Innate immunity 2 Flashcards
Neutrophil function
Phagocytosis
Reactive oxygen and nitrogen species
Antimicrobial peptides
NETs: neutrophil extracellular traps
Macrophage function
Phagocytosis
Inflammatory mediators
Antigen presentation
Reactive oxygen and nitrogen species
Cytokines
Complement proteins
Dendritic cell function
Antigen presentation
Costimulatory signals
Reactive oxygen species
Interferon
Cytokines
Natural killer cell function
Lysis of viral infected cells
Interferon
Macrophage activation
Phagocyte recruitment
Cytokines dilate local blood vessels
Chemokines attract monocytes and neutrophils to the infection
Cell adhesion molecules are upregulated on the endothelium which bind to integrins on the leukocyte
Phagocytosis performed by
Neutrophils and macrophages
Opsonins
Complement components (C3b)
Collectins (mannose binding lectin)
Antibodies
Phagocytic receptors
Complement receptors
Fc receptors
Manose receptor
Scavenger receptor
Neutrophil extracellular traps
When activated some undergo a special form of cell death termed NETosis
During NETosis nuclear chromatin is released from cells trapping microorganisms thus aiding phagocytosis
Pattern recognition receptors
Receptors able to recognise conserved structures
Recognise patterns termed: pathogen associated molecular patterns (PAMPs)
Types of PRRs
Toll like receptors (TLRs)
NOD like receptors (NLRs)
Rig-I like receptors (RLRs)
Cytosolic DNA sensors (CDS)
PAMPs
Microbes evolve rapidly, so innate immunity must focus on highly conserved and essential components of microbes
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
Extracellular
- LRR domain- site of pathogen binding
Cytosolic side
- TIR domain- conserved stretch of 200 amino acids
TLR signalling induces genes that function in host defence
Pro-inflammatory cytokines
Chemokines
MHC and co-stimulatory molecules
Antimicrobial peptides and complement components
Nod like receptors
Cytoplasmic pattern recognition molecules
Two major groups- NLRCs and NLRPs
NLRCs
NLRC1
NLRC2
They have a leucine rich domain which can bind to peptidoglycan which is present on the cell membrane of most bacteria
NOD1 and NOD2
Detect similar yet distinct peptides of peptidoglycan
NOD1 binds y-glutamyl diaminopimelic acid
NOD2 binds muramyl dipeptide
NOD2 gain of function
Mutation linked to early onset sacroidosis where granulomas develop in the organs of the body
NOD2 loss of function
Mutation is associated with susceptibility to Crohn’s disease, a chronic intestinal inflammatory disorder
NLRPs
The best characterised is NLRP3
NLRP3 is activated by cellular stress; K+ efflux, ATP, reactive oxygen species and lysosomal damage
Inflammasome is essential for IL-1 and IL-18
Inflammasome
Activated by cellular infection or cell stress
- uric acid crystals
- asbestos
- silica
- amyloid beta
- islet amyloid polypeptide
- hemozoin
RIG-I-like receptors
RIG-I and MDA5 are sensors of cytoplasmic RNA, a replication intermediate for viruses
They signal to induce pro-inflammatory cytokines and IFN
RIG-I
Binds to single stranded RNA containing 5’-triphosphate
Recognition of
- flaviviruses
- orthomyxoviruses
MDA5
Preferentially recognises long double stranded RNA
Critical for picornavirus detection
Mutations (rare) are beginning to be associated with IFN related diseases
Cytosolic DNA sensors
Stimulator of interferon genes (STING)- associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain of function mutation in TMEM 173, the gene that codes for sting
Patients have abnormal inflammation throughout the body, especially in the skin, blood vessels and lungs
Acute phase response
Induced by cytokines such as TNF, IL6 and IL1 during infection and inflammation
Acute phase proteins are mainly produced by the liver
Induces opsonisation/ phagocytosis
Can activate the complement pathway
Raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are characteristic of an acute phase response and are used clinically to detect inflammation
