L2 - Innate Immunity 1 COPY Flashcards
INNATE IMMUNITY OVERVIEW
i) when is it present and how is it encoded? what does this mean?
ii) how long does it take for it to respond upon pathogen recognition?
iii) what happens if you are lacking innate immunity?
iv) if a pathogen is not elimited by preformed soluble/effector molecules - what is activated? what timeframe does this have effect in
v) if that pathogen is still not cleared - what is activated?
i) present at birth and germline encoded - means it doesnt change much over life
ii) minutes
iii) lacking innate - dont block any micro-organism growth
iv) activate induced innate response - 4 hours to 4 days
v) pathogen still not cleared > activate adaptive
CHARACTERISTICS OF INNATE IMMUNITY
i) does it trigger an immediate response?
ii) what does it recognise? what does it interact with?
iii) does it require gene rearrangement? does it have clonal distribution? is it encoded in multiple gene segments?
iv) can it discriminate between closely related molecular structures
i) yes
ii) recognises broad class of pathogens and interacts with molecular structures
iii) no gene rearrange/clonal expan/multiple gene seg encoding
iv) yes
INNATE IMMUNE MEMORY
i) what are the only organisms to have adaptive immune memory?
ii) name three organisms that have innate immune memory
iii) name three components of an innate response when an organism gets infected with a pathogen? what do all these responses lead to?
iv) what happens if an organism if re challenged with the same pathogen
i) only vertebrates have adaptive
ii) plants, inverts, verts
iii) epigenetic changes eg modification of histones, production of micro RNA and long non coding RNAs
- these all affect gene expression
iv) re challenged - the organism can have a boosted response which is antigen independent
INNATE BARRIERS TO INFECTION
i) what is the first barrier? name three components
ii) name three components of the soluble barrier
iii) if the soluble barrier can eliminate the pathogen, what is activated? name three components of this
i) physical - skin, GI tract, respiratory tract
ii) soluble - complement, defensins, collectins
iii) soluble then induced innate response
- innate immune cells, PRRs and inferon
ANATOMICAL BARRIERS
i) which chemical barrier is found throughout the whole body?
ii) which mechanical barrier is found throughout the whole body?
iii) what does pulmonary surfactant in the lungs contain that acts as a barrier?
iv) which microbiological barrier is found throughout the body?
i) antimicrobial peptides
ii) epithelial cells joined by tight junctions
iii) surfactant contains collectins
iv) normal microbiota
TISSUE DAMAGE
i) what does tissue damage cause the release of? (2) what does this trigger (2)
ii) what happens to capillaries?
iii) what is the name of the process where phagocytes migrate to site of inflammation?
iv) what is the name of the process by which cells move out of the capillaries and into the tissues?
i) damage causes release of vasoactive and chemotactic factors which trigger increased blood flow and increased cap permeability
ii) capillaries become more permeable
iii) phagocytes migrate > inflamm = chemotaxis
iv) cells move out of the tissues = extravasation
SOLUBLE INNATE IMMUNE MOLECULES
i) what do lysozymes do? which two fluids are they found in (2)
ii) where are antimicrobial peptides found? what do they do?
iii) what do collectins, ficolins and pentraxins do? (2)
iv) name three roles of complement components
i) lysozyme > disrupts bacterial cell walls
- found in blood and tears
ii) antimicrob peptides found all over the body
- disrupt microbial membranes
iii) bind to pathogens and target them for phago
- activate complement
iv) lyse bacteria, opsonise bacteria and induce inflammation
LYSOZYME
i) name two cells its secreted from
ii) what does it disrupt? what type of bacteria does this happen in?
iii) how does it cause the disruption?
iv) once the lipid bilayer is exposed - what can disrupt the phospholipids?
v) which type of bacteria is it less effective against? why?
