immunity L18-26 Flashcards
immunity
the ability of an organism to resist a particular infection by a pathogen by the action of specialized cells o molecules
2 types of natural immunity
innate
acquired/ adaptive
innate immunity
present at birth
cells patrol for infection
simple recog systems that identify common pathogen structures
rapid response
many cell types
limited capacity
acquired immunity
specific pathogen recog
not present at birth
learnt from invading organisms
slower response
highly specialised cells
generate “memory”
immune system goal
to clear/kill; potential pathogens in a controlled/ efficient process
- limited pathology to host
- return to homeostasis
- confer future protection against same pathogen
- check for non-healthy cells
factors affecting immunity
general health
infection
nutrition
environmental conditions
microbiome
pregnancy
genetics
stress
Edward Jenner
small pox immunity
18th century
Louis Pasteur
cholera vaccination w attenuated organisms
vaccines
substance used to stimulate production of immunity against 1/ several diseases without inducing disease
made up of: disease causative agent/ products/ synthetic substitute
measles and herd immunity
need > 95% immune population to prevent measles outbreak
MMMR vaccine in 1988
Andrew Wakefield false link between MMR and autism
why no vaccines for malaria/ HIV/ ebola
complex pathogens
pathogen life cycle understanding
expensive/ time consuming clinical trials
4 main groups of vaccines
live
killed (attenuated/ inactivated)
subunits
nucleic acid
innate responses
humoral (molecules found in fluids)
cellular (found in blood as well as tissues)
antibodies
soluble glycoproteins secreted by B-lymphocytes
serology
identifying/ measuring antibodies present in blood
- useful for measuring pathogen response
clonal selection
B and T cells expanded populations of individual clones expressing unique Ag receptor
how do cells of immune system circulate?
via blood and lymphatics
primary/ central lymphoid tissues
bone marrow
thymus
bone marrow
soft spongy, cellular tissue filling internal cavity of bones
- B/T cells continuous generation
thymus
specialized/ v cellular gland
- T cells educated here > only 2-4% survive and exit
mature lymphocytes
clonally diverse
each B and T cell have single antigen receptor
Ag specific
secondary/ peripheral lymphoid tissues
B and T lymphocytes recirculate via blood/ lymphatics through tissues until antigen meet and undergo clonal expansion/ differentiation in tissues
effector mechanisms factors for immune response
pathogen type
location
innate defence mechanisms
barriers
cellular defences
molecular defences (humoral factors)
physical and chemical barriers to infection
skin (physical barrier/ fatty acids/ commensals)
mucus membranes (mucus/ cilia/ commensals/ low pH)
lysozyme in tears
stomach acid
antibacterial enzymes in body
lysozyme
secretory phospholipase A2
tears/ saliva/ phagocytes
AMP
antimicrobial peptides
need for recognition in the immune system
discriminate between self/ non-self
multiple pathogen defence
immunity component deficiencies
PRR
pattern recognition receptors
PRR locations
host cells>
macrophages
neutrophils
dendritic cells
PRR functions
allow pathogen identification
recognise simple molecules/ patterns
‘lock and key mechanism’
types of PRR
toll-like receptors
NOD-like receptors
RIG-I-like helicases
toll-like receptors
repertoire of pathogen-associated molecular patterns (PAMPs)
*10 in humans
NOD-like receptors
nucleotide-binding oligomerisation domain
PAMPs
mannose-rich oligosaccharides
peptidoglycans
lipopolysaccharides
unmethylated CpG DNA
leucocyte production
pluripotent haematopoietic stem cells in bone marrow
leucocyte cells
lymphocytes
monocytes
granulocytes
neutrophils
eosinophils
basophils
tissue mast cells
macrophage activated function
phagocytosis/ bactericidal mechanisms
antigen presentation
dendritic cell activated function
antigen uptake in peripheral sites
antigen presentation
neutrophil activated function
phagocytosis
activation of bactericidal mechanisms
eosinophil activated function
killing of antibody-coated parasites
basophil activated function
promotion of allergic responses
augmentation of anti-parasitic immunity
