Topic 6: Immunology and vaccines Flashcards
what makes up the innate immune system
barriers
leukocytes (phagocytes, NK)
soluble proteins - complement
interferons
local inflammation/body wide fever
what is an example of barrier
keratinised skin
what are neutrophils
Multi-lobed phagocytes that are short lived except in infection, contain granules with specialised lysosomes which release enzymes and H2O2.
what are natural killer cells
A granular lymphocyte that secretes lytic granules to kill virus infected cells
+ can kill infected host cells and bacteria before adaptive immune response kicks in
defensins
+ve charged peptides made by neutrophils which disrupt bacterial membranes through insertion
interferon
interferes with viral replication
IFNalpha, IFNbeta
these increase MHC class I, and activate NK cells
what is complement
extracellular infections
serum proteins
are proenzymes for the next ones
classical pathway C1, 4, 2, 3, 5, 6, 7, 8, 9
which part of complement incudes inflammatory response
C5a binds to receptors on neutrophils and mast cells to induce inflammatory response.
what is opsonisation
which part of complement activates it
why is it important
C3b increased phagocytosis important by aiding binding of phagocytes to pathogenic cells in the defence against gram +ve bacteria
what does the cell membrane attack complex do and what parts of complement activate it
C5b-C9
C9 polymerases to form hollow cylinders
what causes fever and what is its effects
cytokines, LPS
acts of hypothalamus
induced synthesis of prostaglandin 2 (acts on the hypothalamus and increases body temp to inhibit bacterial growth and activate WBC’s)
what are the soluble proteins of the immune system
complement
defensins
interferons
what is Fab
fragment antigen binding the arm of the antibody
what is the cause of the variable region of antibodies
different exons, unprecise system of recombination allows for mutations
what is clonal selection
B cell acquire receptors independent of antigens in the primary lymphoid tissue
when they bind their antigen they become activated
once activated they undergo rapid replication, proliferation and differentiation into plasma and memory cells
what are the characteristics of immunity developed by the adaptive immune system
specific as B and T cells recognise antigens
enhances by second exposure - memory
IgG
blocks adhesion, neutralises toxins, blocks uptake of nutrients
promotes antibody directed cellular cytotoxicity (ADCC) by NK cells
main class in serum
responsible for memory
main chain = gamma
only antibody which can cross the placenta, long lived - 6 months after birth
Can bind to complement and are opsonising.
IgM
blocks adherence, agglutinate bacteria
part of the primary immune response
first made as foetus surfaces
main chain = mu
secreted as a pentamer - therefore large and restricted to blood except in inflammation
Can bind to complement.
IgA
blocks adhesion, neutralises toxins
protects mucosal surfaces
main chain = alpha
monomer in serum
dimer in secretions, dimer can cause agglutination of bacteria
Doesn’t exist in the blood.
IgD
not yet known
main chain = delta
IgE
allergies and parasites
main chain = epsilon
what is class switching
secondary (memory) responses can include IgG, IgA, IgE depending on the type and route of infection
B cells can switch to producing IgM antibodies (since they always start with IgM) to any of the above 3 upon antigen binding - V region gene recombines with the C region gene - this allows response to be modulated based on location and Fc function
what are the 2 light chain types
k and l (greek so l = lamda)
what is opsonins
IgG and monomeric IgA can bind to some bacteria and direct them to phagocytosis
how can antibodies change
V region undergoes somatic recombination, C can class switch
what is affinity maturation
during the immune response the affinity of the antibody increases as increased binding affinity antibodies are selected.
what is somatic hyper maturation
change in v region genes in B cell responding to antigen, mutations that increase affinity are selected (aided by T-cells)
what does the Fc region do
effector regions
Fc functions directs innate immune system
how can antibodies activate compliment
C1q 2 Fc regions are needed for stoichiometry, therefore IgM is more efficient activator than IgG
T helper cells
CD4 +ve
Help B cells make antibody
Activate macrophages and natural killer cells
Help development of cytotoxic T cells
T cytotoxic cells
CD8 +ve
Recognise and kill infected host cells
what is the aim of vaccination
to eradicate disease or reduce its incidence and
transmission
what are the qualities of an effective vaccine
Safe, give long-lasting protection, induce B and T cell immunity, be relatively cheap to produce and easy to store and administer
what is the most effective type of vaccine? what are its downsides
live attenuated
it has safety and storage issues
MHCI
expressed by all nucleated cells display endogenous peptides to CD8+ve Tc cells -> inhibiting NK cell action.
MHCII
expressed by dendritic cells, B cells, and macrophages.
display exogenous peptides to CD4+ve Th cells and promote NK perforin production
What is the immune system:
An integrated system of cells and molecules that defends against disease (infectious pathogens) by amounting an immune response
What determines the magnitude of the immune response?
The pathogen infecting the host.
