Innate Immunity + Complement Flashcards
What do the components of the innate immune system aim to do?
= eliminate pathogens
= initiate an adaptive immune response
Innate vs adaptive immunity in defence against virusus?
Innate
= macrophages, DCs, NK cells, complement cytokines
= immediate response (hours)
= non-specific
= aims to eliminate infection and alert immune system
Adaptive
= T cell, B cells, antibodies
= delayed response (1-2 weeks)
= specific for pathogen
= memory
= aims to eliminate infection and prevent re-infection later
What are some barrier functions in innate immunity?
Physical
= e.g. skin, mucus, cilia, sneezing, coughin
Chemical
= low pH in stomach , urogenital tract
= anti-microbial peptides on skin, in saliva
(defensins and cathelicidin disrupt bacterial membranes)
= enzymes in secretions (saliva, tears)
(e.g. lysosyme cleaves peptidoglycans in bacterial cell wall)
What is phagocytosis?
= the uptake of particulate materials by a cell
(e.g. pathogens, dead cells)
Specialised phagocytes:
= e.g. Neutrophils = phagocytose pathogens, then die
= e.g. Macrophages + Dendritic Cells = phagocytose pathogens + present antigens
Phagocytes have multiple functions in innate and adaptive immunity:
= kill pathogens + take up cell debris
= detect pathogen-associated molecular patterns (PAMPs)
= secrete cytokines
= present pathogen-derived antigens on their surface (as APCs) to activate T and B cells
What are the stages of phagocytosis?
- Attachment
- Ingestion - phagosome
- Phagosome-lysosome fusion
- Killing / digesting
(adaptive)
5. Antigen presentation
6. Cytokines, chemokines
What are PRRs (Pattern Recognition Receptors) and PAMPs (pathogen-associated molecular patterns)?
PRRs = receptors on an in cells that recognise PAMPs (pathogen-associated molecular patterns)
PAMPs = molecular hallmarks of infection that are NOT usually present in / on health cells
4 main families of PRRs
= TLRs = toll-like receptors (macrophage surface / in endosomes)
= CLRs = C-type lectin receptors (in cytosome)
= Intracellular nucleic acid receptors (DNA / RNA receptors inside all cells - detect if virus is infected)
= NLRs = Nucleotide oligomerisation domain / leucine-rich repeat containing receptors (detect bacterial PAMPs)
Macrophages, dendritic cells and NK cells
= have PRRs on surface and in endosomes
(most cells in body have intracellular PRRs)
What are some examples of PAMPs and PRRs?
How does Toll-like receptor (TLR) signalling work?
External LRR (leucine rich repeat) domain recognises ligands
Ligand binding causes oligomerisation of receptor and clustering of TIR domains (Toll/IL-1 receptor homology)
Signalling cascades to activate the transcription factors: NF-kB, IRF3 and IRF7
What are intracellular RNA receptors?
= class of PRR
MDA5 = detects long double-stranded RNA (not in humans)
RIG-I = detects short dsRNA and RNA with a tri-phosphate at its 5’ end
What happens after PAMP detection?
PRR signalling activates transcription factors that then switch on many different genes , leads to secretion of:
= CYTOKINES = regulate immune response (e.g. IL-6, TNF-α)
= INTERFERONS = to warn neighbouring cells of viruses
= CHEMOKINES = to recruit immune cells to the site of infection
= ANTIMICROBIAL PEPTIDES = to kill pathogens directly
= ENZYMES = e.g. COX-2 to make prostaglandins
Different PRRs activate different signalling cascades
= different immune response for different pathogens
What is the role of cytokines in inflammation?
IL-6, TNF-α, IL-1:
Local Effects
= vasodilation, increased blood flow (redness)
= increased vascular permeability (swelling)
= activation of macrophages, B and T cells
Systemic Effects:
= bone marrow: haematopoiesis (neutrophils)
= hypothalamus: fever
= liver: acute phase response (complement)
IL-8 (CXCL8):
= recruitment of neutrophils and DCs
IL-10
= inhibition of macrophages and DCs, resolution of inflammation
What is the interferon response?
e.g. IFN-α, IFN-β
Increased antiviral state
= by inducing resistance to viral replication in all cells by inducing Mx protein, 2’-5’ linked adenosine oligomers, and the kinase PKR
Increased antigen presentation
= by increasing MHC class I expression and antigen presentation in all cells
= by activating dendritic cells and macrophages
Increased killing of infected cells
= by activating NK cells to kill virus-infected cells
Increased adaptive immune response
= by inducing chemokines to recruit lymphocytes
What are NK (natural killer) cells?
Activated NK cells release granules containing perforins and granzymes = kill target cell
NK cells have varierty of germline-encoded receptors:
Inhibitory receptors
= detect self molecules such as MHC I
= when MHC I is down-regulated by viruses, this is detected as ‘missing-self’ (tolerance)
Activating receptors
= e.g. NKG2D
= detects MIC-A and MIC-B expressed on epithelial cells that have detected a virus = ‘altered-self’
What is the complement system?
= group of serum proteins in the blood that performs a critical defence against pathogens (especially extracellular bacteria)
= has links to innate immunity (e.g. phagocytosis) and to adaptive immunity (e.g. antibodies)
= there are about 35 proteins in the complement system (including the processed forms)
= most complement proteins are made in the liver
= some produced in large quantities during the acute phase response stimulated by the pro-inflammatory cytokines (IL-6 and TNF-α)
What are the 7 functional categories of complement proteins?
- Initiators
= bind pathogens components or antibodies - Enzymes (convertases)
- Opsonins
= promote phagocytosis - Anaphylatoxins
= cause inflammation - Membrane attack proteins
= lyse pathogens - Complement receptors
= on phagocytes or neutrophils - Regulatory proteins
= limit complement activation