immunology (6) (Rob Spooner) Flashcards
extracellular pathogens
and examples
bacteria, parasites, fungi
S.pneumonia
C.tetani
Sleeping sickness
S. pneumonia
Gram +ve
90 diff serotypes
only pathogenic when other infections present
C. tetani
Gram +ve
spore forming - heat resistant, on human skin
release toxins that interfere with neural impulses
sleeping sickness
protozoan (C.T brucei)
carried by Tsetse flies
can change varralleles so shift outer coat so immune system can’t recognise
intracellular pathogens
bacteria, parasites
M. leprae
L. donovani
P. falciparum
M. leprae
Gram +ve
infects macrophages and Schwann cells
leprosy
L. donovani
protozoan
infects macrophages
P. falciparum
protozoan
infects erythrocytes
malaria
examples of viruses
smallpox
influenza
chicken pox
flu evolution
recombination of RNA segments
H + N are surface spikes on flu that change
so lots strains
antigenic variation/shift
change coat e.g. malaria
why do we need an innate non-specific response?
if there’s a new pathogen, the specific response is too slow so need innate to survive first few days
1st line of defence, inherited, no memory, ancient origin
adaptive immune response
memory
slow (7-10 days), specific, somatic gene recombination generates response
only in vertebrates
brain immune system
no adaptive response so survives on the innate response
humoural mechanisms/immunity
macromolecules in extracellular fluid like antibodies
soluble-phase defence, secreted proteins in bodily fluids, immunoglobulins
innate - barriers, defensins, complement proteins
adaptive - antibodies
cell-mediated responses
lymphocytes, specialised cells,
innate - phagocytic, APC, natural killer, TLR
adaptive - APC, T cells, B cells
complement proteins
soluble proteins that activated upon infection, proenzymes
cause inflammation
3 lines of innate immune defence
barries - physical and chemical
cell-intrinsic response (phagocytosis)
speciliased proteins and cells
O-linked Glycans
sugars attached by oxygen groups
defensins
small positively charged antimicrobial peptides that kill or inactivate pathogens have hydrophobic (beta sheets) or amphipathic helical domains (coil) multiple classes so target wide range of pathogens
PAMPs
innate system recognises these pathogenic molecules
e.g. fMet - used for bacterial translation initiation, attract neutrophils peptidoglycans from bacterial cell walls bacterial flagellae LPS from Gram -ve Mannans, glucan, chitin from fungi
we don’t make any of these so we recognise it as foreign
how does immune system recognise PAMPs?
pattern recognition receptors (PRRs) - soluble receptors in blood and cellular receptors
blood receptors - complement system perform killing and aid phagocytosis
cell receptors - toll-like receptors that are membrane bound stimulate inflammation
lectin
any protein that bind to sugar
toll receptors
Drosophila trans-membrane protein
large extracellular domain with repeating motifs (leucine-rich repeats) - bind proteins and cause expression of defensins
toll-like receptors
TLR4
TLR5
TLR9
function
bind PAMPs
most on cell membrane on epithelial cells, macrophages, dendritic, neutrophils
LPS
flagellum
CpG motifs in DNA
signal to nucleus to transcribe pro-inflammatory genes and cause interferon response
granulocytes
agranulocytes
neutrophils and eosinophils
granules in cytoplasm (lysosomes and secretory vesicles)
macrophages - but then mature to granulocytes
neutrophils
polymorphonuclear leucocytes - multilobed nucleus
most common granulocyte
1st defence against bacteria
attracted to infected tissue by macrophages/cleaved complement proteins/PAMPs, and cause inflammation
abundant in blood
short lived because suicide
why are neutrophils short lived?
because they suicide
macrophages
monocytes mature to macrophages big, large nucleus longer lived remove dead damaged cells and can ingest large MOs communicate with adaptive immune system
eosinophils
work in gangs and collectively eat - coat parasite and destroy
modulate allergic inflammatory responses
phagocytes have ……. receptors on cell surface and they…
toll like receptors (TLRs)
are activated when contact with a pathogen is made
they act as receptors for antibodies and for complement 3b protein if pathogen is coated in complement
what happens when any ligand binds to receptors on phagocytes (antibody or complement receptors)
activation of phagocytes - inflammation - killing - actin polymerisation
actin polymerisation
actin of our cytoskeleton changes so cell changes shape and wraps around target so traps it inside phagosome
granules go to actin polymerisation site and fuse with phagosome releasing acid hydrolases/defensins/lysozymes
lysozymes
degrade bacterial cell wall (breaks bonds in peptidogylcan)
addition of sialic acid
to capsule components
avoids complement attack and engulfment
inflammation
blood vessels dilate
swelling
accumulation of complement activates TLRs in macrophages so secrete cytokines that attract neutrophils so amplify inflammation
dsRNA
intermediate in virus lifecycle
we make little of it so can detect viruses by this
interferons
autocrine
paracrine
group of signalling proteins called cytokines produced by white blood cells, fibroblasts, or T-cells
response to a viral infection
ability to interfere with the production of new virus particles by limiting replication and spread
work on cells that produce them
work on neighbouring cells
ssRNA nuclease
destroy own mRNA so shut down protein synthesis
can’t make surface proteins so look foreign
signals trouble
immunoproteasome
protealytic
destroy viral proteins
why do foods taste weird when you’re ill?