Why must the immune system be adaptable?
Pathogens divide and evolve more rapidly than the host, therefore the immune system must be adaptable to combat ever-evolving pathogens/
What are the general differences between the innate and adaptive immune system.
Innate:
- Broad Specificity
-No memory component
-Rapid response (within hours)
Adaptive:
-Highly Specific
-Enhanced by prior contact (acquired memory component)
-Slower Response (days-weeks)
What are the different types of barriers to disease?
Physical, Chemical, and Microbiological
What is the microbiological barrier to infection?
The commensals.
What is the chemical barrier to infection?
Skin has a slightly lower pH (slightly acidic), deterring pathogenic growth (also low pH enzymes such as pepsins to disrupt membranes) + Mucous contains lysosomes with lysozymes (hydrolases) which break down the PG mesh of invading bacteria.
What is an example of a pathogen that can directly infect the skin?
Papilloma Virus (warts), Microsporum (ringworm)
Why do most infections occur across mucosal surfaces?
They’re semi-permeable allowing them to be more easily breached.
Examples of mucosal surfaces:
GI-tract, Respiratory Tract, Genito-urinary tract (urethra)
What cells are leukocytes derived from?
Pluripotent hematopoietic stem cells (lymphoid or myeloid cells)
What are the main types of phagocytes:
Neutrophils and Mononuclear phagocytes.
What are the two mononuclear phagocytes?
Monocytes (blood) and Macrophages (tissue)
What are the features of mononuclear phagocytes:
They have a uniformly shaped nucleus, are long lived, and help initiate highly adaptive responses (linking innate and adaptive immunity)
What are the primary immune cells of the CNS and brain?
Microglial cells.
What are the two main types of interferons?
INFalpha (generated by leukocytes) and INFbeta (generated by any nucleated cells)
What chemicals are used to treat viral infection?
Interferons
What are the 3 pathways of complement activation?
The classical pathway, alternative pathway (targets LPS important in gram-negative infection), MB-lectin Pathway
What is the central event of complement activation?
The cleavage of C3 into the peptide fragments C3a and C3b by C3 convertase.
How many proteins make up the complement?
20 serum proteins produced by the liver and WBC’s (leukocytes)
What are LPS?
Bacterial lipopolysaccharides which are major components of Gram-ve bacterial outer membranes.
What is induced by complement activation?
The recruitment of inflammatory cells, opsonisation of pathogens, and killing of pathogens.
How does S.aureus evade inflammatory response?
S. aureus produces chemotaxis inhibitor proteins which bind to C5a receptors, preventing signal transduction and the resultant inflammatory response.
Which components of the complement are chemoattractants?
C5 and C3a (not as potent)
What are chemoattractants?
attract cells like neutrophils out of the blood and into the affected tissues.
How are pathogens recognised by phagocytes?
- Antibodies bound to pathogens (via Fc receptors)
- Complement Components bound to pathogen
- Innate mechanisms: (pattern recognition receptors (PRRs e.g. TLRs) recognise microbe-associated molecular patterns (MAMPs))
What are the shared features of MAMPs?
-Conserved
-Shared between microbes
-Distinct from self (host)
- Critical for survival/function of pathogens
What receptors recognise MAMPs?
Toll-like receptors (TLRs).
What are the examples of Microbe-associated molecular patterns (MAMPs)?
LPS, lipoteichoic acid, chitin, dsRNA
What is the structure of a TLR?
A receptor with a ligand-binding domain and signalling domain. Usually function in dimers, with ligand binding initiating dimerisation.
What are the key classes of agents used by phagocytes to induce lysis of the pathogen within the phagosome:
-Toxic oxygen-derived products (e.g. hydrogen peroxide and oxygen free radicals)
- Toxic nitrogen oxides (nitric oxide NO)
What are Neutrophil “NETs”
Neutrophil extracellular traps made of chromatin impregnated with antimicrobial agents that sequester bacteria
What is the MHC?
The major histocompatibility complex displaying peptides on the surface of the cell.
What downregulates the expression of endogenous MHCI?
Viral infection of the cell.
Perforin mechanism of action: (Lysis by NK cells)
NK cells produce perforin which is then inserted into the membrane of the target cell, allowing the insertion of granzyme which activate the target’s apoptotic pathway -> causing the plasmolysis of the cell.
What types of infection do NK cells target?
Primarily viral infection (major function), however can insert perforin directly into bacterial cells in some case (minor function)
What is the cytokine mechanism of activation?
Recognition of MAMPs activates the gene expression of cytokines in T helper cells and macrophages -> these proteins leave the cell by exocytosis and attach to target cells (e.g. neurones to stimulate temperature control) CYTOKINES ACT LOCALLY
What are the main groups of cytokines?
Interferons, Interleukins, Chemokines, and Tumour Necrosis Factors (TNFs)
What are tumour necrosis factors?
