Introduction to Immunology (9-14) Flashcards
What are the 5 main pathogens that cause disease?
Bacteria
Viruses
Parasites
Fungi
Protozoa
changes in size, location and biochemical composition
→ immune system needs to attack each differently
What is Streptococcus pneumonia?
Gram positive bacterium
→ causes acute sinusitis, meningitis, pneumonia…
→ part of the normal upper respiratory tract flora, but can become pathogenic under the right conditions
How does Streptococcus pneumoniae compete with Haemophilus influenzae?
S. pneumoniae attacks H. influenzae (a gram -ve bacterium that also causes pneumonia and meningitis) with hydrogen peroxide
→ H. influenzae responds by signalling to our immune system to attack S. pneumoniae so it can thrive itself
What is Clostridium Tetani?
Gram positive spore forming bacterium
→ causes tetanus
How does Clostridium Tetani cause tetanus?
C. tetani produces potent toxic spores - tetanospasmin toxin
→ when released in a wound, it oxidises and enters circulation
→ reaches end of motor neurones, interfering with neurotransmitter release, causing tetanus
What is sleeping sickness?
Caused by Trypanosoma brucei carried by Tsetse flies
→ acquire a dense layer of glycoproteins that continually change, allowing it to avoid the immune system - antibodies don’t work anymore
→ symptoms: sleepiness, insomnia, anxiety, fever, weakness
Why are viruses difficult to fight?
Viruses (like smallpox, flu, chickenpox) are difficult to fight
→ always mutating
→ always intracellular - difficult to reach
Why is rapid viral evolution a challenge faced by the immune system?
Rapid viral evolution is a virulence strategy
→ pathogens can mutate (HIV) or recombine (flu) to avoid host immune responses
→ the immune system must be able to respond (must be adaptive) - constant evolutionary race
How does HIV rapidly evolve?
HIV rapidly evolves by mutation
→ the RNA genome is associated with RNA replicase (reverse trancriptase) with a high mutation rate about 1in10,000 bases
→ the antigentic drift is so rapid that it outpaces development of an effective immune response and confounds attempts to develop vaccines
How does flu rapidly evolve?
Flu rapidly evolves through recombination of its RNA segments, giving rise to new flu variants
→ the Spanish flu epidemic was triggered after a bird virus crossed the species barrier - lucky mutation meant it could now infect humans
→ recombination events triggered the Asian and Hong Kong flu epidemics
What is antigenic variation/shift?
A virulence strategy where some pathogens can alter their surface proteins to avoid host immune responses
Why is the adaptive immune response of memory important?
Re-exposure to pathogens is common
→ the immune response must have a memory
→ improves the secondary response to re-exposure - faster/bigger clears pathogens more efficiently
Why do we reply on our innate immunity during initial exposure to pathogens?
Both the primary and secondary adaptive immune responses are slow
→ so we rely on our innate immune system to kick in in the mean time, in the first few critical hours after exposure to a new pathogen
→ bacterial growth is exponential
Does the immune system have tissue specific responses?
Yes e.g.
→ lungs have mucus layer skin dry and keratinised
What is the blood brain barrier?
The blood brain barrier separates circulating blood from the brain extracellular fluid
→ tight junctions around brain capillaries, which don’t exist in normal circulation - obstacle for adaptive immune system
→ brain almost entirely relies on innate immune response
What’s the difference between the innate and adaptive immune system?
Innate
→ first line of defence, rapid
→ no memory, non specific
→ encoded in the germ-line
Adaptive
→ slow to adapt
→ highly specific, has memory
→ somatic gene recombination
What is cell-mediated immunity?
Defence provided by specialised cells in blood and tissues
→ e.g. lymphocytes (adaptive), granulocytes (innate)
What is humoural immunity?
Soluble-phase defence provided by secreted proteins in body fluids
→ e.g. immunoglobulins (adaptive), complement proteins (innate)
What is the structure of the innate immune system?
Humoural arm → barriers, defensins, complement
Cell-mediated arm → phagocytic cells. natural killer cells, toll-like receptors, APC (antigen presenting cells): dendritic cells and macrophages
What is the structure of the adaptive immune system?
