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Flashcards in Innate immunity Deck (111):

define aetiology

the causes of disease


define pathogenesis

how disease develops



the death of a cells in an uncontrolled manner, often but not always due to hypoxia or ischaemia



genetically controlled programmed cell death.
- cell shrinks, nucleus compacts (pyknosis), nucleus fragments (karyorrhexis), and plasma membrane blebbing.
- the activation of proteases (caspases) commits the cell to mitochondrial or death receptor pathways.
- phagocytes engulf apoptotic bodies to prevent collateral damage to the surrounding tissues



the microorganisms always present in or on us but that only cause damage when epithelial barriers are breached.


what are pathogens

infectious organisms that cause disease


what are inflammatory diseases

disease caused by inappropriate or excessive immune responses


the afferent arm of the immune system

the mechanisms responsible for the discrimination of seld from non-self


the efferent limb of the immune system

the mechanisms triggered by the afferent arm that are responsible for inflammation and effector mechanisms to remove the pathogen and return the tissue to homeostasis.


innate immunity?

in place before infection and designed to react immediately


adaptive immunity

develops if the innate system fails to resolve the infection. highly specific for each pathogen


overlap between the innate and adaptive immune systems

- innate responses vary depending on the type of microorganism, and this directs the type of adaptive response that is generated.

2 - the adaptive systems co-operate with many of the effector mechanisms of the innate system to direct them in a highly specific manner.


3 components of the innate system

barriers, cells and soluble proteins


barriers of the innate system

skin, mucosal epithelia, anti-microbial chemicals


cells of the innate system

phagocytes such as neutrophils and macrophages, eosinophils, mast cels and natural killer cells


soluble proteins of the innate system

cytokines, acute phase proteins, complement, inflamatory mediators


bariers of the adaptive system

lymphocytes in the epithelia, antibodies at the mucosal surfaces


cells of the adaptive immune system

T and B lymphocytes


coluble proteins of the adaptive system

antibodies (immunoglobulins)


what does inflammation depend on

an intact vascular system, dead tissue wont undergo inflammation


what is inflammation

a stereotypic response to either microbial infection or tssue injury. the funtion is to eliminate the pathogen, repair the damage and return to a state of homeostasis.
- it is rapid and destructive but specific and self-limiting


trigger for inflammation

the activation of resident cells and complement with the release of inflammatory mediators


general events in inflammation

vasodilatation , increase vascular permeability, eigration of leucocytes, the accumilation of a cellular, protein rich exdate.


overview of the 5 steps of innate inflammatory immune responses

1 - recognition of infection or damage
2 - vascular response to injury
3 - elimintation of the pathogen
4 - resolution of the inflammation, repair and return to hoeostasis
5 - if the innate sytem fails to eliminate the pathogen then adaptive immunity is induced.


what mediates step 1 - recognition

PRRs and complement


step 2 - vascular response to injury

recruitment of cells and soluble factors to form the acute inflammatory exudate


step 3 - mediation of innate elimination

by phagocytosis and complement


step 5 - inaduction of adaptive immunity

Dendritic cells take up pathogen fragments and migrate to the regional lymph node.


3 cell lineages from the hematopoietic stem cell?

1 - common lymphoid progenitor
2 - common myeloid progenitor
3 - common erythroid megakaryocyte progenitor


cells derived from the common lymphoid progenitor

1 - b cells - plasma cells
2 - NK/T cells precursor which gives two lineages : T cell - effector T cell , and the NK cell


2 lines from the common myeloid progenitor

1 - common granulocyte precursor
2 - an unknown precursor that gives rise to the monocyte lineage (gives macrophages and dendritic cells) and the mast cells.


cells from the common granulocyte precursor

1 - neutrophil
2 - eosinophil
3 - basophil


2 lineages from the common erythroid megakaryocyte progenitor

1 - megakaryocyte - platelets
2 - erythroblast - erythrocyte


general funciton of the eosinophils an dbasophils

to defend against helminth worms and parasites


where are complement proteins made?

in the liver


key to complement's rapid response

the proteins form an enzymatic cascade capable of tremendous amplification, regulatory proteins are essential to controlling the cascade.