i) phagocytes and paneth cells in the SI
ii) disrupts peptidoglycan in bacterial cell wall
- most effective in gram positive bacteria
iii) cleaves the bond between alternating sugars that make up the PG
iv) phopholipase A2 can disrupt the phospholipids
v) less effective against gram negative bacteria as its covered in LPS which masks the PG therefore lysozyme cant get to it
ANTIMICROBIAL PEPTIDES
i) what surfaces do they cover? name a fluid they are found in
ii) name three cell types that secrete them? what is the pattern of secretion?
iii) how quickly do they kill bacteria? how do they do this? (2)
iv) name two other micro-organisms they may attack
i) cover epithelial surfaces and found in saliva
ii) secreted from neutrophils, epithelial cells and paneth cells
- constituitively secreted
iii) kill bacteria in minutes (avg 90 mins)
- do this by disrupting the membrane and inhibiting DNA/RNA synthesis
iv) can also attack fungi and viruses
FAMILIES OF ANTIMICROBIAL PEPTIDES
i) where are histatins produced? which type of MO are they active against?
ii) what cathelicidin is found in humans? what is it active against?
iii) what are the two classes of defensins? what situation are these important in?
i) histatins are produced in the oral cavity
- active against pathogenic fungi eg candida
ii) cathelicidin = LL-37
- broad spectrum activity against both gram pos and neg bacteria
iii) defensins = alpha and beta
- important in newborn to defend against first encounter of microbes eg from the vagina during birth
DEFENSINS
i) are small or big? are they hydrophobic or hydrophilic?
ii) which bonds stabilise the structure? how do they do this?
iii) what do defensins do to the microbe? what does this lead to?
iv) do they act on our cells?
i) small peptide
- amphipathic (both hydrophil and hydrophob)
ii) disulphide bonds stabilise the structure as to seperate the positive charged and the hydrophobic region of the defensin
iii) defenins disrupt microbial cell membranes by inserting themselves into the membrane and forming a pore
- pore causes sugar/ions to move out and water to move in causing cell lysis
iv) no
COLLECTINS/FICOLINS/PENTRAXINS
i) how do all three of these induce the innate immune response?
ii) what is the structure of the head/tail of collectins? what do the heads bind on the bacteria? why dont collectins bind host cells?
iii) which is the ficolin head made of? what do they recognise? give an example of what they recognise and where it is found
iv) what type of proteins are pentraxins and where are they found? give a clinically relevant example - what does this bind to on bacteria?
i) activate complement
ii) collectins have globular lectin like head an collagen tail
- heads bind bacterial cell surface sugars
- sialic acid hides mannose antigens on host cells
iii) ficolin head is made of fibrinogen
- recognise acylated compounds such as n-acetylglucosamine which is found in bacterial cell walls
iv) pentraxins are cyclic multimeric proteins found in plasma
- CRP > binds phosphocholine on bacterial surfaces
ACTION OF COLLECTINS, FICOLINS AND PENTRAXINS
i) what type of receptors do they have?
ii) what can they act as that allow cells to be targeted for phagocytosis?
iii) which two pathways do they activate complement through?
iv) which class of molecule is mannose binding lectin?
i) pattern recognition receptors
ii) act as opsonins that bind pathogens/infected cells
iii) activate complement through classical or lectin pway
iv) MBL is a collectin
COMPLEMENT PATHWAY AND C3
i) which molecule to all three pathways converge on?
ii) name three downstream events after this?
iii) name a molecule that activates the classical pathway
iv) name two molecules that activate the lectin pathway
v) what activates the alternative pathway?
i) C3 convertase
ii) phagocytosis, inflammatory events, lysis of infected cell
iii) CRP
iv) collectins and ficolins
v) pathogen surfaces
THE COMPLEMENT SYSTEM
i) what is it?
ii) what happens when complement proteins detect foreign material?
iii) once activated, what do proteins aim to do?
iv) where are most proteins made? give three other cells they are produced by
i) series of 30+ proteins that constantly circulate in blood and fluids that bathe body tissues
ii) detect foreign mat > initiate cascade of reactions that amplify the signal
iii) activated > generate inflammation and rapidly remove the pathogen
iv) most proteins are made by the liver
- also produced by monocytes, macrophages, epithelial cells in intestine and urinary tract
COMPLEMENT COMPONENTS
i) how do they circulate in the blood? why is this?
