Innate Immunity Flashcards
name 3 forms of physical barrier and state where they are found
1) epithelial cells joined by tight junctions (skin, GI, UG, resp)
2) flow of air/fluid (skin, UG, GI, resp)
3) cilia (resp)
name 4 chemical barriers and state where they are found
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)
name 3 types of antimicrobial peptide and state what they do
defensin - disrupts plasma membrane
cathelicidin - disrupts PM (released by neutrophils and macrophages in response to keratinocyte infection)
histatins - active against fungi in oral cavity
name the central event in the complement system. what enzyme catalyses this?
C3 –> C3a + C3b
C3 convertase
name 3 complement pathways
classical
mannose-binding lectin
alternative
name the 3 c3 convertases in each complement pathway
classical: C4bC2a
MBL: C4bC2a
alternative: C3bBb
how is the MBL pathway stimulated?
MBL binding to pathogen surface (trimerises –> oligomerizes = avidity)
or ficolin binding to pathogen
overall: a PRR (ficolin/MBL) recog a PAMP on pathogen
briefly describe the MBL pathway
MBL/ficolin + MASP complex + pathogen activated MASP1 cleaved and activated MASP2 cleaved and activated C4 and C2 formation C4bC2a C3 convertase
what property of C3b and C4b allows them to bind pathogen? why is this useful in regulation?
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
how is the classical pathway stimulated?
C1q direct binding to pathogen
OR
C1q binding Ab-pathogen (more efficient)
briefly describe the classical pathway
C1q (+Ab) + pathogen conformational change in c1r/c1s activated c1r cleaved and activated c1s cleaved and activated c4 and c2 formation c4bc2a c3 convertase
how is the alternative pathway stimulated?
C3b generated by classical/MBL pathway
C3b can bind factor B
C3 undergoes spontaneous hydrolysis (tickover) which binds factor B
briefly describe both versions of the alternative pathway
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
describe the opsonin action created by the complement system
C3b cov bonds to pathogen (via thioester)
phagocytes with C3b receptor ingest complement covered pathogen more efficiently
describe the chemoattractant action created by the complement system
C3b binds C5 convertase
C3a+C5a = chemoattractant which recruits phagocytes (inflammation)
describe how the complement system can activate the MAC
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
how is the complement system regulated
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
why is complement important? which pathogens is it activate against?
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
name 3 types of sentinel cell
1) macrophages (therefore kupffer cells/langerhans cells/alveolar macrophages/microglia)
2) dendritic cells
3) mast cells
how do innate immune cells recog pathogens/pathogenicity
use PRRs to recog:
PAMPs (non-self)
DAMPs (damage to self cells)
name bacterial, fungal, viral and protozoan PAMPs
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
name some DAMPs
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)
name the 3 classes of PRRs and give examples
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)
name some effector functions of soluble receptor PRRs
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
name some effector functions of membrane receptors
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
name some effector functions of cytoplasmic receptors
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
name 7 inflammatory mediators, give egs of them and explain how they work
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)
describe the process of extravasation
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
what are cytokines? are they long or short range acting?
small glycoproteins ‘hormones of IS’
paracrine (locally acting)
name the five groups of cytokines
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
what does IL1 do? which cells produce it?
activates macrophage and T cells and induces fever
made my macs, endothelial and epithelial cell
what does IL2 do? which cells produce it?
stimulates T cell growth and differentiation
T cells
what does IL4 do? which cells produce it?
induces class switching in IgE, promotes TH2 differentiation TH2 cells, mast cells
what does IL8 (CXCL8) do? which cells produce it?
induces neutrophil, basophil and T-cell chemotaxis to site of infection
macrophages, endothelium, fibroblasts, keratinocytes
what does IFNgamma do? which cells produce it?
activates macrophages and NK cells, increases MHCII expression
T cells, NK cells
what does TNFalpha do? which cells produce it?
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
what does GM-CSF do? which cells produce it?
production of granulocytes, macrophages, DCs
produced by T-helpers
what does TGFbeta do? which cells produce it?
anti-inflammatory
produces by monocytes and T cells
which cytokine receptors signal through enzyme-coupled receptor dimers?
homodimeric
heterodimeric with a common chain
heterodimeric with no common chain
TNF
which cytokine receptors signal through G-proteins?
chemokine receptor family
what does IL1beta do? what are its systemic effects?
activates vascular endothelium, activated lymphocytes, local tissue destruction, increases access of effector cells
systemic: fever, production of IL6
what does IL6 do? what are its systemic effects?
lymphocyte activation, increased antibody production
systemic: fever, induction acute phase protein production (proteins produced in response to inflammation)
what does IL12 do?
activated NK cells, induces differentiation of CD4 T cells into TH1 cells
what happens when [TNFalpha] > 1ug/ml?
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
what do interferons do?
interfere with viral replication
name 2 type I interferons, state the receptor that induces their expression and explain their purpose
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
what do t-helper cells differentiate into
TH1 and TH2 cells
which cytokines do TH1 cells produce? what do TH1 cells do? what type of infections are they useful for?
produce: IL2, IFNgamma and TNF-alpha
activate macrophages and induce B cells to make opsonizing antibodies (IgG)
intracellular bacterial infections
which cytokines do TH2 cells produce? what do TH2 cells do?what type of infections are they useful for?
produce: IL4/5/6/10/13 (4 and 13 particularly important)
induce B cells to make IgE
helminths (big ol parasites)
name the 7 professional phagocytes
eosinophils neutrophils basophils mast cells dendritic cells monocytes macrophages
name the 4 polymorphonuclear granulocytes
neutrophils
eosinophils
basophils
mast cells
eosinophils: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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
basophils: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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
neutrophils: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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
mast cells: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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
what is a key common feature of polymorphonuclear granulocytes in pathogen recognition
all express PRRs
name the mononuclear phagocytes
monocytes
macrophages (kupffer cells, microglia, lung alveolar macrophages, langerhans cells)
name the 3 APCs
dendritic cells
macrophages
B-cells
monocytes/macrophages: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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
name the 6 types of phagocytic bactericidal mechanisms and give egs
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)
describe the production of NO in cells
arginine + O2 —> citrulline + NO
catalysed by iNOS2 (inducible nitric oxides synthase)
what is oxygen dependent killing and how does it work?
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
how is inflammation resolved?
when neutrophils become apoptotic they release signals which inhibit further neutrophil infiltration. macrophages phagocytose apoptotic neutrophils
NK cells: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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)
dendritic cells: location and concentration? receptors? defence against which pathogens? how do they kill pathogens? any extra deets?
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
describe the stages of phagocytosis
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
