Innate Immunity II Flashcards
What are the soluble innate immune molecules?
- Enzymes e.g lysozyme
- Antimicrobial peptides
- Collectins and pentraxins
- Complement components
What do lysozymes do?
- Secreted by phagocytes and paneth cells
- Effective against Gram-positive bacteria
- Cleaves bond between alternating sugars
How do collectins, ficolins and pentraxins work?
- Soluble PRRs
- Act as opsonins
- Activate complement through classical/lectin pathway
What is the complement system?
- Acts in sequence of one protein activating another - complement cascade
- Helps antibodies/phagocytic cells clear pathogens
- What happens when complement system activated?
- Where are complement proteins synthesised?
- Cooperates with defence systems to generate inflammation and remove pathogen
- Mostly in liver by also by monocytes, macrophages
Describe complement system components and what they do.
- Proteins C1-C9, factors B,D, H etc. - in order of discovery
- Enhances inflammation, pathogen lysis and phagocytosis (by opsonising antigens)
How does the complement system enhance innate/adaptive immunity?
- Neutralising viruses
- Attracts macrophages and neutrophils by chemotaxis
- Promote antibody formation
Briefly outline the pathways of complement activation.
- CLASSICAL - Antigen-antibody complex or C1q binding to pathogen surface
- LECTIN - MBL or ficolins bind carbohydrates on pathogen surfaces
- ALTERNATIVE - Direct activation when C3 binds antigens
Describe converging within the complement pathways.
- Involves protein activation in orderly sequence
- Each step catalyses the next
- Each pathway converges on C3 - cleaves into C3a and C3b
- Initiates common terminal pathway - enhances lytic pathway
What does the classical pathway involve?
- Involves complement components C1, C2 and C4
- Triggered by binding of antigen-antibody complexes to C1 complex
- C1 made up of C1q, C1r and C1s
How is the classical pathway activated?
- Triggered when C1 binds to Fc region of antibody-antigen complex
- C1 - must bind at least 2 Fc domains of Ig - causes conformational change
- IgM - most efficient at activation - 5 domains
Does serum IgM bind C1?
NO (not in original state)
- Has planar conformation
- C1q binding sites only revealed upon antigen binding
Describe amplification in the classical pathway. PART 1
- Binding C1q to Fc domain of Ig causes conformational change in C1r
- C1s is cleaved and activates C2 and C4 splitting into large and small fragments and bind to form C3 convertase
- Spils C3 into C3a and C3b
Describe amplification in the classical pathway. PART 2
- C3b binds to C3 convertase form C5 convertase
- This cleaves C5 into C5a and C5b
- C5b forms complex with C6-C9 and becomes membrane attack complex
- C5a - anaphylatoxin proinflammatory mediator
Describe alternative pathway. PART 1
- C3 activated by pathogenic antigens - hydrolyses into C3a and C3b
- C3b binds to cell membrane and factor B - susceptible to cleavage by factor D
- Factor D cleaves C3b so C3 convertase forms
Describe alternative pathway. PART 2
- Convertase has short hal-life unless binds to serum protein properdin - extends half life
- Convertase hydrolyse C3 to C3a and C3b - amplifies signal
- C3b forms C5 convertase - cleaves C5 to C5a and C5b
- C5b, C6-C9 form MAC
Describe lectin pathway. PART 1
- Activated by MBL binding to mannose residues or ficolins
- MBL binds mannose residues on carbohydrates/glycoproteins
- Activates MBL-associated serine proteases cleave C4 and C2 to form convertase
Describe lectin pathway. PART 2
- C5b, C6-C9 forms MAC
What does the membrane attack complex do?
- Forms pore in membrane
- Allows diffusion of ions and cause water influx cell - causing cell lysis
- Human cells have proteins to prevent unwanted MAC formation
What do the following complement components do?
- C3b
- C3a
- C5a
- C3b - promotes opsonisation
- C3a - anaphylatoxin - stimulates infammation by attracting neutrophils
- C5a - activates mast cells
Describe viral neutralisation
- Activates classical pathway
- Causes viral aggregation - cannot infect host cells
- Enveloped viruses can be lysed
What is the role of C1 inhibitors and what can happen when they are deficient?
- Prevents C1 activating C4 and C2
- Prevents C3 activation and MAC formation
- DEFICIENCY - causes hereditary angioedema
What are some consequences of complement deficiency?
- Patients deficient of complement pathway experience recurrent infections
- MBL deficiency causes pyogenic infections in neonates