ii) what type of activity do some have?
iii) what happens when they are activated? what does this trigger?
i) circulate in the pro-form (inactive) as they are a powerful inducer of inflammation
ii) some have proteolytic enzymatic activity (are serine proteases)
iii) on activation they split into small and large fragments which triggers an amplification cascade
COMPLEMENT CASCADE
i) what do all three pathways converge on? what then happens?
ii) which protein does C5 convertase come together with to make C5?
iii) what is the terminal stage of the complement cascade?
iv) name a molecule that induces each of the three pathways
i) all converge on C3 convertase
- this causes C3 > C3a and C3b
ii) C5 convertase comes together with C3b to make C5
iii) terminal stage = membrane attack complex
iv) CRP (pentraxin) or antigen antibod complexes > classical
- collectins and ficolins > lectin pathway
- microbial surfaces > alternative pathway
EFFECTORS MEDIATED BY COMPLEMENT COMPONENTS
i) what can complement componets directly cause to a cell?
ii) name three things that complement proteins can mediate in relation to phagocytes
iii) what does the membrane attack complex do?
iv) where are immune complexes transported to once bound to complement components? what happens here?
i) can cause cell lysis
ii) complement proteins can opsonise, activate inflam response (extravasation and degran of mast cells) and clear immune complexes
iii) MAC forms pores in the memrbane of pathogens and causes lysis
iv) once immune complexes are bound to complement proteins they are transported to the liver where phagocytes remove and break them down
CLASSICAL PATHWAY
i) what role does C1 play?
ii) which three proteins is C1 made up of? which one makes up the stalk and most of the molecule?
iii) how many polypeptides is the stalk? what do these form?
iv) what region of the antibody antigen complex does C1 bind?
i) initiates the classical pathway when activated
ii) C1 = C1q, C1s and C1r
- C1q makes up most of the molecule and forms the stalk
iii) 18 polypeptide stalk that forms six collagen like triple helix structures
iv) C1 binds the fc region of antibody/antigen complex
CLASSICAL PATHWAY ACTIVATION
i) what does C1 bind to trigger it?
ii) how many of these must C1 bind for activation?
iii) what is the most efficient immunoglobulin at activating this pathway? why?
iv) which three other immunoglobulins can also activate complement? what is needed for these to activate it? why?
v) in what conformation can IgM not bind C1? what is needed for it to bind?
i) C1 binds the fc domain of antigen/antibody complexes
ii) at least 2 fc domains must bind
iii) IgM is most efficient at activating pathway as it has 5 fc domains on one molecule
iv) IgG1, IgG3 and IgG2 can also activate complement
- need lots of IgG molecules on pathogen for activation to make sure there are two that are close enough together to bind C1 at the same time
v) IgM cant bind C1 in its planar conformation
- needs to change conform > crab like structure to reveal binding site for C1q
AMPLIFICATION OF THE CLASSICAL PATHWAY
i) what does the binding of C1q and Fc domain cause?
ii) cleavage of C1 can activate which two complement components? how are these activated?
iii) which fragments of these come together to make C3 convertase?
iv) what does C3 convertase then activate? how does it do this? what does this result in?
v) what three fragments form C5 convertase? what does c5 convertase do? what does this ultimately result in?
i) binding of C1q and Fc domain causes a conformational change in C1r
ii) cleavage of C1 activates C2 and C4
- activated by splitting into large and small frags
iii) C2a and C4b come together to make C3 convertase
iv) C3 convertase then activates over 200 C3 molecules to produce a massive signal amplification
v) C3 convertase (C2aC4b) and C3b fragments form C5 convertase > membrane attack complex
LECTIN PATHWAY
i) is this pathway antibody dependent or independent? give two things its activated by
ii) what does mannose binding lectin bind on carbohydrates? what does it bind on bacteria/some viruses? what does this activate
iii) which two serine proteases does MBL form a complex with when it binds? what two proteins does this leave to the cleavage of?
