Innate immunity Flashcards
what are the general principles of innate immunity?
- oldest form of immunity - all organisms have a form of innate immunity which has changed on an evolutionary scale
- always available - little exposure required, but no memory
- major form of immunity in infants (period between loss of maternal antibodies and the formation of their own)
- initiates and directs adaptive immunity
- adaptive immunity takes ~4-6 days to develop. Innate immunity is critical in controlling infections before this.
what are the key elements of innate immunity?
- barriers - prevent establishment of infection
- pre-formed mediators - proteins/peptides with broad specificity that damage pathogens, induce inflammation or recruit adaptive immune cells
- innate leukocytes
- recognise and activated by pathogen
- eliminate pathogen
- communicate with other cells to direct adaptive immune response
what is the role of barriers in the innate immune system?
Mechanical barriers help prevent infection; secreted chemicals, anti-microbials and commensals make an unfavourable environment for pathogens
what are the main barriers of the body?
keratinised skin
mucosal membranes:
- GU tract
- GI tract
= respiratory tract
what are the features of keratinised skin?
- generally impermeable unless breached
- keratinocytes produce keratin: tough substance – effective barrier
- sebaceous glands produce sebum – contains fatty acids, defensins
- Shedding – remove microbes from skin surface
- Commensals – deter pathogens from colonising
what are the features of mucosal membranes?
- Mucous – traps pathogens from reaching epithelial lining
- Cilia (respiratory tract) – waft away mucus and the microbes trapped within
- Mucous contains secreted enzymes (e.g. lysozyme in tears and saliva)
- low pH (gut, vagina) – deter pathogens replicating, peristalsis (gut) – expel microbes
- Shedding of epithelia in the gut
- Commensals
what are pre-formed mediators? what are the main ones in the innate immune system?
Proteins/peptides with broad specificity that damage pathogens, induce inflammation or help recruit and activate innate immune cells
- lysozyme
- antimicrobial peptides: defensins, complement
what is lysozyme?
- Present in secretions (tears, saliva, mucous)
- Breaks a bond in peptidoglycan – destabilises the cell wall of gram positive bacteria
- More active against G+ve bacteria, where peptidoglycan is exposed.
what are defensins?
- form of antimicrobial peptide
- 29-47 amino acids
- evolutionarily ancient
- Produced by many epithelial cells and neutrophils
what is the structure of defensins?
Beta-sheet core structure stabilised by 3 conserved intramolecular disulphide bonds
- Two subfamilies (alpha and beta) in humans
- Alpha form already exist in granules of innate cells, whereas beta form is synthesised de novo under infection
how do defensins function?
- cationic, insert into membranes and disrupt lipid bilayers in bacteria, fungi and enveloped viruses (take part of the host membrane with them when they leave the host cell)
what is complement?
-Discovered as a heat-sensitive substance that “complemented” antibodies in killing bacteria
- >20 soluble proteins found in blood and other body fluids
- Components normally inert, but “activated” by presence of pathogens or antibody bound to pathogen
- C3 is the most abundant in the body and is critical for the cascade
- Complement cascade – amplification of reactions
- Originally evolved as part of the innate immune response – ancient form of immune defense
- Provides protection early in infection in the absence of antibodies through other “older” activation pathways
which complement protein is most abundant?
C3
how does complement work?
- Many activated complement components are proteases; act on one another to generate a large and a smaller fragment
- e.g. C3 –> C3b + C3a (b is big fragment, a is small)
what is the central event of all complement activation pathways?
- Cleavage of C3 exposes a reactive thioester bond in C3b, which can bind covalently to adjacent proteins/carbohydrates e.g. on the surface of a pathogen.
- Rapidly inactivated in the fluid phase –> prevents further damage.
- The central event of complement activation is cleavage of C3 by a “C3 convertase
what are the 3 pathways of complement activation?
- classical
- mannose-binding lectin (MBL)
- alternative
what is the classical pathway of complement activation?
- Antibody binding to bacterial surface
- This activates C1 to generate a protease, which activates C4, then C2
- C2 then activates C3 convertase
what is the MBL pathway of complement activation?
- MBL binding to mannose on pathogen surface
- This activates MASP1 which activates MASP2
- MASP2 activates C2, which activates C3 convertase
what is the alternative pathway of complement activation?
- Spontaneously activated by recognition of LPS on surface of bacteria
- Factor B, D and P generate C3 convertase
what is C3 convertase in the classical and MBL pathways of complement?
For Classical and MBL pathway, C3 convertase = C4bC2a complex (from cleavage of C4 and C2 by C1 and MASP2, respectively)
what is C3 convertase in the alternative pathway of complement?
For Alternative pathway, C3 convertase = C3bBb
- some C3b is generated spontaneously in body fluids by a “tickover” mechanism
- If C3b generated binds to LPS on a pathogen surface, factor B binds to C3b
- Factor B is cleaved by factor D → C3 convertase (C3bBb).
- The C3bBb convertase is stabilised by factor P (properdin) and activated (works for longer on the bacterial surface
how can complement amplification occur in classical and MBL complement pathways?
C3b generated by the Classical or MBL pathway can also bind factor B – amplification of complement
what are the later stages of complement activation?
- C3 convertase cleaves C3 to C3a and C3b
- C3 convertase + C3b opsonin –> C5 convertase –> C5a and C5b
- C5b, C6, C7, C8, C9 = membrane attack complex
what are the 3 major biological activities of complement?
- recruitment of phagocytes and inflammation
- opsonisation
- membrane attack complex –> cell lysis