T1 L3 Innate immune defences and inflammation 2 Flashcards
What are the functions of neutrophils?
Phagocytosis
Reactive oxygen and nitrogen species
Antimicrobial peptides
What are the functions of macrophages?
Phagocytosis Inflammatory mediators Antigen presentation Reactive oxygen and nitrogen species Cytokines Complement proteins
What are the functions of dendritic cells?
Antigen presentation Costimulatory signal Reactive oxygen species Interferon Cytokines
What are the functions of natural killer cells?
Lysis of viral infected cells
Interferon
Macrophage activation
What are the 4 stages of phagocyte recruitment?
1) Rolling
2) Activation
3) Arrest / adhesion
4) Transendothelial migration
What is phagocytosis?
Capture and digestion of foreign particles
Performed by neutrophils and macrophages
What stimulates phagocytosis?
Opsonins
Phagocytic receptors
Give examples of some opsonins that trigger phagocytosis
Complement components
Collectins (mannose-binding lectin)
Antibodies
Give examples of some phagocytic receptors that trigger phagocytosis
Complement receptors
Fc receptors
Mannose receptors
Scavenger receptors
What initiates the active process of phagocytosis?
Binding to the pathogen
What are the steps of phagocytosis?
1) Macrophage receptors that recognise components of microbial surface
2) Microorganisms bound by phagocytic receptors on macrophage surface
3) Microorganisms are internalised by receptor-mediated endocytosis
4) Fusion of endoscope with a lysosome to form phagolysosome in which microorganisms are degraded
Describe the acidification of antimicrobial mechanism of phagocytes
Macrophage and neutrophil products:
- pH around 3.5 to 4
- Bacteriostatic or bactericidal
Describe the toxic oxygen-derived products
Macrophage and neutrophil products:
- superoxide
- hydrogen peroxide
- singlet oxygen
- hydroxyl radical
- hypohalite
Describe the antimicrobial peptides of macrophage products
Cathelicidin
Macrophage elastase-derived peptide
Describe the antimicrobial peptides of neutrophil products
Alpha-defensins Beta-defensin Cathelicin Azurocidin Bacterial permeability inducing protein Lactoferricin
Describe how enzymes contribute to the antimicrobial mechanism
Macrophage and neutrophil products:
- lysozyme
- acid hydrolyses e.g. elastase and other proteases
Describe the competitors of antimicrobial mechanisms of phagocytes for neutrophil products
Lactoferrin (sequesters Fe2+)
Vitamin B12
Binding protein
What happens during NETosis?
Activation of neutrophil Cell bursts Nuclear chromatin is released from cells Forms NETs Traps microorganisms Aids phagocytosis
Give examples of types of pattern recognition receptors
Toll-like receptors (TLRs)
NOD-like receptors (NLRs)
Rig-I like receptors (RLRs)
Cytosolic DNA sensors (CDS)
What are DAMPs?
Damage associated molecular patterns that are released from necrotic cells
What is the structure of the toll-like receptor?
Extracellular: LRR domain which is the site of pathogen binding
Cytosolic side: TIR domain conserved stretch of around 200 amino acids
Describe how toll-like receptors form functional hetero/homodimers
Convex surfaces of TLR-1 and TLR-2 have binding sites for lipid side chains of triacyl lipopeptides
Binding of each TLR to same lipopeptide will induce dimerisation which brings their cytoplasmic TIR domains into close proximity
What TLRs are on the surface?
TLR-1 TLR-2 TLR-4 TLR-5 TLR-6
What exogenous products do cell surface TLRs recognise?
Mainly bacterial products:
- lipopolysaccharide
- flagellin
- lipoteichoic acid
What endogenous products do cell surface TLRs recognise?
HSP70
Fibrinogen
Fibronectin
What TLRs are endosomal?
TLR-3 TLR-7 TLR-8 TLR-9 TLR-10
What exogenous products do endosomal TLRs recognise?
Mainly recognise viral products
- dsRNA
- ssRNA
- DNA
What endogenous products do endosomal TLRs recognise?
dsRNA
ssRNA
DNA
What genes does TLR signalling induce?
Genes that function in host defence
- pro inflammatory cytokines
- chemokines
- MHC and co-stimulatory molecules
- antimicrobial peptides and complement components
What are the 2 main pathways that TLR signals down?
MyD88 dependent pathway
Trif pathway
What does the MyD88 pathway activate?
AP-1
NF-kB
What does the trif pathway activate?
IRF family members which drive production of type 1 interferon
What TLR adaptor proteins only use Myd88?
IL-1R TLR5 TLR7 TLR8 TLR9
What pathway does TLR1/2 use?