3 main funcitons of complement in eliminating the pathogen

1 - activation of inflammation
2 - opsonisation of microbes
3 - lysis of target cells.


the basis of C3's reactivity

an internal thioester bond that is normally stable but can become highly reactive following conformational changes. activation by cleavage


functions of C3a

1 - stim vascular permeability
2 - recruit effector cells
3 - so its an anaphylatoxin


funciton of C3b

the larger fragment
1 - complement fixation (binds bacterial surfaces) to target for phagocytosis (opsonisation)
2 - cleaves C5


function of C5a

an anaphylatoxin


funciton of C5b

formation of the membrane attack complex


3 complement pathways

1 - classical
2 - lectin
3 - alternative


what's common to all the complement pathways ?

they al lead ot the formation of some sort of C3 convertase to activate C3. so whilst they are activated by different things, they all have the same effector functions.


what complement pathway acts first

the alternatve pathway


what initiates the alternative pahtwya

the spontaneous hydrolysis of C3 - termed tick over


alternative pathway tick-over?

cleavage of the thioester bond in C3 to form C3(H2O).
- Factor B binds this complex.
- factor D then cleaves factor B to make Ba and Bb to form C3(H2O)Bb - this is the C3 convertase and is stabilised by the serum protein Properdin. C3(H2O)BbP

- Properdin mutation/loss of function causes susceptibility to infectious diseases particularly bacterial meningitis.

- when C3 is cleaved by the convertase, the C3b portion forms the positive feedback loop, being bound by Factor B, cleaved by D and stabilised by properdin to make the C3 convertase - C3bBbP


what are PAMPs

pathogen associated molecular patterns - highly conserved structures present on the surface of many microbes


what are PRRs

pathogen recognition receptors - they can be expressed by cells (TLR) or be soluble (CRP)


describe the activation of the lectin pathway

Mannose binding lectin (MBL) is a soluble PRR and forms oligomers to bind mannose and fucose residues on pathogens with high avidity.
- MASPs associate (proteases) and are activated when MBL binds pathogens.
- the MASPs activate C4 and C2
- the C3 convertase C4b2a is formed


describe activation of the classical pathway

C1 binds pathogens or bound antibodies (so innate and adaptive).

- C1 consists of C1q (the pathogen sensor), and the proteases (C1r and s) which activate when C1q binds.


what does C1q of the classical pathway bind?

1 - bacteria directly
2 - CRP which binds the phosphocholine component of lipopolysaccharides
3 - the Fc region of Ig that are bound to pathogens (specific directing of the innate system)


dynamics of the complement cascade

the alternative pathway is firt ot be effective but as the acute phase response develops and masses of MBL and CRP are released from the liver, these other 2 pathways become highly effective.


host methods of complement inhibition

1 - decay accelerating factor
2 - membrane cofactor protein
- prevent formation and promote degredation of C3 convertases.


what complement components are anaphylatoxins are how do they act

C3a and C5a
- act on blood vessels to increase permeability, upregulate endothelial cell adhesion molecules and increase smooth muscle contraction.
- cause mast cell degranulation
- excessive production can cause anaphylactic shock


process of opsonisation and phagocytosis

- receptors for complement and Fc are present on phagocytes = opsonins
1 - receptor binding, acting assembly triggered to engulf
2 - particle enclosed in the phagosome. fuses with acidic lysosomes containing hydrolytic enzymes to form the phagolysosome.
3 - killing and degradation of pathogen, sometimes with oxidative burst using ROS


difference between macrophages nad neutrophils

both are phagocytes but they complement each other.
- macrophages are resident as sentinel cells, neutrophils infiltrate in response to infection and are relatively short lived. the presence of neutrophils is a hallmark of acute inflammation.
- dead neutrophils are phagocytosed by macrophages.


what is pus

dead and dying neutrophils and fibrin and other debris.