mast cell activated function
release of granules containing histamine and active agents
location of dendritic cells
around lymphatic system
big sa
specialised antigen presenting
innate immunity cells
granulocytes>
neutrophils/ eosinophils/ basophils/ monocytes
adaptive immunity cells
B cell
T cell
cellular defences
phagocytosis
extracellular killing
inflammation
phagocyte pathologies
bacterial infections
fungal infections
recurrent infections
e.g. leukocyte adhesion disease syndromes > unable to make pus
phagocytosis
ingestion and killing of microorganisms by specialised cells
neutrophils
short-lived (<24h)
multi-lobed nucleusabundant in sites of acute inflammation
most common
PMN
polymorphonuclear cells
mononuclear phagocytes
blood monocytes
macrophage in tissue
longer lived (months)
phagocytosis process
- RECOG macrophage expresses receptors for bacterial constituents (components/ complement/ antibody)
bacteria binding to macrophage receptors initiate cytokine release - INTERNALISATION in membrane-bound vacuole engulfment and digestion
- RELEASE
phagolysosome
phagasome fusion with lysosome
phagocytic killing mechanisms
acidification
toxic nitrogen oxides
antimicrobial peptides
enzymes
competitors
oxygen-dependent killing
hexose monophosphate shunt > NADPH generation
NADPH oxidase generates reactive oxygen intermediates
CGD problem w NADPH pathway
reactive oxygen intermediates characteristics
bacteriostatic/ bactericidal
macrophages additional functions
activated by bacterial products/ cytokines
secrete cytokines
present antigen to lymphocytes
extracellular killing
active against organisms too large for phagocytosis/ infected cells
cells involved in extracellular killing
eosinophils
natural killer T cells
natural killer T cells
innate cells lacking antigen-specific receptors
active against viral infected cells
attack some tumour cells
release lytic granules (granzyme/ perforin)
NK cells
activated by cytokines
can produce IFN > control infections
contain viral infections whilst adaptive/ specific response kicks in
NK cell deficiency
increased herpes risk
cytokines
innate and adaptive
low molecular weight proteins (5-25kDa) secreted by cells stimulating/ inhibiting activity/ proliferation/ differentiations of other cells
20
sub-groups of interferons, lymphokines, interleukins, chemokines
complement
protection in early infections
affector system of humoral branch of innate / adaptive immune response
group of nearly 30 serum and membrane proteins
initial activation and regulated enzyme cascade
complement goal
inflammation / phagocytosis / membrane attack for pathogen kill
complement roles
opsonizing of bacteria
regulate inflammatory response
activate B cells
membrane attack complex for pathogen lysis
3 pathways of complement activation
classical pathway
lectin pathway
alternative pathway
classical complement pathway
antibody binds to specific antigen on pathogen surface
lectin complement pathway
mannose-binding protein binds to pathogen surface
acute phase protein initiation binding glycoproteins/ carbs on micro-organisms
alternative complement pathway
pathogen surface creates local environment conducive to complement activation
complement activation effects
recruitment of inflammatory cells
opsonization of pathogens, facilitating uptake and killing by phagocytic cells
lysis and death of pathogens
C3 CONVERTASE GENERATION > membrane attack complex production
nomenclature of classical pathway
C(number)
cleavage reaction products designated w different uppercase letters
alternative pathway nomenclature
factor D
factor B
properdin (factor P)
classical pathway structure
C1 (complement activation first component) = C1q/ C1r/ C1s complex
2 molecules of C1r/C1s bind to each C1q
classical pathway process
pentameric IgM binds to antigens (‘staple form’)
C1q binds to IgG molecules > activates C1r> cleaves and activates serine protease C1s
C1q molecule
6 globular heads joined to common stem
each head can bind to one Fc domain on an antibody
>2 globular heads bind to Fc domains for C1q activation
C1q binding
to single IgM/ 2+ IgG > conformational change > proteoytic site reveal on C1r
C1r
enzymatic activity when proteolytic site revealed