Myd88
Mal
What pathway does TLR3 use?
Trif
What pathway does TLR4 use?
MyD88
Mal
TRAM
Trif
What is Waldenstrom macroglobulinaemia?
Rare type of non-Hodgkin lymphoma
B cells make large amounts of IgM which causes excess bleeding, Vision problems and headaches
Lymphoma cells proliferating in bone marrow can cause anaemia, neutropenia and thrombocytopenia
Why does the clinical status of children with MyD88 deficiency improve with age?
Compensatory effect of adaptive immunity or other innate immune mechanisms
What are the consequences of TLRs deficiency?
Herpes simplex encephalitis
What TLRs are involved in causing HIV?
TLR8
What TLRs are involved in causing sepsis?
TLR2 and TLR4
What TLRs are involved in causing tuberculosis?
TLR2
TLR4
What TLRs are involved in inflammation of systemic lupus erythematous?
TLR7
TLR8
TLR9
What TLRs are involved in inflammation of Alzheimer’s disease?
TLR2
TLR4
What TLRs are involved in inflammation of atherosclerosis?
TLR2
TLR4
What TLR agonist are used to treat genital warts?
TLR7
What TLR agonists are used to treat melanoma?
TLR7 ligand
What TLR agonists are used to treat allergy to ragweed pollen?
TLR9
What TLR antagonists are used to treat autoimmunity?
TLR7
TLR8
What TLR antagonists are used in treatment of sepsis?
TLR4
What are NLRs?
Nucleotide-binding leucine rich (NLR)
Cytoplasmic pattern recognition molecules
What are the 2 major groups of NLRs?
NLRCs = NLR caspase recruitment domain NLRPs = NLR pyrin domain
What are 2 examples of NLRCs and what do they bind?
NLRC1 (NOD1) - bind iE-DAP
NLRC2 (NOD2) - binds muramyl dipeptide
What is a NOD2 gain of function mutation associated with?
Early onset sarcoidosis where granulomas develop in organs of the body
What is a NOD2 loss of function mutation associated with?
Susceptibility to Crohn’s disease
What is NLRP3 activated by?
Cellular stress K+ efflux ATP Reactive oxygen species Lysosomal damage
What is the consequence of NLRP3 gain of function mutation?
Cryopyrin-associated periodic syndromes
- Muckle wells syndrome
- familial cold auto inflammatory syndrome
Describe Muckle Wells syndrome
Occurs spontaneously or triggered by cold, heat, fatigue or other stressors
Symptoms: fever, rash, arthralgia, conjunctivitis, uveitis, sensorineural deafness, potentially life-threatening amyloidosis
Describe familial cold auto inflammatory syndrome
Triggered by exposure to cold
Symptoms: fever, urticarial rash with headache, arthralgia, conjunctivitis
How is muckle wells syndrome and familial cold auto inflammatory syndrome treated?
Anakinra (IL-1RA)
What activates the inflammasome?
Cellular infection or cell stress
- uric acid crystals (gout)
- asbestos
- silica
- amyloid beta (Alzheimer’s)
- Islet amyloid peptide (type 2 diabetes)
- Hemozoin (malaria)
What does activation of the inflammasome lead to?
Cleavage of pro-IL-1 and pro-IL-18 to allow secretion
What are RIG-I like receptors?
Sensors of cytoplasmic RNA that signal to induce pro-inflammatory cytokines and IFN
Describe RIG-I
Binds to single-stranded RNA containing 5’-triphosphate
What does RIG-I recognise?
Flaviviruses (hepatitis C)
Orthomyxoviruses (influenza)
What does MDA5 recognise?
Long double-stranded RNA
Describe cytosolic DNA sensors
1) Double-stranded DNA from viruses activates cGAS
2) Produces cGAMP from ATP and GTP
3) cGAMP or other bacterial-derived cyclic dinucleotides bind to STING dimer on ER membrane which activates its signalling
4) STING activates kinase TBK1 which phosphorylates IRF3, which enters nucleus and induces expression of type 1 interferon genes
What is SAVI?
Autoinflammatory disease
STING-associated vasculopathy with onset in infancy
What is SAVI caused by?
Gain of function mutations in TMEM173 (gene that codes for STING)
What does SAVI cause?
Abnormal inflammation throughout body, especially in skin, blood vessels and lungs
What induces the acute phase response?
Cytokines such as TNF, IL-6, IL-1
What does the acute phase response induce?
Opsonisation / phagocytosis
Can activate complement pathway
How can we detect inflammation clinically?
Raised ESR and CRP which are characteristic of acute phase response