Cell mediated arm → APC (antigen presenting cells): dendritic cells and macrophages, T cells, B cells
Humoural arm → antibodies
How do barriers of the innate immune system defend against pathogens?
Physical + chemical - stop pathogens entering blood stream
→ e.g. thick layer of keratinised dead cells - skin
→ tight junctions between epithelial cells
→ acid stomach pH
→ mucus layers
What are mucus layers?
Made up of secreted mucins and other glycoproteins
→ slippery - hard for pathogens to attach to mucus-coated epithelia
→ found on moist epithelial surfaces - epithelial cells often have beating cilia which facilitate clearance of pathogens
→ contain defensins - wide antimicrobial activity
What are defensins?
Small positively-charged antimicrobial peptides
→ hydrophobic or amphipathic helical domains
→ can kill or inactivate: gram +/-ve bacteria, fungi, parasites (inc. protozoa and nematodes), enveloped viruses (HIV)
→ although non specific different types of defensins work better on different pathogens
How do defensins work?
Their hydrophobic domains or amphipathic helice4s may enter into the core of the lipid membrane of the pathogen and destabilise it → cell lysis
Following membrane disruption, the positive charges may interact with (negatively-charged) nucleic acids in the pathogen
How do defensins lyse pathogens, but not our own epithelial surfaces?
Defensins are much more active on membranes that don’t contain cholesterol
→ our membranes contain cholesterol
How does the innate immune system recognise pathogens as ‘non-self’?
The innate immune system recognises pathogen-associated molecular patterns (PAMPs) that are common to many pathogens
→ PAMPs are absent in the host
→ e.g. N-formyl methionine (fMet), peptidoglycans from bacterial cell walls, bacterial flagellae, LPS from gram -ve bacteria, mannans, glucans, chitin from fungi, ‘CpG’ motifs in bacterial or viral DNA
How are PAMPs recognised?
PAMPs are recognised by soluble receptors in the blood and by cellular receptors: Pattern Recognition Receptors (PRRs)
Blood receptors recognise peptidoglycans, mannans, chitin→ complement system → direct killing + aid phagocytosis
Cell receptors recognise LPS, ‘CpG’ motifs, flagellae → toll-like receptors → an alarm system
What is the complement system?
Complement activation targets pathogens for lysis
→ complement: about 20 soluble proteins that are activated sequentially upon infection
- early complement components - proenzymes that activated the next member by cleavage → amplified proteolytic cascade
- pivotal proteolysis - cleaves C3 into C3a & C3b
- C3a → calls for help - attracts phagocytes, lymphocytes stimulating inflammation
- C3b → binds covalently to pathogen’s plasma membrane
- Pathogen-bound C3b stimulates local cascade (reactions C5-C8)
- C9 is inserted into the membrane
- A C9 pore breaches the membrane - form a membrane-attack complex
- pathogen lysis
What are toll-like receptors (TLRs)
An alarm system
→ on the cell membrane of epithelial cells and macrophages, dendritic cells and neutrophils
→ looks out for PAMPs, signals to the nucleus, gene expression changes - promotes inflammation
How does Neisseria Gonorrhoeae evade the innate immune system?
The capsule of N. gonorrhoea lacks LPS, instead contains lipoligiosaccharide (LOS)
→ N. gonorrhoea can add sialic acid from host to its LOS
→ human cells display sialylates glycoproteins - allows to mask as a human cell evading the innate immune system
What are phagocytes?
Phagocytes seek, engulf and destroy pathogens
→ 3 major classes: neutrophil, eosinophil, macrophage
→ contain numerous lysosomes and secretory vesicles (or granules)
What are neutrophils?
Most common type of granulocyte, have multilobes nucleus
→ phagocytose and destroy microorganisms, mainly bacteria - have a key role in innate immunity to bacterial infection
→ short-lived cells, abundant in blood, not present in normal healthy tissues
→ rapidly recruited by: activated macrophages, peptide fragments of cleaved complement proteins, PAMPs
What are macrophages?
Larger and longer-lived than neutrophils
→ recognise and remove senescent, dead, and damaged cells in many tissues
→ able to ingest large microorganisms like protozoa
What are eosinophils?
Team players, they help to:
→ destroy parasites
→ modulate allergic inflammatory responses
→ have double lobed nucleus
How to phagocytes engulf their targets?
