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Pathology > Innate immunity > Flashcards

Innate immunity Flashcards

lectures 1-4 p 1 - 29

1
Q

define aetiology

A

the causes of disease

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2
Q

define pathogenesis

A

how disease develops

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3
Q

necrosis

A

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

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4
Q

apoptosis

A

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
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5
Q

commensals

A

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

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6
Q

what are pathogens

A

infectious organisms that cause disease

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7
Q

what are inflammatory diseases

A

disease caused by inappropriate or excessive immune responses

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8
Q

the afferent arm of the immune system

A

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

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9
Q

the efferent limb of the immune system

A

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.

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10
Q

innate immunity?

A

in place before infection and designed to react immediately

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11
Q

adaptive immunity

A

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

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12
Q

overlap between the innate and adaptive immune systems

A
  • 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.

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13
Q

3 components of the innate system

A

barriers, cells and soluble proteins

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14
Q

barriers of the innate system

A

skin, mucosal epithelia, anti-microbial chemicals

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15
Q

cells of the innate system

A

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

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16
Q

soluble proteins of the innate system

A

cytokines, acute phase proteins, complement, inflamatory mediators

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17
Q

bariers of the adaptive system

A

lymphocytes in the epithelia, antibodies at the mucosal surfaces

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18
Q

cells of the adaptive immune system

A

T and B lymphocytes

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19
Q

coluble proteins of the adaptive system

A

antibodies (immunoglobulins)

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20
Q

what does inflammation depend on

A

an intact vascular system, dead tissue wont undergo inflammation

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21
Q

what is inflammation

A

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

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22
Q

trigger for inflammation

A

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

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23
Q

general events in inflammation

A

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

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24
Q

overview of the 5 steps of innate inflammatory immune responses

A

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.

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25
Q

what mediates step 1 - recognition

A

PRRs and complement

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26
Q

step 2 - vascular response to injury

A

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

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27
Q

step 3 - mediation of innate elimination

A

by phagocytosis and complement

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28
Q

step 5 - inaduction of adaptive immunity

A

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

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29
Q

3 cell lineages from the hematopoietic stem cell?

A

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

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30
Q

cells derived from the common lymphoid progenitor

A

1 - b cells - plasma cells

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

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31
Q

2 lines from the common myeloid progenitor

A

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

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32
Q

cells from the common granulocyte precursor

A

1 - neutrophil
2 - eosinophil
3 - basophil

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33
Q

2 lineages from the common erythroid megakaryocyte progenitor

A

1 - megakaryocyte - platelets

2 - erythroblast - erythrocyte

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34
Q

general funciton of the eosinophils an dbasophils

A

to defend against helminth worms and parasites

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35
Q

where are complement proteins made?

A

in the liver

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36
Q

key to complement’s rapid response

A

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

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37
Q

3 main funcitons of complement in eliminating the pathogen

A

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

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38
Q

the basis of C3’s reactivity

A

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

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39
Q

functions of C3a

A

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

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40
Q

funciton of C3b

A

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

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41
Q

function of C5a

A

an anaphylatoxin

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42
Q

funciton of C5b

A

formation of the membrane attack complex

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43
Q

3 complement pathways

A

1 - classical
2 - lectin
3 - alternative

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44
Q

what’s common to all the complement pathways ?

A

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.

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45
Q

what complement pathway acts first

A

the alternatve pathway

46
Q

what initiates the alternative pahtwya

A

the spontaneous hydrolysis of C3 - termed tick over

47
Q

alternative pathway tick-over?

A

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
48
Q

what are PAMPs

A

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

49
Q

what are PRRs

A

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

50
Q

describe the activation of the lectin pathway

A

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
51
Q

describe activation of the classical pathway

A

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.
52
Q

what does C1q of the classical pathway bind?

A

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)

53
Q

dynamics of the complement cascade

A

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.

54
Q

host methods of complement inhibition

A

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

55
Q

what complement components are anaphylatoxins are how do they act

A

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
56
Q

process of opsonisation and phagocytosis

A
  • 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
57
Q

difference between macrophages nad neutrophils

A

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.
58
Q

what is pus

A

dead and dying neutrophils and fibrin and other debris.

