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MBB311 - Molecular Immunology > Innate Immunity > Flashcards

Innate Immunity Flashcards

1
Q

name 3 forms of physical barrier and state where they are found

A

1) epithelial cells joined by tight junctions (skin, GI, UG, resp)
2) flow of air/fluid (skin, UG, GI, resp)
3) cilia (resp)

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2
Q

name 4 chemical barriers and state where they are found

A

1) fatty acids (skin)
2) low pH enzymes eg pepsin (GI and UG)
3) lysozyme - breaks down peptidoglycan (resp)
4) antibacterial peptides - create pores in pathogen walls (defensins) (everywhere)

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3
Q

name 3 types of antimicrobial peptide and state what they do

A

defensin - disrupts plasma membrane
cathelicidin - disrupts PM (released by neutrophils and macrophages in response to keratinocyte infection)
histatins - active against fungi in oral cavity

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4
Q

name the central event in the complement system. what enzyme catalyses this?

A

C3 –> C3a + C3b

C3 convertase

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5
Q

name 3 complement pathways

A

classical
mannose-binding lectin
alternative

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6
Q

name the 3 c3 convertases in each complement pathway

A

classical: C4bC2a
MBL: C4bC2a
alternative: C3bBb

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7
Q

how is the MBL pathway stimulated?

A

MBL binding to pathogen surface (trimerises –> oligomerizes = avidity)
or ficolin binding to pathogen
overall: a PRR (ficolin/MBL) recog a PAMP on pathogen

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8
Q

briefly describe the MBL pathway

A 
MBL/ficolin + MASP complex + pathogen 
activated MASP1
cleaved and activated MASP2
cleaved and activated C4 and C2
formation C4bC2a C3 convertase
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9
Q

what property of C3b and C4b allows them to bind pathogen? why is this useful in regulation?

A

cleavage of C3 exposes a thioester on C3b (same for C4 and C4b) which can covalently bond OH/NH2 on pathogen. if no pathogen around, thioester rapidly hydrolyzed = inactivation C3b/C4b

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10
Q

how is the classical pathway stimulated?

A

C1q direct binding to pathogen
OR
C1q binding Ab-pathogen (more efficient)

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11
Q

briefly describe the classical pathway

A 
C1q (+Ab) + pathogen
conformational change in c1r/c1s
activated c1r
cleaved and activated c1s 
cleaved and activated c4 and c2
formation c4bc2a c3 convertase
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12
Q

how is the alternative pathway stimulated?

A

C3b generated by classical/MBL pathway
C3b can bind factor B
C3 undergoes spontaneous hydrolysis (tickover) which binds factor B

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13
Q

briefly describe both versions of the alternative pathway

A

C3b binds factor B
C3bB binds factor D
factor D cleaves factor B to form C3bBb + Ba
formation of C3bBb C3 convertase OR
C3 spontaneous hydrolysis: C3(H2O) binds factor B
C3(H2O)B cleaved and activated by factor D which produces C3(H2O)bBb+Ba
formation of C3 convertase: C3(H2O)bBb

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14
Q

describe the opsonin action created by the complement system

A

C3b cov bonds to pathogen (via thioester)

phagocytes with C3b receptor ingest complement covered pathogen more efficiently

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15
Q

describe the chemoattractant action created by the complement system

A

C3b binds C5 convertase

C3a+C5a = chemoattractant which recruits phagocytes (inflammation)

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16
Q

describe how the complement system can activate the MAC

A

C5b generated by C3b triggers late events of complement system
C5bC6C7 binds pathogen membrane
C8 binds and inserts into membrane
C9 binds complex and polymerizes –> formation of MAC pore

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17
Q

how is the complement system regulated

A

thioester bond hydrolysis
components rapidly hydrolysed in fluid phase
regulatory proteins:
C1 inhibitor
carboxypeptidase N inactivates C3a and C5a
CD59 on host cells bind C9 - prevents MAC formation
factor H competes with C3b for factor B binding

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18
Q

why is complement important? which pathogens is it activate against?