MAC formation?

membrane attack complex
- C5 activation by C3b on the pathogen surface is the initiating event.
- C5b complexes with C6,7 and 8 to form a complex in the membrane that C9 polymerises on to form a channel.

- not as imp as C3b deposition but effective for some infections.


MAC component deficiency causes?

susceptible to gonorrhoea or nisseria meningitis


regulation of MAC formation on human cells?

CD59 binds the MAC to revent C9 polymerisation.


what's paroxysmal nocturnal haemoglobinuria?

RBCs lack in CD59 and are lysed by complement.


four soluble components of innate immunity other than complement

1 - cytokines
2 - histamine
3 - inter-related soluble protein systems eg kinin system
4 - lipid inflammatory mediators


paracrine cytokines?

act on other cell types


autocrine cytokines

act on the same cell type


endocrine cytokines?

act systemically


3 characteristics of cytokines

1 - act via specific receptors
2 - redundancy - overlapping funcitons
3 - pleiotropism - one cytokine has multiple functions.


major source of cytokines in acute inflammation?



3 classes of cytokine, general function and some examples

1 - interleukins - affect cell activation and behaviour - IL-1, IL-2 etc
2 - interferons - antiviral, cell activation - INF alpha, beta, gamma
3 - tumour necrosis factors - diverse functions - TNF alpha and beta


3 inter0related soluble protein systems used in the acute inflammatory response

1 - the kinin system - makes bradykinin = potent inflammatory mediator
2 - clotting system - fibrin strands
3 - fibrinolytic system to break down the clot


lipid inflammatory mediators and production

1 - arachidonic acid - prostaglandins and leucotrienes
2 - platelet activating factor - chemotactic
- made in membranes of neutrophils, macrophages, mast cells


TLR general signalling

activation, recruitment of adaptor molecules (MyD88), signalling to activate NF-kB , release inflammatory cytokines, Type 1 interferons, chemokines and antimicrobial peptides - acute inflammatory exudate.

- also leads to DC maturation and the induction of adaptive immunity


generally what do TLRs recognise

- PAMPs on the surface of microbes eg TLR4 homodimer for LPS on gram-negative bacteria

2 - nucleic acids of pathogens within endosomes in the cell. eg TLR8 for ssRNA of viruses such as influenza


2 PRRs other than TLR

1 - C-type lectin receptors (CLR) - imp in fungal infection
2 - cytosolic NOD-like receptors (NLR) - some sense stress and form complexes called inflammasomes with activation of caspase 1 and release of IL-1beta


endogenous ligands for PRRs?

molecules released on cell death, injury or tumours.
1 - dying cells - HSPs, matrix. oxidised LD = TLR4/TLR6
2 - Gout - inflammation caused by urate crystals


what does fibrin do in the exudate

forms a web of insoluble strand to contain the infection and inflammation


4 stages of leukocyte migration in inflammation

1 - rolling = weak tethering
2 - tight adhesion
3 - diapedesis
4 - migration


describe rollin/ weak tethering

1 - rapid induciton of P-selectin on endothelial cells due to histamine/thrombin activation
2 - E-selectin induced by cytokines (IL-1 and TNF-alpha) after 1 -2 hours.
3 - selectins bind glycoprotein SIalyl_lex ligands on neutrophils .
4 - bonds easily broken by blood flow causing rolling.


describe tight adhesion in inflammation

1 - cytokines induce ICAMs on the endothelial cells to bind integrins on the neutrophils.
- integrins activated to high affinity by chemokines
- result is tight binding to the endothelium


describe diapedesis

emigration into the tissue
- leukocytes reorganise their cytoskeleton to allow spreading out on the surface of the endothelium


describe migration

chemkines stimulate the migration down their chemical gradient.
- CXCL8 is principally responsible for recruiting neutrophils.