cleaves C1s > serine protease enzyme C1s
C1s
active
cleaves C4 > C4a/C4b
cleaves C2 after binding to C4b > C4b2a complex (C3 convertase)
C3 convertase
c4b2a complex
cleaves C3 molecules > C3b/ C3a
therefore many C3b on pathogen surface
effect of many C3b on pathogen surface
opsonisation of pathogens
phagocytosis of pathogen by cells w complement receptors
can also activate alternative pathway > further amplification
c3b if doesn’t bind to pathogen surface immediately
rapid hydrolysis by water
inactive
MAC overview
C4b2a3b + C5
C5 cleaved > C5a/C5b
C5b + C6 > C5bC6
C5bC6 +C7 > C5b67
conformational change and C7 insertion into lipid bilayer
C8 +Cb5b67 +C9 and polymerise
membrane pore formation
MAC
membrane attack complex
- displaces cell membrane phospholipids
- channel
membrane disruption
cell lysis
death
alternative pathway
can be activated by lectin/ classical pathway/ C3 spontaneous hydrolysis
C3b binding to factor B
factor D cleaves into Ba/Bb
C3bBb C3 convertase
properdin stabilizes
alternative pathway process
C5b binds C6/C7
C5b67 complexes bind to membrane via C7
C8 binds and inserts into membrane
10-16 C9 molecules form membrane pore
lectin pathway
soluble receptors
recognise microbial surface/ activate complement cascade
CHO on microbial surface
mannose complexes binding lectin and MBL-associated serine proteases
MASP-1/MASP-2 (cleaves C4/C2)
cleavage and activation
lectin pathway process
activated MASP-2 w MBL/ Ficolin l cleaves C4 > C4a and C4b
C4b binds C2 / MASP-2 cleaved >C2a/C2b and C4b2a complex
many c3b molecules on surface
lectin pathway comparison to classical
same C3 convertase
same C5 convertase
initiated differently
C3 deficiency
life-threatening infections w bacterial range
opsonisation/ inflammation/ cytolysis functions affected
C6/C7/C8/C9 deficiency
cytolysis affected
neisseria infection problems
cytokine secretion
by immune cells
brief-self-limited event
pleitropic/ redundant
pleotropic
multiple biological actions
redundant
shared biological actions
cytokine action initiation
bind to specific membrane receptors on target cells
cytokine regulation
via external signals regulating cytokine receptors/ responsiveness of cells to them
cellular response to most cytokines
changes in gene expression of target cells
expression of new functions
proliferation of target cells
3 major functional categories of cytokines
- mediators/ innate immunity regulators
- mediators/ adaptive immunity regulators
- haematopoiesis stimulators
mediators and regulators of innate immunity
produced by macrophages in response to infection
ediators and regulators of adaptive immunity
produced by T lymphocytes in response to antigen recognition
haematopoiesis stimulators
bone marrow stromal cell/ leukocyte production
stimulate growth/ differentiation of immature leukocytes
important cytokines
IL2
IL1
TNFa
interferons
chemokines
chemotractive cytokines
CXC/CC group
effects of cytokines secreted by macrophages
inflammation (chemotactic/ act on vascular endothelium)
fever
acute phase response
act on lymphocytes
antimicrobial mechanisms of phagocytes
acidification
toxic oxygen-derived products
toxic nitrogen oxides
antimicrobial peptides
enzymes
competitors
antimicrobial peptides
innate
ampipathic> lipid bilayer> destabilis
immunomodulatory effects on host cells
signs of inflammation
oedema
erythema
heat
pain
loss of function
inflammation mechanisms
brings cells and molecules from blood to site
^blood supply via vasodilation
^ adhesion molecule expression
inflammation aim
restore homeostasis
limit damage
recovery
inflammation triggers
pathogens
tissue damage
disruptive/ inappropriate immune response
inflammation process
bacteria trigger macrophage to release cytokines/ chemokines
vasodilation / ^vascular permeability cause redness, swelling and heat
inflam cells migrate into tissue> release inflam mediators
inflammation mediators
complement products
macrophage/ t-cell-derived cytokines
mast cells
local inflammation
PRR on macrophage stimulated
TNFa release
positive outcome
endotoxic shock
excessive cytokine release in gram-negative bacterial infection
vascular endothelium effects> circulatory shock / DIC
DIC
disseminated intravascular coagulation