i) antibody independent
- activated by mannose binding lectin and ficolins
ii) MBL binds mannose on carbohydrates
- binds glycoproteins in bacteria/some viruses
- this activates similar ds mechs to classical pathway
iii) MBL forms a complex with MASP-1 and MASP2 serine proteases > cleavage of C2 and C4 (to C3 convertase etc)
ALTERNATIVE PATHWAY
i) what complement protein does it start with? what happens to it?
ii) which fragment binds the pathogen cell membrane? what factor can it come across to make it susceptible to cleavage by factor D?
iii) what is the cleavage product? what is the half life of this
iv) which serum protein can extend the half life by 30 mins? how does it do this?
v) what effect can the cleavage product have on C3? what does this allow?
vi) which molecule an alternative form of C3 convertase in this pathway?
i) starts with C3 > hydrolyses to C3a and C3b when it comes into contact with a microbial cell surface
ii) C3b binds pathogen cell membrane and if it comes across factor B = susceptible to cleavage by factor D
iii) cleavage product is C3bBb (C3b + factor B)
- half life of 5 mins
iv) serum protein properdin can extend the half life to 30 mins by protecting it from serum proteases
v) C3bBb can hydrolyse more C3 and therefore amplify the signal
vi) C3bBb is an alternative form of C3 convertase here
TERMINAL COMPLEX COMPONENTS
i) which molecule is the start of the common terminal pathway?
ii) what fragment of C5 joins with C6,7,8,9? what does this form?
iii) how does MAC kill a cell? (3)
iv) why don’t MACs target human cells?
i) C5 convertase
ii) C5b joins C6,7,8,9 to form the membrane attack complex
iii) MAC forms a pore that inserts into the cell membrane
- allows diffusion of ions and small molecules out
- water moves into the cell > kills it
iv) MACs dont target human cells as they have soluble and cell surface proteins that prevent MAC formation
COMPLEMENT INHIBITORS
i) what type of proteins may these be? (2)
ii) what are the three types?
iii) what do MAC inhibitors do?
iv) what condition is caused by C1 inhibitory deficiency? what happens? how can it be treated?
i) can be soluble or membrane bound
ii) C1 inhibitor, C3 inhibitors, MAC inhibitors
iii) MAC inhibitors prevent insertion of MAC into the membrane
iv) C1 inhibitory deficiency > Hereditary angioedema
- classical complement cascade is easily activated and leads to lots of oedema in face and lips
- treat with an injection of C1 inhibitor
COMPLEMENT DEFICIENCY
i) what do patients deficient in components of complement pathway experience?
ii) what can MBL deficiency cause in neonates and children?
iii) which deficiency is the most severe? what does it lead to?
iv) which infection are patients deficient in C8 prone to?
i) deficiency in any part > recurrent infections
ii) MBL defic can cause serious pyogenic infections (pus forming) in neonates and children
iii) C3 deficiency is most severe > successive severe infecs
iv) C8 deficiency are prone to neisseria meningitis
COMPLEMENT DEFICIENCY IN SLE
i) which complement protein are 90% of SLE patients deficient in?
ii) why does this deficiency lead to lower C3b levels?
iii) what receptor does C3b normally bind on erythrocytes? what happens to the RBCs once this has bound?
iv) in SLE what triggers heightened innate immune response and production of pro inflam cytokines?
i) C4 deficiency
ii) C4 deficiency leads to lower levels of C3b as C4b is a part of C3 convertase (less C4 = less C3 > C3b)
iii) C3b normally binds CR1 on erythrocytes which transports them to phagocytes in liver and spleen > phagocytes recog immune complexes via FC receptors and engulf them
iv) in SLE - patients have lots of autoantibodies that bind to own DNA/RNA which triggers immune response
