Innate immunity Flashcards
The immediate response occurs within 4 hours of pathogen invasion. Describe what happens
- pathogen invades tissue and proliferates
- it is recognised by preformed soluble effector molecules and resident effector cells in infected tissue
- pathogen is eliminated and the infection ends
Result: very minor tissue damage is repaired
The induced response occurs between 4 hours and 4 days post infection.
- pathogen invades tissue and proliferates
(if pathogen is not eliminated in immediate response then proceed with induced innate immune response) - activation of cells resident in the infected tissue + recruitement of effector cells to the infected tissue = inflammation, fever, acute-phase response
- soluble effector molecules and effector cells recruited to the infected tissue recognise and attack the pathogen
Result 1: pathogen is eliminated and minor tissue damages is soon repaired
Result 2: pathogen is not eliminated, proceed with adaptive immune response
What is the difference between the innate and adaptive immune system?
INNATE
- genome determined
- expressed by all cells of a particular type (variable)
- immediate response
- recognises BROAD classes of pathogens
- interacts with a range of molecular structures of a given type
ADAPTIVE
- encoded in multiple gene segments
- require gene rearrangements
BOTH able to discriminate between even closely related molecular structures
What can be said about learning in innate immunity?
Some learning does occur via epigenetic changes- theres are some things that occur to boost response to antigen exposed recently
Consider the anatomical barriers
Describe those in and around the SKIN
- epithelial cells and tight junctions
- longitudinal flow of air
- fatty acids
- antimicrobial peptides
- normal microbiota
Consider the anatomical barriers
Describe those in and around the GUT
- epithelial cells and tight junctions
- longitudinal flow of fluid
- low pH
- antimicrobial enzymes + peptides
- normal microbiota
Consider the anatomical barriers
Describe those in and around the LUNGS
- epithelial cells and tight junctions
- movement of mucus by cilia
- pulmonary surfactant
- antimicrobial peptides
- normal microbiome
Consider the anatomical barriers
Describe those in and around the EYE/NOSE/ORAL CAVITY
- tears, nasal cilia
- antimicrobial enzymes in tears and saliva
- normal microbiome
How does tissue damage trigger an immune response?
- damage causes release of vasoactive and chemotactic factors that trigger a local increase in blood flow and capillary permeability
- permeable capillaries allow influx of exudate and cells
- phagocytes migrate to site of inflammation (chemotaxis)
- phagocytes and antibacterial exudate destroy bacteria
Consider the soluble innate immune molecules
How do lysozymes mediate an immune response
- disrupt peptidoglycan; only effective against gram +
- secreted by phagocytes and paneth cells from s.bowel
- cleaves the bond between the alternating sugars that make up peptidoglycan
Consider the soluble innate immune molecules
How do antimicrobial peptides generally mediate an immune response
- they cover epithelial surfaces and found in saliva
- secreted by neutrophils, ep. cells and paneth cells in crypts of s.bowel
- kill bacteria in minutes by disrupting membrane
- also attack fungi, viruses (influenza + herpes)
- inhibit DNA and RNA synthesis
Give three examples of antimicrobial peptides. Describe them
HISTATINS
- produced in oral cavity against pathogenic fungi e.g. Candida albicans
DEFENSINS (alpha and beta)
- 35-40 AAs amphipathic peptides
- disulfide bonds stabilise the structure to have a positive charge region separated from a hydrophobic region
CATHELICIDINS
- LL-37 broad spectrum antimicrobial activity against gram -/+ bacteria
Consider the soluble innate immune molecules
How do collectins mediate an immune response
Have a globular lecti like head that binds bacterial cell surface sugars. Sialic acid hides mannose antigens on host cells
Consider the soluble innate immune molecules
How do ficolins mediate an immune response
Recognise acylated compounds such as n-acetylglucosamine, a monosaccharide found in bacterial cell walls
Consider the soluble innate immune molecules
What are pentraxins?
Cyclic multimeric protiens found in plasma
What is CRP used for?
C reactive protein is used as a clinical measure of inflammation
Outline the activation of the classical complement pathway
C1= C1q (dominates), C1r, C1s
C1 binds to the Fc region of an antibody-antigen complex. Must bind at least 2 FC domains
IgM is the most efficient at activating complement as it has 5 Fc domains. IgG1 and G3 to a lesser extent. IgG2 can also acitivate complement when close to antigen.
What is the complement system?
Series of proteins that constantly circulate in blood (as proform)and fluids that bathe tissues. When they detect foreign material that initiate a cascade of reactions that amplify the signal.
- Aid in inflammation and removal of pathogen
- Most proteins made by liver but also produced by monocytes, macrophages and ep. cells of intestine and urinary tract.
Can serum IgM activate complement?
No because it cannot bind C1 as it has a planar conformation, she shape changes on binding antigen to reveal binding sites for C1q.
How does amplication occur via the classical complement pathway?
- binding C1q with the Fc domain causes a conformational change in C1r
- C1s is cleaved and can activate C2 and C4 splitting into small and large fragments
- C3 convertase then activates over 200 C3 molecules producing a massive amplification of the signal
- C4b, C2a and C3b fragments form the c5 convertase that activates C5 –> membrane attack complex
How is lectin complement pathway activated?
- Antibody independeny, activated by ficolins and MBL (binds mannose on surface of bacteria and viruses)
- Upon binding, MBL forms a complex with MASP1 and MASP2
- Active complex cleaves C2, C4
Describe the alternative pathway
- Activated by pathogen surfaces
- C3 spontaneously hydrolyses into C3a and C3b
- C3b binds to a cell membrane and factor B making it susceptible to cleavage by factor D to Bb (C3 convertase)
- C3 convertase hydrolyses more C3 creating more C3b thus amplifying the signal
State the downstream consequences of activated C3 convertase
C3a + C5a
- peptide mediators of INFLAMMATION
- PHAGOCYTE RECRUITEMENT
C3b
- binds to complement receptors on phagocyte–> opsonisation of pathogens and removal of immune complexes
C3b also forms terminal complement components (C5b, C6, C7, C8, C9) which form membrane attack complex causing lysis of certain pathogens and cells
Which 4 effects are mediated by complement components?
- lysis
- opsonisation
- activation of inflammatory response
- clearance of immune complexes
How can the half life of C3 convertase be altered?
C3 convertase has a half life of 5 minutes unless it binds to the serum protein PROPERDIN, which extends its half life to 30 minutes by protecting it from proteases
Describe the membrane attack complex
- C5b binds C6 initiating the formation of the MAC
- MAC forms a pore that inserts into the membrane allowing diffusion of ions and small molecules, water moves into the cell killing it
- Human cells have soluble and cell surface associated proteins that prevent MAC formation
Describe a disease in which complement is inhibited
HERIDITARY ANGIOEDEMA
- C1 inhibitor deficiency
- classical complement cascade easily activated (causes unwarranted immune reaction)
but can be treated with an injection of C1 inhibitor
What happens in complement deficiency
Recurrent infections
- MBL deficiency causes serious pyogenic infections in neonates and children
- C3 deficiency most severe –> severe successive infections
- C8 deficiency –> prone to N.meningitidis infection
How is complement relevant to the pathogenesis of SLE?
- 90% deficient in C4 develop this AID
- C4 deficiency –> low C3b (as C4b2a = c3 convertase)
- C3b bound to immune complexes bind to CR1 on erythrocytes which transports them to phagocytes in the liver and spleen
- Phagocytes recognise the immune complexes via Fc receptors and engulf them