toxic shock/ systemic inflammation
PRR on macrophage stimulated
TNFa release uncontrolled
negative outcome
cytokine storm
^circulating cytokines level
immune cell hyper-activation
immune response> organ failure/ DIC
GI host-immune interactions
tight junctions
paneth cells secrete AMPs/ IgA secretion
complement
saliva/pH/bile/peristalsis
microbiome
microbiome host immune interaction
supresses proliferation/ colonization of pathogens
IL1 beta activation/ AMP production/ TH17 cell differentiation
Crohn’s disease
inflam bowel disease
autoimmune
autoreactive T cells against intestinal floral antigens
Crohns treatment
immunomodulation
surgery
diet
antibodies
immunoglobulins Ig
‘y-shaped’ secreted glycoproteins
bind to specific Ags
hat do antibodies bind to
proteins/ polysaccharides/ lipids/ nucleic acids/ chemicals/ metals
Ig basic units
2 identical heavy chains + 2 identical light chains
non-covalent interaction/ disulphide bridge connections
N-terminal variable region on each chain
Ig secretion and expression
secreted from mature B-cells
expressed as membrane-bound B cell antigen receptor
Fab
fragment antigen binding fragment
contains antigen-binding region
bind to epitopes on pathogens
allows antibody and Ags w high affinities
Fc
fragment crystalizable fragment
antibodies funcions
neutralise
agglutinate
opsonize
activate complement
improve phagocytosis
ADCC
degranulation
antibody neutralisation
bind to bacteria/virus/toxin surface
prevent cell receptor interaction/ pathogen uptake by target cells
prior to uptake and destruction by macrophages
direct opsonization
binding of antibody constant region to phagocyte receptors
indirect opsonization
increase complement (C3b) deposition on pathogen and binding to complement receptors (CR1)
complement activation
classical pathway
antigen-antibody complex binds C1qrs
act on C4/C3 > C3 convertase
ADCC
antibody dependent cellular cytotoxicity
binding of antibodies by FcR inducing degranulation
lyses target cells#
*NK cells
degranulation
eosinophils attack schistosome larva in serum presence
degranulation via Fc receptors
degranulation of mast cells
killing by NK cells/ eosinophils
fusion of B cells w B cell tumour line
hybridoma generation > unlimited supply of monoclonal antibody
monoclonal antibody use in the lab
ELISA (enzyme-linked immunosorbent assay)
lateral flow test
antigen detection
antibody use in the lab
western blotting (protein identification/ establishment in cells)
immunofluorescence
flow cytometry
types of chains in antibody
kappa
lamda
regions of antibody
variable regions (antigen binding site)
constant regions
12 domains
domains
compactly folded globular units within proteins
functional units
~110 A.A. w intra-chain disulphide bridge
Ig superfamily
T cell receptor
MHC molecules
cell adhesion molecules
signalling molecules
(2 beta strands and intra-chain disulphide bridge)
hypervariability regions
in H and L variable regions
3
V domain
hypervariable/ complementarity-determining regions
3 HV loops on each H/L chain
6 CDRs (antigen-binding sites)
less variable framework for other CDR loops
C domains
control effector function of Ig
5 heavy chain isotypes determining size, structure and function of C region
mu/ delta/ gamma/ epsilon/ alpha
antibody valency
quantity of antigen binding sites
differing isotypes and valencies
IgM
macroglobulin pentamer
covalently bound to J chain
MW 900,000
found in blood
1st isotype produced
mu / 5 domains
low affin/ high avidity
IgM locations
on B cell surface during B cell development
in blood
IgM functions
Ig produced v rapidly
complement activation
agglutination
primary response
pathogen protect
IgD
delta chain
4 domains
long hinge
BCR during B cell development
low conc in serum
IgG
gamma chain
4 domains
most prevalent
^ in secondary responses
4 subclasses IgG1-4
serum location
IgG functions
complement activation
opsonization
antibody-dependent cell cytotoxicity
crosses placenta for unborn protection
IgA
monomer in serum
dimer in secretions
bound to J chain/ secretory component alpha chain> 4 domains
2 subclasses: 1(serum) 2 (secretions)
IgA functions
mucosal membranes
microbial adherence inhibition
neutralise toxins/ pathogens