Phagocytes display cell-surface receptors for PAMPs and chemicals produced by the immune system (TLRs, antibodies, complement C3b protein)
Binding activates them -
→ enhances killing power
→ causes release of cytokines to attract more white blood cells
→ induces actin polymerisation: the phagocyte’s plasma membrane surround pathogen and engulfs in phagosome
What are granules?
Dense membrane-bound lysosomal derivatives
→ fuse with the phagosome membrane and release their contents (lysozyme acid hydrolases) inn an attempt to digest pathogen cell wall
→ contain defensins - destabilise pathogen’s membranes
What do NADPH oxidase complexes on the phago-lysosomal membrane do?
A respiratory burst (a transient increase in O2 consumption) by the phagocyte allows the NADPH oxidase complexes to produce highly toxic oxygen-derived compounds
→ e.g. superoxide O2-, hypochlorite HOCL, hydrogen peroxide H2O2
Can neutrophils survive the chemicals of a killing frenzy?
No - most macrophages can
→ neutrophils appear to be suicide squads - will use own DNA to trap bacteria preventing escape
→ dead neutrophils/pathogens = pus (can be green due to release of copper-containing compounds)
How can pathogens survive a killing frenzy?
→ addition of sialic acid to capsule components avoids complement attack and subsequent engulfment (Neisseria gonorrhoeae)
→ some survive and replicate inside neutrophils - express virulence factors that protect against respiratory burst, until neutrophils die (Neisseria gonorrhoeae)
→ neutralise actin polymerisation and therefore phagocytosis, inject a toxin that disrupts assembly of the actin cytoskeleton (Yersinia pestis)
→ survive inside macrophages, which usually survive the killing frenzy (Salmonella)
How does inflammation aid in a killing frenzy?
Inflammation (good when controlled/acute) - blood vessels dilate, local swelling, accumulation of components of the complement cascade
→ activation of TLRs in epithelia and activated macrophages contribute to inflammation
→ macrophages secrete cytokines, including chemokines that attract neutrophils
What can go wrong with inflammation?
Systemic release of inflammatory cytokines can lead to excessive blood vessel dilation, resulting in sudden lowering of blood pressure (shock)
→ if widespread inflammation, swelling and blood clotting occurs - septic shock
→ significant decrease in BP, blood supply to vital organs is reduced - organ failure
What are interferons?
Interfere with viral infection
→ most important cytokines in virology
→ produced by cells in response to viral dsRNA
→ induce changes in the infected cell - autocrine action
→ induce changes in neighbouring cells - paracrine action
How do interferons limit viral replication?
- make virally-infected cells and neighbours into much less efficient factories - warn neighbouring cells of infections to induce expression of other cytokines, activate a ssRNA nuclease and other mechanisms that shut down host cell synthesis
- limit viral spread by promoting apoptosis of infected cells
- upregulate display or viral peptides - signals for recognition by activated T cells
- stimulate expression of the immunoproteasome to process and destroy viral proteins
- call for help: attract natural killer cells, activate macrophages
- fight cancers
What are natural killer cells?
Viruses and cancers down-regulate expression of immune system recognition molecules - unusually low expression likely to be infected or transformed
→ NK cells recognise their targets by monitoring the level of expression of these molecules
→ NK cells are attracted to virally-infected cells by INFs
→ NK cells persuade cells to die by apoptosis
What is the adaptive immune system?
Destroys invading organisms and toxins they produce
→ highly specific to a particular pathogen
→ long-lasting protection (immunological memory)
→ recruited and trained by the innate immune system
What are antigens?
(ANTIbody GENerators)
Any substance capable of generating an adaptive immune response
How do immunisations help understand the adaptive immune system?
- an antigen is injected into a mouse in the form of a suspension containing adjuvant
- adjuvant activates innate immunity responses, contains:
→ immunological stimulants - inactivated mycobacterial proteins
→ irritants - aluminium hydroxide - the activated innate response also responds to the antigen in the vaccine
- the innate immune response trains the adaptive immune response - very specific
What are the benefits and problems of immunisations?
benefits → reduces reported cases due to immunological memory
problems → anti-vax movements causing increase in cases (e.g. false link with MMR vaccine and autism)
What are lymphocytes?