A

important bc: interacts with adaptive immune system (classical), aids in clearing immune complexes, activates T&B cells
active against: extracellular bacterial and fungal infections and possibly against some viruses

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19
Q

name 3 types of sentinel cell

A

1) macrophages (therefore kupffer cells/langerhans cells/alveolar macrophages/microglia)
2) dendritic cells
3) mast cells

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20
Q

how do innate immune cells recog pathogens/pathogenicity

A

use PRRs to recog:
PAMPs (non-self)
DAMPs (damage to self cells)

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21
Q

name bacterial, fungal, viral and protozoan PAMPs

A 
bac: 
gram -ve: LPS
gram +ve: LTA
all: flagellins, un-meth CpG, N-formylated proteins
fungi: 
chitin
beta-glucans
viruses:
dsRNA
protozoa:
GPI-linked proteins
mannose-rich proteins
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22
Q

name some DAMPs

A

fragments of extracellular proteins
phosphatidylserine (inner leaflet of PM therefore apoptosis must have occured)
Heat shock proteins (abnormally associated with PM)
Mitochondrial components in cyt
uric acid (kidney damage/ oxphos stress)
DNA
HMGB1 (histone-like should be in nuc)

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23
Q

name the 3 classes of PRRs and give examples

A

1) soluble receptors (MBL/complement/ficolins/pentraxins)
2) membrane-bound receptors (complement receptors/scavenger receptors/lectin receptors/toll-like receptors/chemotactic receptors)
3) cytoplasmic receptors (NOD-like receptors)

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24
Q

name some effector functions of soluble receptor PRRs

A

identify non-self/altered-self
opsonins that facilitate engulfing and clearing of apoptotic cells
Neutrophil extracellular traps (NETs) contain g/mDNA which are targets for ficolins and pentraxins
SP-A and SP-D enhance clearance of pathogens by recruitment lung alveolar macs and antibodies respectively

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25
Q

name some effector functions of membrane receptors

A

phagocytosis:
c-type lectins recog beta-glucans in fungi
mannose receptors recog mannose in bac/fungi/virus
scavenger receptors recog anionic polymers (CD14 for LPS CD36 for LDL)
chemotaxis:
chemotactic receptors recog chemoattractants (eg f-MLP receptor for N-formylated proteins)
signalling:
Toll-like receptors (TLR-4 recog LPS when associated with MD-2 and CD14: LPS-CD14-TLR4 –> signalling)
TLRs dimerise and recruit kinases and ubiquitin ligases to activate transcription of inflammatory genes

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26
Q

name some effector functions of cytoplasmic receptors

A

NOD-like receptors (NLRs) recog bac components eg flagellin/peptidoglycan, induction signalling and assembly inflammasomes
RIG-1-like receptors (RLRs) recog viral RNA produced within a cell, signalling induces expression interferons

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27
Q

name 7 inflammatory mediators, give egs of them and explain how they work

A

1) lipid mediators: prostaglandins (breakdown phospholipids to allow fluid entry into tissue)
2) cytokines: TNF-alpha (activates endothelial cells –> increased vascular dilation and permeability)
3) chemoattractants: fMLP (stimulates macrophage presence)
4) complement proteins: C5a (activates local mast cells and causes release of granules)
5) Vasoactive amines: histamine/bradykinin (bradykinin increases vascular permeability, plasma proteins enter tissue)
6) clotting factors
7) small molecules: ROI, RNI (destroy pathogens)

28
Q

describe the process of extravasation

A

1) cytokine signalling results in P-selectin production on endothelium. E-selectin is induced by TF-alpha/LPS presence on endothelium. Sialyl-Lewis X on macrophages interacts with selectins –> rolling of WBCs
2) cytokines induce endothelium to express adhesion molecules
3) integrins activated on WBCs and bind adhesion molecules (ICAM1/VCAM1) on endothelium
4) EXTRAVASATION - WBC crosses endothelium

29
Q

what are cytokines? are they long or short range acting?

