innate immune system Flashcards
Key components of the innate immune system
- Epithelial barriers
- Phagocytes
○ Neutrophiles, monocytes, macrophages, dendritic cells - Innate cell of type 2 immunity
○ Mast cells, eosinophils, basophils - Innate lymphoid cells
○ ILC1,2,3 and Nk cells - Innate T cells
○ Nk cells
Complement
- Phagocytes
Innate vs Adaptive
- Day 0
○ Billions of IIC respond
○ Only tens of adaptive immune cells can respond
○ 2 weeks post- Adaptive immune response increases
- PRR broadly specific and cannot distinguish between PAMPS
- Antigen receptors unique and specific
The innate immune response has no conventional memory
- each innate immune cell can express many PRR
- adaptive immune cell express a single Ag receptor
Physical barriers prevent pathogen entry
- Epithelial cells express PRR upon activation and secrete chemokines and cytokines to recruit IIC
- Mucosal epithelial cells can secrete antimicrobial compounds
ILC3 and th17 can secrete IL-22 which promotes defensin secretion, epithelial cell proliferation and barrier integrity
- Mucosal epithelial cells can secrete antimicrobial compounds
Mucociliary transport
- Epithelial cells from a barrier
- Goblet cells secrete mucus
- Cilia
○ Protrude luminal surface of epithelial cells
○ Move mucus
○ Defected in smokers, anaesthetics, infections, CF
§ Recurrent respiratory infections
CF fills airway with thick mucus blocking airway and allowing bacteria to stick and not move out
Complement
A series of serum proteins (C1-C9) that collectively form a biochemical pathway
Alternative pathway
non-specific chemical reaction
- C3 spontaneously hydrolyses to form C3a and C3b - C3b then form a C3 convertase which triggers the rest of the pathway
Classical pathway
activate by complexes of antibody with antigen
- C1q recognises IgG or IgM bound to antigen - C1q also contains proteases that cleave C4 - C2 is then cleaves generated the C3 convertase - C3b converts the C3 convertase into a C5 convertase
Lectin pathway
triggered by recognition of unique microbial carbohydrates
- Mannose binding lectin (MBL) is a soluble PRR that binds to mannose found on surface of microbes - Proteases associated with MBL cleave C4 - The rest is the same as the classical pathway
lysis by complement
C5 gets cleaved into C5a and C5b
C5a is a very potent pro-inflammatory factor
C5b stuck on microbe surface initiates assembly of membrane attack complex (MAC) comprised of C5b, C6, C7, C8 and C9
Mac generates pores in membrane causing lysis by osmotic shock
inflammation by complement
Proteolysis of C3 and C5 release C3a and C5a
Leucocytes have receptors for C3a and C5a
C3a and C5a are chemo attractants
opsonisation by complement
All complement pathways deposit C3b on cell surface
Phagocytes have receptors for C3b
A microbe covered in C3b recognised by complement receptor, activating phagocyte leading to phagocytosis
macrophages
- Long lived
- All tissues
- Antigen presenting
- Can differentiate
○ M1 inflammatory macrophages secrete pro-inflammatory cytokines
M2 anti-inflammatory macrophages wound healing immunoregulation
monocytes
- Mononuclear phagocyte
- Upon inflammation and infection, monocytes leave and differentiate into macrophages
Monocyte arrive slower than neutrophils (2-3 days vs 2-3 hours)
- Upon inflammation and infection, monocytes leave and differentiate into macrophages
Neutrophils
- Most common
- Short lived
- Rapidly migrate out of circulation to site
- Non presenting antigen
- Effective killers of rapidly growing extracellular organisms
○ Phagocytosis
○ Degranulation
§ Release granules that contain ant-bacterial proteins
○ Neutrophil extracellular traps (NETS) that are a DNA web released, trap and destroy extracellular bacteria
Some bacteria escape by secreting DNAse
Phagocytosis
- PRR specialised in uptake bind to microbes
- Microbial uptake into phagosome
- Phagosome fuses with lysosome, degrading the microbe
Mycobacteria block phagolysosome fusion + acid resistant
4 major classes of PRR’s
- Toll-like receptors (TLR)
- Rig-like helicases (RLH)
- Nod-like Receptors (NLR)
C type Lectin receptors (CLR)
TLR
- Expressed on surface or in endosomes
Recognise PAMPS from a diversity of pathogens
CLR
- Expressed on surface
- Recognise polysaccharides expressed by pathogens
○ Dectin-1 glucan, fungal cell wall
○ Dectin-2 mannan, fungal cell wall
DC-sign n-linked mannan expressed in mycobacteria and viruses
- Recognise polysaccharides expressed by pathogens
RLH
- Located on cytoplasm
Recognise viral dsRNA
NLR
- Cytoplasmic
Damage associated molecular patterns (DAMPS)
Are released upon cellular damage
5 pillars of inflammation
- Heat
- Redness
- Swelling
- Pain
Loss of function
Tissue resident macrophages activated via pattern recognition
- Cytokines activate vascular endothelium leading to vasodilation and increase in vascular permeability (redness, heat, swelling)
- Chemokines recruit leucocytes (pain, loss of function)
- Neutrophils are the first to arrive
Monocytes take 2-3 days
Inflammasome
- Multimeric complex comprised of NLR, the adaptor protein and protease caspase 1
- Structure forms after the NLR binds its ligand
- Cleaves IL-1b
○ Requires 2 signals
§ PRR recognition leads to transcription and translation of Pro-IL-1b
Cleavage of Pro-IL-1b by inflammasome
Stages in leucocyte recruitment
- Cytokines activate vascular endothelium
- Selections: adhesion molecules allow leucocytes to roll on the vascular endothelium
- Chemokines: activate integrins to become high affinity
- Integrins: adhesion molecules that allow leucocytes to stably adhere
- Leucocyte transmigrate out of vasculature and follow chemotactic gradient towards the site of infection
Triggering PRR leads to type I interferon production
- Type 1 interferons (IFNa and IFNb) are cytokines with potent antiviral activity
- Signalling through type I receptor
○ Inhibits viral protein
○ Degrades viral RNA
○ Inhibits viral gene expression and virion assembly - Type I also activate
○ NK cells
Dendritic cells
- Signalling through type I receptor
NK cells
- Innate equivalent of CD8 cells
Activated by IFN
Dendritic cells
- Bridge between innate and adaptive immune system
- Activate naïve t cells
- Morphology maximises contact with T cells
- Short life
Only APC to active naïve T cells
MHC
- Class 1 presented by all nucleated cells
- Class 2 presented by only professional antigen presenting cells
MHC signal recognition
Peptide displayed is recognised by t cell receptor
Costimulation
- CD80 and CD86 interact with T cell CD28
CD28 transduces signals (signal 2) that synergise with signal 1 and lead to T cell proliferation
Cytokine production
Dendritic cells secrete cytokines to drive t cell differentiation
Dendritic cells
- Quiescent/ immature ○ High phagocytic ○ Low mhc II ○ Low costimulation - Mature ○ Low phagocytic ○ High mhc II ○ High costimulation Activated by PAMPs
triggering PRR on dendritic cells
○ Increases MHC and antigen expression
○ Increases cytokine production
Increases costimulation