prevent commensal bacteria entry to bloodstream
neonate intestinal production
IgE
5 domains
epsilon chain
binds w high affin to FCRepsilon on mast cells/ basophils
> vasoactive/ inflam mediator release
ADCC/ helminth/ protozoa infection
allergy role
induces eosinophils/ basophils to release histamine/ proteases
anaphylaxis
^ histamine release /TNF alpha/ vasodilation
epinephrine epipen
^vasoconstriction/ blood glucose levels
Ig in brain
devoid
IgG locations
blood mainly
extracellular fluid
foetus receives from mother
IgM locations
blood
IgA locations
monomeric in extracellular fluid
dimeric in secretions
IgE locations
mast cels below epithelial surfaces
B cell isotypes of Ig production
B cell formation> IgM/IgD BCRs and then IgM/D antibodies
isotype switch w progression via irreversible DNA recombination
main functions of T cells
intracellular infection control
key regulators of activities of other cells
immune memory
cellular specific immunity
transferred with cells
cell-associated antigen recognition
T lymphocyte mediated
T cells
use TCR to recognise pieces of antigen on cells generated by enzymatic processing
or histocompatibility complex molecules
T cell function initiation
direct killing of cells displaying Ag
alert/help other cells of immune system
TCR
T cell antigen receptor
heterodimer w alpha/ beta chains linked by disulphide bridge
V and C region per chain
hydrophobic trans-membrane region on each chain w short intracellular tail
T cell vs B cell receptor
BCR secreted as antibody recognising native extracellular Ag
TCR not secreted recognizing pieces of Ag on cell surfaces as MHC molecule complexes
MHC class I
expressed by nearly all cell types infected with intracellular pathogen
usually express CD8, kill infected cell via apoptosis
MHC class II
expressed by specialized immune cells
allows detection of extracellular Ag captured by specialized immune cells (APC)
dendritic cells
APC initiating acquired immune responses
exogenous antigen transport to secondary lymphoid tissue
MHC II recognition
CD4+ T cell activation to “help” other cells > specific acquired immune response
cellular immunity
transferred w cells
cell-associated antigen recognition
T lymphocyte mediation
MHC
major histocompatibility complex
present processed antigen pieces on surface of nucleated cell
HLA (human leukocyte antigens) class I molecule
TCR recognition outcomes
direct killing of infected cells displaying Ag pieces
alert/ help other immune cells
TCR structure
heterodimer
alpha /beta chains linked by disulphide bridge
V (Ag interactor) and C region of each chain
hydrophobic transmemebrane region and short intracellular tail
Ag recognition in B vs T cells
BCR secreted as antibody/ native extracellular Ag recognition
TCR not secreted/ recognises Ag pieces n surfaces as MHC
MHC class 1 molecule
allows detection of any cell infected
T cells recognising express CD8 > apoptosis of infected cell
CD8+ cells
cytotoxic T cells
MHC class 2 molecule
allows detection of extracellular Ag captured by specialized immune cells > APC
CD4 T cell activation/priming
dendritic cells
APC initiating acquired immune responses > exogenous antigen transport to secondary lymphoid tissue
activated CD4 cells
Th cells (helper function)
via cell-cell interactions/ secretion of cytokines
different subsets based on cytokines
naive Th cells
leave thymus to secondary lymphoid structures
polarization upon MHCII recognition
CD4 Th1
activate macrophages
help kill intracellular pathogens
NK cell activation
more Th1 cells produced
CD4 Th2
kill extracellular parasites
recruit eosinophils/ mast cells/ basophils
produce cytokines for B cell class switching to IgE class switch induction
more Th2 produced
CD4 Tfh
help B cells class switch to plasma cells
activate antibody secretion
CD4 Th17
help kill fungi
recruit neutrophils
promote antimicrobial peptide production
inflammation/ anti-microbial immunity at epithelial/ mucosal barriers
CD4 Treg
inhibit unwanted immune responses
inhibit/ regulate T cell activation
prevent autoimmunity
MHC structure
heterodimer alpha chain (a1/a2) 2 helices
8 stranded Beta sheet binding peptides
MW 44kDa
HLA-A/B/C have own alpha chain pairing w beta 2 microglobulin