A

small glycoproteins ‘hormones of IS’

paracrine (locally acting)

30
Q

name the five groups of cytokines

A

1) interleukins (IL family) - req activation from inflammasome
2) hematopoietin superfamily - v large and varied
3) interferons
4) TNF family: mainly TM proteins that can be removed from PM
5) chemokines - 2 groups CC/CXC

31
Q

what does IL1 do? which cells produce it?

A

activates macrophage and T cells and induces fever

made my macs, endothelial and epithelial cell

32
Q

what does IL2 do? which cells produce it?

A

stimulates T cell growth and differentiation

T cells

33
Q

what does IL4 do? which cells produce it?

A 
induces class switching in IgE, promotes TH2 differentiation
TH2 cells, mast cells
34
Q

what does IL8 (CXCL8) do? which cells produce it?

A

induces neutrophil, basophil and T-cell chemotaxis to site of infection
macrophages, endothelium, fibroblasts, keratinocytes

35
Q

what does IFNgamma do? which cells produce it?

A

activates macrophages and NK cells, increases MHCII expression
T cells, NK cells

36
Q

what does TNFalpha do? which cells produce it?

A

promotes inflammation, endothelial activation (increased vascular permeability leads to increased entry of IgG, leukocytes and complement into tissue and well as increased drainage to lymph nodes), cachexia (wasting), fever (by acting on hypothalamus), microthrombus, influx platelets (clotting)
T cells, macrophages, NK cells

37
Q

what does GM-CSF do? which cells produce it?

A

production of granulocytes, macrophages, DCs

produced by T-helpers

38
Q

what does TGFbeta do? which cells produce it?

A

anti-inflammatory

produces by monocytes and T cells

39
Q

which cytokine receptors signal through enzyme-coupled receptor dimers?

A

homodimeric
heterodimeric with a common chain
heterodimeric with no common chain
TNF

40
Q

which cytokine receptors signal through G-proteins?

A

chemokine receptor family

41
Q

what does IL1beta do? what are its systemic effects?

A

activates vascular endothelium, activated lymphocytes, local tissue destruction, increases access of effector cells
systemic: fever, production of IL6

42
Q

what does IL6 do? what are its systemic effects?

A

lymphocyte activation, increased antibody production

systemic: fever, induction acute phase protein production (proteins produced in response to inflammation)

43
Q

what does IL12 do?

A

activated NK cells, induces differentiation of CD4 T cells into TH1 cells

44
Q

what happens when [TNFalpha] > 1ug/ml?

A

SEPSIS
widespread increase in vascular permeability
disseminated thrombus formation can lead to cardiac infarction and organ damage
consumption clotting factors causes internal bleeding and spread of infection
multiple organ failure
septic shock

45
Q

what do interferons do?

A

interfere with viral replication

46
Q

name 2 type I interferons, state the receptor that induces their expression and explain their purpose

A

IFNalpha
IFNbeta
induced by RIG1 and some TLRs when dsRNA sensed in cell
induce a endoribonuclease that degrades viral RNA and protein kinase that P’s eIF2 inhibiting protein transl

47
Q

what do t-helper cells differentiate into

A

TH1 and TH2 cells

48
Q

which cytokines do TH1 cells produce? what do TH1 cells do? what type of infections are they useful for?

A

produce: IL2, IFNgamma and TNF-alpha
activate macrophages and induce B cells to make opsonizing antibodies (IgG)
intracellular bacterial infections

49
Q

which cytokines do TH2 cells produce? what do TH2 cells do?what type of infections are they useful for?