White blood cells (T or B) that perform adaptive responses
→ develop in central or primary lymphoid organs - bone marrow, thymus
→ migrate to peripheral or secondary lymphoid organs - adenoids, tonsils, lymph nodes, spleen, skin, respiratory tract
→ highly concentrated in blood and lymph
How did experiments from the 1950s confirm that lymphocytes are responsible for adaptive immune response?
Mice were heavily irradiated
→ unable to produce apatite immune responses, could still do innate
Lymphocytes transferred into these mice restored adaptive immunity
What are dendritic cells?
Type of phagocyte and APC
Display wide variety of TLR and pattern receptors
→ activated by binding of pathogen to any of these receptors
→ activated DC phagocytose and degrade invading microbes
→ peptides from degrade organisms are displayed on their cell surface
→ migrate to lymphoid organ to activate adaptive immune responses (training to recognise displayed peptide fragments)
How do dendritic cells (DC) find T cells?
innate immune response activates DC → digests pathogen → mature into APC → migrate to lymphoid organ → find T cells
How to T cells develop?
T cells develop in thymus tissue from thymocytes derived from common lymphoid progenitor cells derived from a haemopoietic stem cell (liver - foetuses, bone marrow - adults)
How do dendritic cells (DC) activate T cells?
- DC present peptides to T cells in lymphoid organs
- T cell TCR recognises ‘self’ antigen - no action taken
- T cell TCR recognises no antigen - no action taken
- T cell TCR recognises ‘non-self antigen’ - clonal expansion of specific T cells
Why do APCs only present to T cells?
highly specific 2 step recognition to stop groove proteins wrongly activating non T cells
→ co-stimulatory molecules on APC dock with T-cell specific co-stimulatory molecules
→ peptide held in groove of APC presenting protein and scanned by the TCR
no recognition - no activation, cells undock
recognition - T cells activated - migrate to site of infection
What are the 3 types of T cell?
T regulatory (or supressor)
T cytotoxic
T helper
What are T helper cells?
Activated macrophages (phagocytes), dendritic cells, B cells (lymphocytes) and maintain cytotoxic T cell activity by secreting variety of cytokines
What are T regulatory cells?
Inhibit the function of helper T cells, cytotoxic T cells and dendritic cells
→ regulate inflammation, prevent too many cytokines released
What are cytotoxic T cells?
Kill infected host cells by persuading them to undergo apoptosis
→ recognise the antigens that activated it, binds specifically to target cell forming an immunological synapse
How do cytotoxic T cells kill target cells?
- secrete perforins, assemble and form channel in target cell wall
→ T cell secretes specific proteases which enter target and activate caspases (effector proteins of apoptosis) - bind to receptors on target cell that send a signal that activates caspases → apoptosis
Why is T cell activation an amplifying process?
The apoptotic bodies (causes by cytotoxic T cells) are phagoctyosed by antigen-presenting cells - can therefore retrain T cells
→ why T regulatory cells are needed
What is the difference between T cells and B cells?
Both derived from common lymphoid progenitor cells, which are derived from haemopoietic stem cells but,
T cells → develop the thymus, recognise antigens from dendritic cells
B cells → develop in bone marrow, recognise antigens as soluble proteins
How to B cells recognise their antigens?
- soluble antigens in blood or lymph
- B cell receptor (BCR) recognises ‘self’ antigen - no action taken
- BCR recognises no antigen - no action taken
- BCR recognises ‘non-self’ antigen - activation, mitosis and clonal expansion of specific B cells
How do resting B cells differentiate?
Differentiate into effector B cells (plasma cell)
→ increase in ER, can secrete lot of antibodies
→ specific to antigen that activated in lymphoid organ
What is the structure of an antibody?
Tetrametric - Y shae
→ 4 polypeptide chais, 2 identical heavy chains and 2 identical light chains
→ held together by covalent disulphide binds at the hinge between H and L chains
How many antigens can one antibody tetramer bind?
2 identical antigens
What can occur if an antigen has two identical antigenic determinants?
Antibodies can cross-link the antigens making small cyclic complexes or linear complexes
→ antibody cross-linking can generate lattices
→ antibodies with different specificity can co-operate
How do antigens make it easier for phagocytes to engulf pathogens?
