Innate Immune Responses Flashcards
What does innate immunity involve?
- Antimicrobial peptides
- Phagocytosis
- NK cells
- Interferons
- Complement system
- Acute inflammatory response
What are the host defences in order?
- Anatomical and chemical barriers- skin, mucus, antimicrobial peptides in mucus
- Intrinsic immunity
- Innate immunity
- Aquired immunity
Outline intrinsic immunity
Always present in uninflected cells
• Apoptosis, autophagy, RNA silencing, antiviral proteins
• Cellular proteins that inhibit viral replication (TRIM, APOBEC3, Tethering)
What are permissive and non-permissive cells?
Whether they allow viral infection within themselves
Which cellular proteins inhibit viral replication?
TRIM
APOBEC3
Tetherin
What are the soluble mechanisms of innate immunity?
• Antimicrobial enzymes (lysozymes) and Antimicrobial proteins (defensins, cathelicidins, histatins)
—> present in skin (from keratinocytes and epithelial cells) and in cell granules
• Complement, cytokines, acute phase proteins
Outline defensins
• Small cationic (+ve) antimicrobial peptides
• Kill bacteria, fungi, some viruses
• Insert into negatively charged membrane to create holes
• Widely expressed (leukocytes and epithelium), intracellular and secreted
• Two structural families
- α-Defensins- constitutively expressed
- β-Defensins- Some induced (by lipopolysaccharide LPS)
Outline innate cellular responses
Respond to threat or communicate to other cells
• must distinguish infectious agents from commensals, self-antigens and environmental antigens- present auto/allergy
• Pattern recognition receptors (PRRs) recognise pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs)
Outline antigen recognition
Innate:
• about 1000 molecules can be recognised, <100 types of receptor
• germ-line encoded so limited diversity
Adaptive:
• recognises specific epitopes
• >10^7 molecules recognised, 2 receptor types- TCR and antibody
• Somatic recombination so huge diversity
Outline pattern recognition receptors PRRs
Soluble molecules: • pentrexins (eg CRP) • collectins (eg mannose binding lectin) • ficolins • complement proteins- recognise lipopolysaccharides (LPS) or terminal sugars on microbial cell wall
Cell-associated molecules:
• cell surface (C-type lectins, TLR 2,4,5, scavenger receptors on phagocytes)
• endosome/phagosome (some TLRs- 3,7,8,9- recognise nucleus acids not wall)
• cytosolic (NOD-like receptors NLRs, RIG-like receptors, c-GAS)- sense DNA in cytoplasm- damage
Outline the function of Toll-like receptors TLRs
Major group of PRR
Ligand engages TLR
- > association of protein kinases to adaptor proteins
- > activation of transcription factors
- > respiratory burst, cytokines, chemokines, MMPs, antimicrobial peptides, expression of costimulatory molecules (APCs)
Give examples of TLRs
Plasma membrane: • TLR2- bacterial lipopeptides and lipoproptein • TLR4- bacterial LPS • TLR5- bacterial flagellin —> IRF, NFκB (B cell activation)
Endosomal:
• TLR3- viral dsDNA
• TLR7+8- viral ssRNA nucleotide analogues
• TLR9- bacterial unmethylated CpG DNA
—> IRF (interferon regulatory factor)/NFκB
Outline the classes of PRR
• NOD-like receptors (NLRs)
- NOD1/2 recognise peptidoglycans in bacterial cell wall to prevent escape from phagosome
- NLRP3 forms part of inflammasome and recognises bacterial products and DAMPs (ATP, ROS)
- RIG-like receptors- recognise viral RNA (RIG1, MDAS)
- Cytosolic DNA sensors- recognise microbial DNA in cytoplasm (c-GAS/STING pathway)
What are the cells of innate immunity and what do they do?
- Macrophages
- Dendritic cells
- Polymorphonuclear leukocytes (neutrophils, eosinophils, basophils)
- mast cells
- NK cells (borderline innate/adaptive)
—> Phagocytosis, inflammation, cytotoxicity
Outline phagocytosis
• Neutrophils first to respond, then monocytes enter tissue and become macrophages
- Chemotaxis/scavenger molecule recognition of pathogen
- Adherence via PAMP recognition
- Cell activation via PRR
- Phagocytosis initiation- encloses pathogen
- Phagosome formation
- Phagolysosome formation- joining to lysosome
- Enzymes, pH, killing of bacteria (respiratory burst-> O2 dependent killing- ROS and RNS generated)
- Release of degradation products
What is opsonization?
- Complement or antibody coating of a microbe to make phagocytosis more efficient
- Antibodies (with Fc) bound to microbes bind to FcR on phagocytes
- Complement (can be activated by antibodies)-> more opsonization and chemotaxis and increased vascular permeability-> influx of phagocytes
What are the microbicidal mechanisms of phagocytic cells?
- Reactive oxygen intermediates:
H2O2-> HOCl + •OH chloramines (damage bacterial cell wall) - Nitric oxide:
O2-> NO• -> •ONOO peroxide nitrile radical
- Inhibited by L-NMMA arginine analogue - Oxygen-independent mechanisms (enzymes):
• Damage microbial membranes
-Cathepsin G
-bacterial permeability increasing protein BPI)
• Split mucopeptide in bacterial cell wall (crystal lattice structure)
-lysozome
• Complex with iron
-lactoferrin
• Digestion or killed organisms
-proteolytic enzymes
-other hydrolysis enzymes
Describe natural killer cells
- Large granular lymphocytes
- 5-10% of circulating leukocytes
- Destroy abnormal host cells (infected, tumour, stressed)
- Granules contain killing molecules
- Makes interferon-γ in response to signals
Describe the activation of NK cells
• Missing self- lack of MHC class 1 which usually inhibits NK response from activated receptors
- tumours- lymphoma, melanoma
- infection- adenovirus, CMV
• Activators- many activators can cause response despite MHC class 1 presence- eg viral haemagglutinins/antibody coated cells
Describe the mechanisms of NK cell killing
• Granules contain perforin and granzymes
- perforin punches holes (pores) in target cell
- granzymes enter through pore and digest cell
- OR endocytosis and perforin-assisted release from vesicle
• Fas ligand pathway to apoptosis
- FasL binds Fas (both on membranes) and activates FADD
- FADD-> Procaspase-8-> Caspase-8-> Caspase-3inactive-> Caspase-3-> APOPTOSIS
Outline dendritic cells and the difference between immature and mature DCs
Link between innate and adaptive
• Immature DCs pick things up by endocytosis/phagocytosis
• Mature in inflamed tissues following antigen capture and cytokine signals
• Mature DCs migrate to lymph nodes and present antigenic peptides to T cells
• DCs are professional APCs- at birth they are only cell able to APC
Immature DCs
- high antigen uptake- highly phagocytic
- low surface MHC class II
- low costimulatory molecules (needed to activate T cells)
- CCR7+, CCR1,2,5,6+ chemokine Rs
Mature DCs
- low antigen uptake- poorly phagocytic
- high surface MHC
- high costimulatory molecules
- CCR7+++
