2. Innate Immunity Flashcards
What are the 3 lines of defence in innate immunity?
- Physical/ Chemical barriers
> epithelial layers of skin/ mucosal tissue/ glandular tissue
> acidic pH/ antimicrobial proteins - Cellular responses
> innate immune cells recognize pathogens and trigger phagocytosis/ production of antimicrobial proteins/ cytokines - Activation of adaptive immune responses
> through cytokines/ DCs that present antigens
What are the main phagocytic cells?
- macrophages/ neutrophils/ DCs in tissues
- monocytes in blood
What are the 5 steps of phagocytosis?
- Pathogen binds to PRR on pseudopodia
- Pathogen ingested forming a phagosome
- Phagosome fuses with lysosome
- Pathogen is killed/ digested by low pH of lysosomal enzymes
- Digestion products are released from cell
How are phagocytosed microbes killed?
- antimicrobial proteins/ peptides
> defensins- disrupt membranes of pathogens - acid-activated hydrolytic enzymes
> lysozymes- disrupt bacterial cell wall - molecules that mediate oxidative attack
> ROS/ RNS- damage intracellular components
How do antimicrobial ROS/ RNS alter microbes?
- oxidation/ hydroxylation/ chlorination/ nitration
How do phagocytes recognize microbes?
- Direct recognition > through PRRs
- Indirect recognition > through opsonin receptors
How do phagocytes respond to microbes?
- killing through phagocytosis/ complement activation
- inflammation (cytokines)
- initiation of adaptive responses
What is direct recognition by phagocytes?
- PRRs on phagocytes bind to PAMPs on surface of microbes
What are some examples of PRRs/ PAMPs?
- PRRs > mannose receptors/ SR-A
- PAMPs > mannans/ LPS (lipopolysaccharide)
What are MAMPs?
- PAMPs can be expressed by microbes whether or not pathogenic
- MAMPS > more general term can be used
What is indirect recognition by phagocytes?
- opsonin receptors on phagocytes bind to opsonins
- opsonins > soluble proteins that bind to PAMPs on surface of microbes
What are some examples of opsonin receptors/ their ligands (opsonins)?
- opsonin receptors > CD91/ FcyRs
- opsonins > L-ficolin/ C-reactive protein
- PAMPS > acetylated sugars/ phosphorylcholine
What is opsonization?
- phagocyte recognition of opsonins bound to microbial PAMPs enhances phagocytosis
How does phagocytosis contribute to cell turnover/ clearance of dead cells?
- PPRs on phagocytes recognize DAMPs on dead/ dying/damaged cells
How does RBC cell turnover occur?
- as RBCs age, phosphatidyl serine flips from inner > outer membrane leaflet
- phosphatidyl serine is recognized by its receptor on macrophages
> phagocytosis/ degradation of old RBCs
What are the 4 families of PRRs?
- TLRs > toll-like receptors
- CLRs > c-type lectin receptors
- RLRs > retinoic acid-inducible gene-I-like receptors
- NLRs > nod-like receptors
Where are TLRs located/ what do they do?
- exist both on PM/ lysosome and endosome membranes
- TLRs on plasma membrane > recognize PAMPs on outer surface of extracellular microbes
- TLRs on endosomes/ lysosomes > recognize internal microbial components
- detect DAMPS from dead/ dying/damaged tissues
- do not promote phagocytosis
Where are CLRs located/ what do they do?
- plasma membrane receptors
- recognize carbohydrate components of extracellular pathogens
Where are RLRs located/ what do they do?
- soluble PRRs that reside in cytosol
- sense viral infection > distinguish viral/ cellular RNA
- bind viral RNA in cytosol of infected cells
Where are NLRs located/ what do they do?
- cytosolic proteins activated by intracellular PAMPs/ DAMPs
- some activate gene transcription > cytokines/ antimicrobial proteins
- some assemble with other proteins into a complex > activates proteases that convert IL-1 precursor > mature form
> IL-1 is very inflammatory > NLR complex = Inflammasome
What are inflammasomes?
- complexes of NLRs that activate proteases > convert IL-1 precursor > inflammatory mature form of IL-1
How does PRR signalling contribute to the expression of innate immunity proteins?
- PRR-activated signalling pathways > expression of genes with functions in immunity > production of antimicrobial proteins/ cytokines/ chemokines
What is the structure of TLRs?
- exterior domain
> leucine-rich repeats (LRRs) make up the ligand-binding domain - membrane-spanning domain
- TIR domain (intracellular)
> interacts with other members of TLR signaling pathway
What happens when TLRs bind their ligands?
- induced to dimerize
What is the cellular location of TLRs?