Ability to cross-link antigens + flexible hinge region
→ soluble antigens and viruses can be trapped in large cross-linked networks that often precipitate
What are the classes of antibody?
Collective name for antibodies is immunoglobulin (Ig)
IgM - μ heavy chain
IgD - δ heavy chain
IgG - γ heavy chain
IgA - α heavy chain
IgE - ε heavy chain
What are IgMs?
The most primitive immunoglobulins
→ the first antibodies B cells will make
→ expressed my immature B cells in bone marrow
→ once B cell has IgM and IgD can respond to antigens
→ T helper cells aid clonal expansion
How can IgMs cause inflammation?
IgMs bound to targets can activate the complement pathway (classical pathway)
Why is IgM efficient at activating complement?
Phagocytic cells don’t have a receptor for IgM
→ ineffective at assisting phagocytosis
but IgM is very efficient at activating complement - considered opsonin
→ targets antigens for phagocytosis
→ IgM is part of humoural arm of adaptive immune system
What are the functions of IgG?
→ toxic neutralisation
→ binding to micro-organisms and opsonisation by coating pathogen + activating complement - phagocytosis
→ provision of passive immunity to foetuses (pinocytosis) and newborns (maternal milk)
What is IgA?
A dimer of two tetrameric structures held together by a J chain and S chain which allows secretion into
→ saliva, tears, milk and mucus
How do plasma cells switch the class of immunoglobulin secretion?
Heavy chain changes only
→ specificity stays the same
IgM can switch to: IgG, IgA, IgE
What is IgE?
Standard tetrametric structure
→ same specificity as IgM
→ bound IgE acts as receptors for the particular antigens
→ triggers mast cell/basophil degranulation
→ results in histamine release - pro inflammatory mediator
→ uncontrolled IgE - hay fever, asthma
What is the antigen binding site made from?
The n-terminal domains of both heavy and light chains are called variable (V) domains
→ the antigen binding site is made from V light and V heavy domain interactions
What are the functions of the different constant domains?
Cy1, Cy2 - bind complement components
Cy2, Cy3 - bind Fc receptors on neutrophils
Cy3 - binds Fc receptors on macrophages and NK
Do heavy chain structures differ considerably?
Yes
What cells does class switching occur in?
Mature B cells
→ can switch classes from IgM to other Ig classes
→ whilst maintaining the same specificity for antigens
→ required same variable chains and different heavy chains
How is the H chain gene segmented?
There is one antibody H chain gene
→ Ig H gene encodes a variable (VH) domain and all the H chain constant regions separated by non-coding regions
How do mature B cells class switch?
Somatic recombination of DNA
→ cuts out small segments of DNA to allows expression of variable heavy chain with different constant components
Summarise class switching:
Primary response
→ antigen stimulates clonal expansion of B and T cells, that already have receptors that already recognise the antigen
→ mature B cells produce IgM
→ can switch antibody heavy chain classes by somatic recombination, maintaining their variable domains and specificity
What is the clonal selection theory?
Following infection an antigen activates only lymphocytes committed to respond to it
→ they display cell surface recptors that specifically recognise the antigen
→ upon encountering the antigen lymphocytes undergo clonal expansion and differentiation
How are there so many antibodies that recognise different antigens?
To do with variable domains that encode specificity
1. there are only 3 antibody genes → two classes of light chains which increases diversity and possible binding sites
2. there are multiples gene segments encoding V domains that can be combined with C domains by somatic recombination
3. the somatic recombination used to select V gene segment is complex → link V domain with constant domains at protein level creating 10^14 proteins with unique potential antigen binding sites
What is affinity maturation?
Over time antibodies made by B cells improve in affinity and become more specific
→ due to accumulation of point mutations in the V domains
→ occurs in the lymph nodes
→ evolution of a high affinty antibody
What is the antibody secondary response?
Second exposure results in a greater and more efficient secondary response with a short lag period
→ immune system has memory
→ greater and more specific as it made up of class-switched antibodies that have undergo somatic hypermutation
How is immunological memory generated?
After clonal expansion T and B effector cells produced
→ some antigen-stimulated cells multiple and differentiate into memory cells
→ memory cells can be induces to become effectors by antigenic stimulation
→ most effectors die after an immune response, memory cells do not