59
Q

MAC formation?

A

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.
60
Q

MAC component deficiency causes?

A

susceptible to gonorrhoea or nisseria meningitis

61
Q

regulation of MAC formation on human cells?

A

CD59 binds the MAC to revent C9 polymerisation.

62
Q

what’s paroxysmal nocturnal haemoglobinuria?

A

RBCs lack in CD59 and are lysed by complement.

63
Q

four soluble components of innate immunity other than complement

A

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

64
Q

paracrine cytokines?

A

act on other cell types

65
Q

autocrine cytokines

A

act on the same cell type

66
Q

endocrine cytokines?

A

act systemically

67
Q

3 characteristics of cytokines

A

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

68
Q

major source of cytokines in acute inflammation?

A

macrophages

69
Q

3 classes of cytokine, general function and some examples

A

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

70
Q

3 inter0related soluble protein systems used in the acute inflammatory response

A

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

71
Q

lipid inflammatory mediators and production

A

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

72
Q

TLR general signalling

A

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
73
Q

generally what do TLRs recognise

A
  • 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

74
Q

2 PRRs other than TLR

A

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

75
Q

endogenous ligands for PRRs?

A

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

76
Q

what does fibrin do in the exudate

A

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

77
Q

4 stages of leukocyte migration in inflammation

A

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

78
Q

describe rollin/ weak tethering

A

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.

79
Q

describe tight adhesion in inflammation

A

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
80
Q

describe diapedesis

A

emigration into the tissue

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

81
Q

describe migration

A

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

82
Q

4 harmful effects of inflammation

A

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

83
Q

why do monocytes migrate later than neutrophils?

A

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

84
Q

innate system pro-inflam cytokines from macrophages - 5

A 
1 - IL-6 
2 - TNFalpha
3 - IL-1beta
4 - CXCL8
5 - IL-12
85
Q

IL-6 function

A

1 - fever

2 - acute phase proteins

86
Q

TNFalpha functions

A

1 - activate vascular epitelium
2 - fever
3 - shock

87
Q

IL-1beta function

A 
1 - activate vascular epithelium
2 - activate lymphocytes
3 - local tissue destruction to aid effector access
4 - fever
5 - IL-6 production
88
Q

CXCL8 function

A
  • neutrophil an dbasophil chemotactic
89
Q

IL-12 function

A

activate NK cells

90
Q

purpose of fever?

A

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

91
Q

2 acute phase proteins

A

1 - MBL
2 - CRP
opsonins

92
Q

sepsis

A

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

93
Q

issue with sepsis?

A

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.

94
Q

what causes the switch from inflammatory damage to repair

A

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.

95
Q

first stage of repair?

A

the organisation of the exudate into granulation tissue

96
Q

what cell types coordinates the repair process

A

macrophages

97
Q

5 functions of macrophages

A

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.
98
Q

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

A

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

99
Q

recruitment and function of fibroblasts

A
  • recruited by cytokines eg FGF from macrophages

- secrete collagen and other ECM proteins to form the collagen scar.

100
Q

steps of angiogenesis

A
  • 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.
101
Q

are NK cells a feature of acute inflammation?

A

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

102
Q

where are NK cells

A

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

103
Q

cells infected with a virus make what?

A

type 1 interferons= INFalpha and beta.

- these interfere with viral replication, alert neighbouring cells and activate NK cells.

104
Q

what makes type 2 interferon?

A

activated NK cells. type 2 = IFNgamma

it activates macrophages.

105
Q

what normally inhibits NK cell action

A

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

106
Q

missing self?

A 
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.
107
Q

what upregulates ligands for activating NK receptors

A

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

108
Q

what’s KIR

A

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

109
Q

whats’ s HLA?

A

human leukocyte antigen = MHC

110
Q

recognition of paternal non-self in pregnancy

A

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

111
Q

3 NK cells effector functions

A

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.

Pathology (38 decks)

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