Pro-inflammatory cytokines that stimulate apoptosis of tissues -> they are very toxic and when unregulated cause sepsis.
What regions of the chains that make up antibodies are variable?
The N-terminal domains.
What are antibodies?
Antibodies are flexible adaptor with Fab arms (for antigen recognition) fixed to the Fc region (which interacts with elements of the immune system)
How do the Variable Region exons increase variable region diversity of antibodies?
They can recombine during early B cell differentiation (somatic recombination) in an imprecise process leading to mutations increasing diversity.
T-helper Cells (CD4 +ve) :
- Augment the immune response, aiding the production of antibodies and activating B cells, macrophages, and NK cells.
- ## Help to develop cytotoxic t-cells.
Mechanism of T-cell recognition:
Have a dimeric receptors which bind to antigen, (structured similar to immunoglobulins with variable regions and constant regions and also identical diversity with same genetic mechanism of recombination) upon binding the receptors dimerise and transduce the signal.
T-cytotoxic cells (CD8 +ve):
-Recognise and kill infected host cells. -> recognising antigen presenting cells (APCs) which form during infection by intracellular pathogens.
What is the difference between NK and T-cytotoxic cells?
NK cells don’t require activation, whereas T-cytotoxic cells require activation by antigen binding. However Cytotoxic are more efficient and much faster.
Structure of an MHC?
Made of 3-alpha micro globulins and 1-beta microglobulin (looks like two towers) -> there are 2 alpha units on the top with a small peptide binding groove. These structures are anchored to the membrane by cytoplasmic tails.
What are the different types of T-helper cells:
TH1, TH2, TH17, THFH, THreg
TH 17:
T-helper cell 17 -> releases Interleukins 17 and 22, targeting epithelial cells of mucosal surfaces, inducing inflammation, synthesis of antimicrobial peptides, and recruit neutrophils.
-> Treats extracellular bacterial or fungal infection
TH1:
Releases interferon gamma (activating macrophages, B and B cells), interleukin 2, and TNF -> treats extracellular bacteria and microbes that persist in macrophages.
TH2:
Releases interleukins 4, 5, and 13 -> inducing the switching of B cells to produces IgE and activate mast cells and eosinophils. This is used to treat allergens and parasites.
THFH:
Follicular T helper Cells produce interleukin 2 and induce B cell differentiation, class switching, and affinity maturation -> more generally targeting most microbes.
THreg:
Regulatory T Helper cells produce interleukin 10 and TGF-beta.
Suppresses inflammation and inhibits actions of other TH subsets and B cells.
Down regulating the immune system to prevent responses against commensals.
What method is used by viruses to evade cytotoxic t cells?
Down regulation of MHCI.
What features of a disease would aid global eradication efforts?
- If the disease is limited to humans and there’s no animal reservoir (not zoonotic)
- no long term carrier state + few unrecognised cases ->easy surveillance
- One or few serotypes
-> Stable cheap and effective vaccines
What is the function of neutralising antibodies?
Neutralise toxins produced by the pathogen.
What are the 3 main types of vaccine:
Attenuated pathogens (cause mild infection), Killed pathogens (unable to replicate), Subunits (molecular components of the cell)
What is the safest type of vaccine?
Subunit vaccines because there is no living components.
What is required for non-living vaccines but not living?
Adjuvant (a substance that enhances the bodies immune response e.g. aluminium salts)
DNA/RNA vaccines:
-Use DNA or RNA to transiently express pathogen antigen in host cells -> the genetic information is stored in a lipid coat and the produced peptides will be treated like APCs.
Barriers to effective vaccination campaigns?
-Expense, lack of patient complaince, lack of appropriate medical infrastructure (e.g. Measles Vaccine very heat sensitive and requires refrigeration that can’t be afforded in poorer countries)
-Personal/religious objections
Recombinant Vector Vaccines:
a vector is genetically engineered ( a pathogen gene inserted into viral vector genome) -> the gene will then be expressed in a host cell APC.
Why do attenuated vaccines tend to be more effective?
They mimic a real infection and-so induce a more realistic immune response.
What are the different methods of attenuating a pathogen for vaccination?
-Serial passage through cell culture in vitro viruses e.g. Sabin oral vaccine
-Serial passage in vitro (bacteria) - decreases virulence and reduces growth in humans
-Adaptation to low temperatures (viruses) -> become less suited for warm human environment -> limits their growth and makes them less likely to cause disease
-Genetic manipulation.
Killed Vaccines:
Pathogen is inactivated by chemical or heat treatment so unable to replicate. -> safer than attenuated however side effects can still occur due to the whole organism being used.
What’s a toixoid?
A chemically inactivated toxin used in vaccines to induce the production of neutralising antibodies. (e.g. tetanus vaccine)