4 harmful effects of inflammation

1 - pain - RA
2 - prolonged inflam - abcess
3 - wrong place - meningitis
4 - pneumonia - exudate into airways and drown


why do monocytes migrate later than neutrophils?

the VCAM-1 they bind with their integrin VLA-4 is upregulated more slowly (24hrs)


innate system pro-inflam cytokines from macrophages - 5

1 - IL-6
2 - TNFalpha
3 - IL-1beta
4 - CXCL8
5 - IL-12


IL-6 function

1 - fever
2 - acute phase proteins


TNFalpha functions

1 - activate vascular epitelium
2 - fever
3 - shock


IL-1beta function

1 - activate vascular epithelium
2 - activate lymphocytes
3 - local tissue destruction to aid effector access
4 - fever
5 - IL-6 production


CXCL8 function

- neutrophil an dbasophil chemotactic


IL-12 function

activate NK cells


purpose of fever?

possibly to accelerate adaptive immunity and make non-optimal temp for pathogens


2 acute phase proteins

1 - MBL
2 - CRP



where pathogens enter the blood stream. can be a result of widespread burns


issue with sepsis?

massive release of TNFalpha into the blood stream causing widespread vasodilation causing vascular collapse and septic shock.
also DIC in capillaries causes consumption of clotting factors and organ failure.


what causes the switch from inflammatory damage to repair

a shift towards the anti-inflammatory mediators. important are the lipid derived mediators from the lipoxygenase pathway.
- helped by signals from macrophages that are phagocytosing apoptotic neutrophils.


first stage of repair?

the organisation of the exudate into granulation tissue


what cell types coordinates the repair process



5 functions of macrophages

1 - phagocytosis of debris, apoptotic cells etc
2 - killing of microbes by secreting ROS and NO
3 - enhancing inflammation and adaptive immunity - cytokines and complement factors
4 - tissue remodelling - FGF and VEGF and metalloproteinases
5 - enhanced antigen presentation and adaptive response induction - increased MHC and co-stimulator production.

- some functions are for healing some for destruction. they coordinate the balance between the 2.


3 other leukoctyes other than macro and neutro that are found in granulation tissue

1 - T cells
2 - plasma cells
3 - eosinophils - to kill parasites
- exact composition depends on type of injury


recruitment and function of fibroblasts

- recruited by cytokines eg FGF from macrophages
- secrete collagen and other ECM proteins to form the collagen scar.


steps of angiogenesis

- ndothelial cells break off of hte basement membrane of a preexisting vessel
- migrate to site of repair
- proliferate and then differentiate to for a lumen and then acquire supporting pericytes.


are NK cells a feature of acute inflammation?

no. but they are considered part of the innate system.


where are NK cells

a few in the periphery but most in a partially activated state in the blood


cells infected with a virus make what?

type 1 interferons= INFalpha and beta.
- these interfere with viral replication, alert neighbouring cells and activate NK cells.


what makes type 2 interferon?

activated NK cells. type 2 = IFNgamma
it activates macrophages.


what normally inhibits NK cell action

inhibitory receptors that bind to MHC class 1 molecules. overrides all else.


missing self?

when viruses or whatever downregulate MHC class 1 then the NK cells can be activated if an activating receptor is engaged.
- the NK cells respond to the rpesence of a difference or the absence of a similarity.


what upregulates ligands for activating NK receptors

cell stress due to DNA damage or infection. allows this to override normal MHC inhibition.


what's KIR

a highly polymorphic family of NK cell receptors that are both inhibitory and activating.
= killer immunoglobulin-like receptors
- bind HLA


whats' s HLA?

human leukocyte antigen = MHC


recognition of paternal non-self in pregnancy

by KIR on uterine NK cells binding to paternal HLA in the placenta.


3 NK cells effector functions

1 - kill cells via release of perforin and granzymes (induce apoptosis)

2 - specifically enhance the adaptive response by using their FcR to cause ADCC

3 - secrete cytokines eg IFNgamma to activate macrophages and help initiate adaptive immune responses.