Innate immune defences and inflammation 2 Flashcards
What are the functions of neutrophils?
Phagocytosis
Reactive oxygen + nitrogen species
Antimicrobial peptides
NETS -> neutrophil extracellular traps
What are the functions of macrophages?
Phagocytosis Inflammatory mediators Antigen presentation Reactive oxygen + nitrogen species Cytokines Complement proteins
What are the functions of dendritic cells?
Antigen presentation Co-stimulatory signals Reactive oxygen species Interferons Cytokines
What are the functions of natural killer (NK) cells?
Lysis of virally-infected cells Interferon Macrophage activation Granzyme Perforin
How are phagocytes recruited?
Cytokines dilate local blood vessels.
Chemokines attract monocytes + neutrophils to infection -> cell adhesion molecules ICAM-1 + ICAM-2 are upregulated on endothelium which bind to integrins on leukocytes.
Rolling -> activation -> adhesion -> transendothelial migration.
What is required for phagocytosis and which cells can perform phagocytosis?
Neutrophils, dendritic cells, macrophages.
Opsonins -> complement components (C3b), collectins (mannose-binding lectin), antibodies.
Phagocytic receptors recognise opsonins -> complement, Fc, mannose, scavenger.
What are the antimicrobial mechanisms of phagocytes?
Macrophage + neutrophil: Acidification -> pH 3.5-4, bactericidal Toxic oxygen-derived products Toxic NO Antimicrobial peptides -> macrophage: cathelicidin, macrophage elastase-derived product, neutrophil: a+b defensins, cathelicin, BPI, lactoferricin Lysozyme Neutrophil: Competitors -> neutrophil: lactoferrin
What are Neutrophil Extracellular Traps (NETs)?
Netosis -> form of cell death -> nuclear chromatin released from cells -> traps microorganisms -> aids phagocytosis
What is the function of pattern recognition receptors (PRRs)
recognise pathogen-associated molecular patterns (PAMPs) -> important due to rapid replication rate.
C type lectin (CLRs), Toll-like (TLRs), NOD-like (NLRs), Rig-I like (RLRs), cytosolic DNA sensors (CDS).
What are PAMPs and DAMPs?
PAMPs -> peptidoglycan, lipopolysaccharide, DNA,
RNA.
Damage Associated Molecular Patterns -> molecules released from necrotic cells.
Which cells express C-type Lectin Receptors and what are their functions?
Most cell type thatphagocytose glycoproteins + microbes for antigen presentation to T lymphocytes.
Bind to carbohydrates in calcium-dependent manner.
Type I -> assist with antigen uptake by phagocytes
Type II -> fungal recognition
Soluble -> e.g. MBL binds carbohydrates on pathogen surfaces.
What are the two members of the toll receptor family for invertebrates and what are their functions?
dToll + 18-wheeler -> for development + immunity to fungal + bacterial infections
What is the structure of toll-like receptors?
Extracellular: LRR domain –> site of pathogen binding
Cytosolic side: TIR-domain
Form functional hetero/homodimers -> binding each TLR to same lipopeptide induces dimerisation -> brings cytoplasmic TIR-domain to close proximity.
Outline the cellular location of TLRs and their PAMPs
Cell surface: TLR-2 + TLR-6 -> diacyl lipopeptides TLR-2 + TLR-1 -> triacyl lipopeptides TLR-5 -> flagellin TLR-4 -> lipopolysaccharide Endosome: TLR-3/10 -> dsRNA TLR-7 -> ssRNA TLR-8 -> ssRNA TLR-9 -> CpG DNA
What is the function of TLR signalling?
Induces genes that function in host defence.
Pro-inflammatory + anti-inflammatory cytokines
Chemokines
MHC + co-stimulatory molecules
Antimicrobial peptides + complement components
What are the consequences of having the TLR adaptor protein Myd88?
Recurrent pyogenic bacterial infections, normal resistance to other microbes.
Improved with age possibly due to compensatory effect of adaptive immunity or other innate immune mechanisms.
What are the consequences of TLR-3 deficiency?
Herpes simplex encephalitis -> inflammation of brain due toinfection with HSV-1 -> dsDNA, produces dsRNA during viral replication.
Defects in other signalling molecules in TLR3 signalling pathway -> HSE.
Over-activation of TLRs are associated with which conditions?
Infection: HIV -> TLR-8 Sepsis, TB -> TLR-2,4 Inflammation: SLE -> TLR-7,8,9 Alzheimer's, atherosclerosis -> TLR-2,4
What are the TLR-agonists and antagonists that can treat potential conditions?
Agonist: Infection -> genital warts -> TLR-7 Cancer -> melanoma -> TLR-7 ligand Allergy –> ragweed pollen -> TLR-9 Antagonist: Autoimmunity -> TLR-7,8,9 Sepsis -> TLR-4
What are NLRs and what are the two major groups?
Cytoplasmic pattern recognition molecules.
NLRCs + NLRPs (‘C’ -> ‘caspase recruitment domain, ‘P’ -> pyrin domain).
What are two examples of NLRCs and what are their functions?
Their leucine rich domain can bind to peptidoglycan:
NOD1 binds iE-DAP -> mainly Gm-ve bacteria.
NOD2 binds muramyl dipeptide -> Gm+ve + Gm-ve bacteria.
What are the mutations of NOD2?
Gain of function -> early onset sarcoidosis -> granulomas develop in organs.
Loss of function -> susceptibility to Crohn’s disease.
How are NLRPs activated?
Cellular stress, K+ efflux, ATP, ROS, lysosomal damage. e.g. crystals -> uric acid crystals (gout), amyloid beta (Alzheimer’s), islet amyloid polypeptide (T2DM).
Inflammasome has ASC + caspase 1 filaments, essential for IL-1 + IL-18 secretion.
What does inflammasome activation lead to?
Cleavage of pro-IL-1 + pro-IL-18 to allow secretion
What is an example of a gain of function mutation in NMRP3 and what is it treated by?
Cryopyrin-Associated Periodic Syndromes (CAPS):
mutations in exon 3 of NLRP3 gene -> over production of IL-1.
Anakinra (IL-1RA)
What are the RLRs and what are their functions?
RIG-I + MDA5 -> sense cytoplasmic RNA, signal to induce pro-inflammatory cytokines + IFN.
RIG-I -> binds to ssRNA containing 5’-triphosphate,
recognises hep C (HCV), influenza.
MDA5 -> recognises dsRNA, detects picornavirus,
mutations (rare) -> IFN related diseases.
What is a cytosolic DNA sensor and what is its mutation?
cGAS recognises viral dsDNA -> binds, converts ATP + GTP into cyclic G AMP.
STING-SAVI -> auto-inflammatory disease caused by gain-of-function mutations in STING gene ->abnormal inflammationthroughout body, especially skin, blood vessels, lungs.
What is the function of acute phase proteins and what are they mainly produced by?
Liver, induced by TNF, IL-6 + IL-1 during infection + inflammation.
Activate complement -> induce opsonisation/phagocytosis.
Raised erythrocyte sedimentation rate (ESR) + CRP -> characteristic of acute phase response + used clinically to detect inflammation.