interferons can alter structure of taste buds so change tastes
natural killer cells
counts grooves in receptors
viruses down regulate display of receptors so attract natural killers and cause apoptosis -persuades death
apoptosis
signals condense chromatin cytoplasmic condensation cytoplasm and nucleus fragmented phagocytosis neighbouring cells phagocyte too
antigen
immunisation
anything an adaptive immune system can recognise
present harmless form to immune system
adjuvant
enhances body’s immune response to antigen
activate innate system that trains adaptive system
where are T cells when they are stem cells (before they mature)?
in bone marrow in adults and liver in fetus
how long does clonal expansion take?
a week
TCR
T-cell receptor
T-helper
activate macrophages, dendritic celles, B cells
maintain T-cytotoxic, amplify innate system
how do T-helper cells maintain T-cytotoxic activity?
by secreting cytokines
so amplify innate system
T-regulatory
inhibit function of T-helper and T-cytotoxic, dendritic cells
turn off immune system
T-cytotoxic
T-killer
kill infected cells by apoptosis
flatten against antigen and form immunological synapse, secrete perforins which punch pores in membrane and secrete granzyme to cytosol
granzyme
convert procaspase into active caspase so cleavage and cell death
caspase induces apoptosis
difference between B cells and T cells
B cells recognise antigen by themselves while T cells recognise antigens on APCs
antibody structure and properties
light chains on outside
disulfide bonds between light and heavy chain
flexible hinge region allows crosslinks and networks
1 bind to 2 same antigens or cross link if antigen has 2 determinants
3 or more is a network - entrapped
5 classes of antibodies
IgM IgD IgG IgA IgE
IgM
1st antibody B cells make - B cell receptor
5 Y-shaped antibodies held by J (joining) chain and disulfide bonds
activates C3a and C3b
is an opsonin because activates complement (aids in phagocytosis)
IgD
developmental marker
B cell receptor after migrated to lymphoid tissue
recognise same antigens as IgM
opsonisation
coat target with IgM/complement so recognise by macrophages
IgG
which domains do what?
classic antibody structure
most abundant
neutralisation
opsonisation - phagocytes recognise tail region
secreted into milk and can cross placenta
constant domain (C) 1 and 2 bind complement components
C2 and 3 bind Fc receptors on neutrophils
C3 binds Fc receptors on macrophages and NK
passive immunity
antibodies secreted into breast milk
IgA
dimeric
2 antibodies joined by J chain
secretory component - into mucosal surfaces
also in breast milk
hardly any N-glycans so very flexible
IgE
binds Fc receptors on mast cells/basophils/eosinophils and cause release of histamine - inflammation
receptor for eosinophils so help phagocytosis
heavily N-glycosylated - stiff so target large pathogens
class switching
there is only 1 heavy chain gene that encodes all antibodies so somatic recombination of DNA occurs which removes specific parts and loops so alignment of variable heavy chain upstream to different Igs so diff chains are generated when loop taken off
primary mRNA –> mature mRNA
e.g. B cell to plasma cell
antibody antigen binding site
made from variable-light and variable-heavy domain interactions
N-glycans
complex carbohydrates added to asparagine residues during folding prior to secretion
large so hold domains apart allowing exposure of functional motifs
clonal deletion
lymphocytes that react inappropriately with self-antigens are destroyed
3 antibody genes
1 HC heavy chain gene
2 LC light chain genes (lambda and K)
so 2 versions of every antibody with lambda or K LC
affinity maturation
and evolution of high affinity antibodies
antibodies in lymph nodes get better and become more specific
when activated, B cells are released or stay in lymphoid follicles but expand to germinal centres where high rate mutation in variable domains
somatic hypermutation
B cells remain in follicles forming germinal centres
generate B cells with altered V domain specificity