A

produce: IL4/5/6/10/13 (4 and 13 particularly important)
induce B cells to make IgE
helminths (big ol parasites)

50
Q

name the 7 professional phagocytes

A 
eosinophils
neutrophils
basophils
mast cells
dendritic cells
monocytes 
macrophages
51
Q

name the 4 polymorphonuclear granulocytes

A

neutrophils
eosinophils
basophils
mast cells

52
Q

eosinophils: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

small amount in the blood and also found under mucosal surfaces in connective tissue
receptors for C3b, IgG, IgA, IgE
defence against parasitic infections
release toxic proteins/free radicals from granules
synthesize cytokines and prostaglandins
also have a role in allergy

53
Q

basophils: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

low numbers in blood, more in tissue
have high affinity receptor for IgE (FcεRI) as well as C3a, C5a
granules contain histamine, ser-proteases and release interleukins
defence against parasites, role in allergy

54
Q

neutrophils: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

most common leukocyte in blood
IL8 receptor
v short lived unless moved into tissue (pus is essentially neutrophils)
kill pathogens by: phagocytosis, release lysozyme and defensins, production ROI, production cytokines, NETs

55
Q

mast cells: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

restricted to tissue - protect mucosal surfaces
receptors for C3a, C5a and IgE
release histamine and ser-proteases from granules
sentinel cells
defence against parasites, role in allergy

56
Q

what is a key common feature of polymorphonuclear granulocytes in pathogen recognition

A

all express PRRs

57
Q

name the mononuclear phagocytes

A

monocytes

macrophages (kupffer cells, microglia, lung alveolar macrophages, langerhans cells)

58
Q

name the 3 APCs

A

dendritic cells
macrophages
B-cells

59
Q

monocytes/macrophages: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

monocytes in blood –> macrophages in tissue
most are classical subset: enter tissue and are inflammatory monocyte upon infection
some are non-classical and roll along the endothelial wall
phagocytic, kill by ROS/RNS also clear up cellular debris that could be harmful to body
present extracellular pathogens on on MHCII

60
Q

name the 6 types of phagocytic bactericidal mechanisms and give egs

A

acidification
toxic oxygen-derived products (superoxide, hydrogen peroxide etc)
toxic-nitrogen oxides (NO)
antimicrobial peptides (cathelicidin)
enzymes (lysozyme)
competitors (lactoferrin - sequesters Fe2+ needed for bacterial survival - only in neutrophils)

61
Q

describe the production of NO in cells

A

arginine + O2 —> citrulline + NO

catalysed by iNOS2 (inducible nitric oxides synthase)

62
Q

what is oxygen dependent killing and how does it work?

A

generation of superoxide anions by NADPH oxidase
enzyme is activated by TLRs, chemotactic and some cytokine receptors
generation of ‘respiratory burst’: transient increase in oxygen following phagocytosis due to activation of NADPH oxidase

63
Q

how is inflammation resolved?

A

when neutrophils become apoptotic they release signals which inhibit further neutrophil infiltration. macrophages phagocytose apoptotic neutrophils

64
Q

NK cells: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

found in blood
recognition of cells by combination of stimulatory and inhibitory receptors
stimulatory: natural cytotoxicity receptors
inhibitory: killer immunoglobulin-like receptors (KIRs) eg MHCI
kills cells by inserting cytoplasmic granules into plasma membrane by perforin. also use FasL and Fas and TRAIL and receptor
NKs also use Antibody Dependent Cellular Cytotoxicity to kill infected (virus) and cancer cells (ADCC: abs bind pathogen, NK CD16 Fc receptors crosslink to ab –> apoptosis of pathogen)
made my common lymphoid progenitor unlike all other innate cells)

65
Q

dendritic cells: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?

A

skin and lymphoid tissue
activate naive T-cells in 2ndary lymphoid as well as differentiating T-helper into subpopulations
take up foreign material by phagocytosis and show antigen to T-cells
constitutively express high levels of MHCII

66
Q

describe the stages of phagocytosis

A

bacterium binds surface phagocyte
phagocytosis of pathogen by pseudopods
invagination of phagocytic membrane traps pathogen in phagosome
lysosome fuses with phagosome and deposits enzymes which cleave macromolecules and generate ROS/RNS
release of microbial debris

MBB311 - Molecular Immunology (2 decks)

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