Flashcards in 3. Innate immune defences & inflammation 2 Deck (49)
Innate immune cells
neutrophils, macrophages, dendritic cells, natural killer cells
reactive oxygen and nitrogen species
NETs (neutrophil extracellular traps)
reactive oxygen and nitrogen species
reactive oxygen species
phagocyte recruitment steps
Rolling and extravasation
4. transendothelial migration
How does phagocyte recruitment happen?
1. cytokines e.g. TNF-alpha dilate local blood vessels
2. chemokines attract monocytes and neutrophils to the infection
3. cell adhesion molecules (ICAM-1 and ICAM-2) are upregulated on the endothelium which bind to integrins (family of adhesion molecules) on the leukocytes
What is phagocytosis?
Phagocytosis is the capture and digestion of foreign particles
Performed by neutrophils and macrophages
Put out processes to feel for foreign objects, but not always recognise them sometimes recognises opsonins on opsonised things
What initiates phagocytosis
Active process initiated by binding to pathogen
How does phagocytosis occur?
Macrophage receptors recognise components of microbial surfaces
Microorganisms are bound by phagocytic receptors on the macrophage surface
Microorganisms are internalised by receptor-mediated endocytosis
Fusion of the endosome with a lysosome forms a phagolysosome in which microorganisms are degraded
Antimicrobial mechanisms of phagocytes
Acidification, toxic oxygen-derived profucts, toxic nitrogen oxides, antimicrobial peptides, enzymes, competitors (e.g. lactoferrin)
What are NETs?
When activated some neutrophils undergo a special form of cell death termed ‘NETosis’
During NETosis nuclear chromatin is released from cells trapping microorganisms thus aiding phagocytosis
What are pattern recognition receptors (PRRs)
Receptors able to recognise conserved structures
They recognise patterns termed:
pathogen-associated molecular patterns (PAMPs)
What are some examples of PRRs?
Toll-like receptors (TLRs)
NOD-like receptors (NLRs)
Rig-I like receptors (RLRs)
Cytosolic DNA sensors (CDS)
Pathogen-associated molecular patterns (PAMPs)
PAMPs - Microbes evolve rapidly, so innate immunity must focus on highly conserved and essential components of microbes (cell wall structures; nucleic acids)
DAMPs – Damage associated molecular patterns, molecules released from necrotic cells
Drosophila Toll receptor
Mutagenesis work on Drosophila revealed two members of the Toll family, dToll and 18-wheeler
Important for development
Important for immunity to the fungal and bacterial infections
Mammalian equivalent are the Toll-like receptors
Toll-like receptor structure
LRR domain – site of pathogen binding
TIR-domain - conserved stretch of ~200 amino acids
TLRs form functional hetero/homodimers
The convex surfaces of TLR-1 and TLR-2 have binding sites for lipid side chains of triacyl lipopeptides
Binding of each TLR to the same lipopeptide induces dimerization, bringing their cytoplasmic TIR domains into close proximity
Different TLRs and their ligands
TLR1 and 2- triacyl lipopeptides
TLR2 and 6- diacyl lipopeptides
TLR5 - flagellin
TLR4 - LPS
TLR3, 7, 8 and 9 - DNA and RNA
TLR signalling induces genes that function in host defense
MHC & co-stimulatory molecules
antimicrobial peptides & complement components
What does TLR activate?
IRF3/7, AP1 (thru MAPKs), NFK-beta
TLR adaptor proteins
Myd88 (used in all pathways except TLR3)
Mal used by TLR1/2 and TLR4
TRAM just TLR4
TRIF TLR3 and TLR4
Myd88 gain of function mutation
Waldenström macroglobulinemia is a rare type of non-Hodgkin lymphoma.
B cells make large amounts of IgM that can cause excess bleeding, vision problems and headaches.
Lymphoma cells proliferating in the bone marrow can cause anaemia (low levels of red blood cells), neutropenia (low levels of neutrophils) and thrombocytopenia (low levels of platelets).
Myd88 loss of function mutation
Nine MyD88 deficient children suffered from life-threatening, often recurrent pyogenic bacterial infections, but were otherwise healthy, with normal resistance to other microbes.
Their clinical status improved with age, possibly due to a compensatory effect of adaptive immunity or other innate immune mechanisms.
Herpes simplex encephalitis (HSE): Inflammation of the brain due to infection with herpes simplex virus (HSV-1)
HSV-1 is a dsDNA virus, but during viral replication it produces dsRNA
Defects in other signalling molecules involved in the TLR3 signalling pathway have also been associated with HSE
TLRs in infection
HIV – TLR8
Sepsis – TLR2 and 4
Tuberculosis – TLR2 and 4
TLRs in inflammation
Systemic Lupus Erythamatosus –
TLR7, 8 and 9
Alzheimer's Disease – TLR2 and 4
Atherosclerosis – TLR2 and 4
Infection- genital warts (TLR7)
Cancer - Melanoma (TLR7 ligand)
Allergy – Ragweed pollen (TLR9)