3 class 1 genes/ molecules
HLA-A
HLA-B
HLA-C
all pair w beta 2 microglobulin MW 12,000
MHC class II
specialized APC expression
heterodimer alpha (34kDa) and beta (29kDa)
3 types> HLA-DR/ HLA-DQ/ HLA-DP
MHC class II structure
alpha1/ beta1 domains form alpha helix and 8-stranded beta-sheet
genes encoding MHC
clustered to form large genetic region/ complex
class I: HLA-A/HLA-B/HLA-C
class II: HLA-DRA/B HLA-DQA/B HLA-DPA/B
amino acid polymorphisms common and clustered within grooves
endogenous acquisition of peptides
cytoplasmic proteins (from intra pathogens/ normal cellular proteins)
processed and presented by MHC class I molecules
exogenous acquisition of peptides
proteins outside cells (extracel pathogens/normal proteins)
processed and presented by MHC class II
MHC class I molecule peptide loading
cytoplasmic protein synthesis > cleaved to peptides by proteasome
transport into ER by TAP complex
assemble w newly synthesised MHC class I molecules > cell surface transport
MHC class II molecule peptide loading
APC ER class 2 molecule synthesis w invariant chain > moves from ER to endocytic pathway > exogenous proteins into endocytic pathway> loading and transport to cell surface
class II molecule invariant chain function
blocks groove
prevents MHC class II binding peptides present in ER
pMHC complex recognition
initiates intracellular signalling cascade
via CD3 complex
ITAM (immuno receptor tyrosine-based activation motif)
MHC recog by T cell stabilisation
by co-receptors CD8/CD4
MHC II > CD4
binding of peptides by MHC
single peptide at time
broad specificity
polymorphic residues in peptide-bonding domains affect specificity
differences affect immune response
MHC polymorphic genes
graft rejection
genetic influence on some disease
MHC molecule expression
can be-upregulated/ induced on other tissues
co-dominant
course of infection
local infection epithelium penetration> local infection of tissues> lymphatic spread> adaptive immunity
pathogenicity
symptoms of infectious disease caused directly by pathogens/ indirectly by uncontrolled immune responses
pathogenic mechanisms of tissue damage
exotoxin production
endotoxin
direct cytopathic effect
tissue damage examples
infectious agent
immunodeficiency
vaccination
immunopathology
hypersensitivity
tumour immunology
leprosy infectious agent
mycobacterium leprae
intracellular bacteria
granulomatous lesions
nasal droplet/ armadillo spread?
tuberculoid leprosy
low infectivity
low levels
local/ granulomous inflammation
peripheral nerve damage
normal serum immunoglobulin levels/ T-cell responsiveness
cytokine patterns in leprosy
tuberculoid > Th1 response effective
lepromatous> inappropriate Th2 response
immunodeficiency
decreased ability to fight infection
primary/ secondary
primary immunodeficiency
intrinsic defect in immune system
genetic/ rare
secondary immunodeficiency
consequence of another condition
e.g. malnutrition/ immunosuppressive or cytotoxic drugs/ infection/ lymphoproliferative disease/ stress
type I hypersensitivity
allergy
IgE reactant
soluble antigen
mast-cell activation
GI tract immunopathology
^fluid secretion/ ^peristalsis
content expulsion
eyes/ nasal passage/ airway immunopathology
decreased airway diameter
^mucus secretion
> blockage / congestion/ swelling/ mucus secretion
blood vessel immunopathology
^blood flow/ permeability
Type II sensitivity
IgG/ IgM mediated red blood cell destruction
type III sensitivity
systemic lupus erythematosus
autoantibodies to DNA/ nuclear Ags
immune complex formation and susceptible site deposition
> glomerulonephritis/ rash/ arthritis
Type IV sensitivity
organ-specific autoimmune disease
insulin-producing beta cells in pancreas
autoreactive effector T cell mediation
no insulin/ blood glucose^/death
IgG to self-antigens
complex formation
cause inflammation
autoimmune disease possible causes
loss of self-tolerance
^western culture frequency
more common in females
common autoimmunity diseases
rheumatoid arthritis
lupus
Crohn’s disease
multiple sclerosis
T1 diabetes
immunotherapy
activating immune system ^anti-tumour responses
antibodies as therapeutics to bind to tumours (specific-killing)
block activation signals leading to autoimmune responses