- TLRs that bind extracellular ligands > in plasma membrane
- TLRs that bind internal microbial components > lysosomes/ endosomes
- upon ligand binding, the TLR4/4 dimer moves from plasma membrane > endosomal/ lysosomal compartment
How is TLR signalling initiated?
- TLR-signalling is initiated after ligand-induced TLR dimerization
- the signal transduction pathway activated by TLR dimer is determined by the protein adaptor that binds to TLRs cytoplasmic TIR domain
> 2 key adaptors recruited to TLR dimers: MyD88 (most)/ TRIF
What are the steps in TLR signalling? (signal transduction pathway)
- MyD88 adaptor protein binds to cytoplasmic TIR domain of TLRs
> recruits kinases IRAK1/ IRAK4 > phosphorylate self/ other proteins
What are 4 common strategies used in many signalling pathways?
- ligand binds to receptor > conformational change in receptor ex) dimerization of TLRs
- some receptors require receptor-associated molecules
> if cytoplasmic tails too short, can not get phosphorylated - tyrosine kinases activated > tyrosine phosphorylation
- ubiquitination > may inhibit/ enhance signal transduction
What do adaptor proteins do?
- gather members of signalling pathways
What is the complement system?
- set of serum proteins that cooperate with immune system to eliminate pathogens
How does the complement system cooperate with the immune system to eliminate pathogens? (3x)
- various complement components bind/ opsonize pathogens
- some complement proteins elicit inflammatory responses/ clear immune cells/ eliminate apoptotic cells
- MAC assembled from complement proteins > kills pathogens by creating pores in microbial membranes
What are the 7 functional categories of complement components?
- complement pathways initiated by proteins that bind to pathogens
> C1q = initiator of cascade - enzymes are the central proteins of the complement cascade
> C3/ C5 convertase (cleave C3/C5 > releasing active components) - opsonization (C3b opsonin)
- inflammation (C5a anaphylatoxin)
- generation of MAC
- complement effectors act by binding to their receptors (CR1/CR3)
- regulatory proteins limit the effects of complement by promoting their degradation/ preventing their binding to host cells
What is psoriasin?
- antimicrobial protein secreted by skin that kills E.coli
Why does lysozyme not damage human cells?
> antimicrobial protein that cleaves glycosidic bonds in cell walls of bacteria
- mechanism of action > cleaves glycosidic bonds in cell walls
> human cells do not have cell walls
What are the 5 hallmarks of inflammation?
(localized inflammatory response)
- redness/ swelling/ heat/ pain/ loss of function
What are the 3 steps of inflammation?
(innate response triggered by local infection/ tissue damage)
- Initiation > activation of macrophages/ DCs by PAMPS/ DAMPs
> release of mediators IL-1/ histamine > vasodilation
> recruitment of neutrophils/ monocytes - Amplification > recruited cells do phagocytosis/ release additional mediators
- Resolution > cytokines (mainly TNF/ IL-1/ IL-6) induce AFR
> cytokines act on hepatocytes > secrete AFR proteins at ↑ levels
What are AFR proteins?
- serve as opsonins/ activate complement-mediated attack on microbe
- ex) mannose-binding lectin/ C-reactive protein
What is NETosis?
- form of regulated cell death induced by PAMP-activated PRR signalling
- catching/ killing pathogens by neutrophil extracellular traps (NETs)
> NETs are filaments of chromatin that neutrophils expel to entrap pathogens
What are the steps of NETosis?
- signals from PRRs activate neutrophils
- NADPH oxidase activated > generation of ROS damages cell compartments
- cell membrane disintegrates > cellular contents (chromatin filaments) expelled to form NETs
- NETs trap pathogens > cell dies from NETosis
How do NETs indirectly contribute to innate immunity?
- DNA/ chromatin components serve as DAMPs
> further activates innate responses
What are the innate immune response mechanisms of plants?
- no phagocytosis
- generation of ROS/ RNS
- ↑ internal pH
- induction of antimicrobial peptides (including defensins)
- induction of antimicrobial enzymes > digest cell walls
- production of organic molecules > antibiotic activity (phytoalexins)
- plants have PRRs with leucine-rich repeats > recognize PAMPs
What are some structural changes of plants in response to pathogens?
- binding to PRRs induces closure of leaf stomata
> limits infection by preventing any further microbial invasion - strengthening walls of surrounding noninfected cells
- induced death (necrosis) of cells surrounding infection to limit spread
What is the only vertebrate that does not make antibodies?
- Jawless fish > have VLRs instead (variable lymphocyte receptors)
How do immune responses differ between multicellular organisms?
> plants/ invertebrate animals/ vertebrate animals
- plants > only innate immunity/ no phagocytosis
- invertebrates > innate immunity/ phagocytosis
- vertebrates > both innate/ adaptive immunity
