble protein produced by many different cell types that mediate inflammatory and immune responses
e. g. IL-2, TNFa
13
Q
What is are chemokines?
A
- Chemokines are a large family of low molecular weight cytokines that act as chemoattractants (substance that attracts cells) and regulates the migration of leukocytes from blood to tissue during infection
14
Q
What are the 4 major cytokines involved in an innate immune response?
Which innate cytokine prevents viral infections?
A
- Tumor necrosis factor (TNF):
- produced by macrophages and T cells
- activates endothelial cells and neutrophils
- acts on hypothalamus to produce fever - IL-1:
- produced by macrophages, endothelial cells and some epithelial cells
- activates endothelial cells
- acts on hypothalamus to produce fever
- causes T-cells to differentiate - IL-12:
- produced by macrophages and dendritic cells
- causes T-cell differentiation and proliferation
- increases IFN-y production and cytotoxic activity of T cells and NK cells - IFN-y:
- produced by NK cells and T lymphocytes
- activation of macrophages to become more efficient phagocytic killers
- Type 1 IFN
15
Q
Explain how the activation of a macrophage triggers a cytokine cascade:
A
- The macrophage (and also dendritic cells) engulf pathogens and become activated causing them to secrete IL-2 (activating NK cells) as well as TNF and IL-1 (to act on endothelial cells activating them and causing inflammation)
- The NK cell activated by the IL-1 secretion goes onto secrete IFN-y which upregulate macrophages
