Immunology Flashcards
(151 cards)
1
Q
what is the immune system?
A
- The immune system is the integrated system of cells and molecules that act together to defend against disease
- it reacts against infectious pathogens – bacteria, viruses, fungi, small parasites (protozoa)
2
Q
what does the type of immune response depend on?
A
the type of the pathogen
3
Q
what are the key characteristics of the innate immune system?
A
- Present in all organisms
- We are born with it – infants have innate immunity
- Broad specificity – doesn’t distinguish between different strains
- Not affected by prior contact – response is always the same
- Rapid response (minutes-hours)
4
Q
what are the key characteristics of adaptive/acquired immunity?
A
- Evolved more recently
- Is gained/acquired over lifetime based on what pathogens we experience
- When we are born, adaptive immunity isn’t yet developed – rely on milk, placenta
- Highly specific – can distinguish between strains and species
- Enhanced by prior contact – the second time you come across the same pathogen, the immune system is ready
- This immunity is lifelong
- Slower response (days-weeks)
5
Q
can innate and adaptive immunity work together?
A
Yes, these 2 systems evolve together and interact:
- Both primarily involve white blood cells (leukocytes) and soluble factors
6
Q
what are the 4 key defensive mechanisms of the innate immune system?
A
- Barriers – prevent pathogens entering organism
- Leukocytes – phagocytes and natural killer cells
- Soluble proteins – complement (important in bacterial), interferons (important in viral)
- Local and systemic responses – inflammation, fever (coordinated responses)
7
Q
what areas of the body can pathogens enter?
A
- skin
- GI tract
- GU tract
- respiratory tract
8
Q
what are the physical barriers of the body?
A
- Epithelial cells joined by tight junctions which hold the cells together so pathoegns cannot penetrate
- Flow of air or fluid – helps move pathogens away from epithelium
- Cilia are specialised structures on epithelia which waft away mucus which may carry pathogens
these are found in all tracts
9
Q
what are the chemical barriers of the body?
A
- Sebaceous glands on skin produce sebum which contains fatty acids with a low pH to deter pathogens
- Enzymes in GI tract such as pepsin can destroy microbes
- In GI and GU tracts, low pH prevents microbial growth
- In respiratory tract, lysozyme disrupts cell walls of bacteria
- Antibacterial peptides such as defensins are present on all surfaces
10
Q
what are the microbiological barriers of the body?
A
commensals
11
Q
what are the 2 main barriers of the body?
A
- keratinised skin - 2m^2 surface area
- mucosal surfaces - surface area varies
12
Q
what are the features of the keratinised skin barrier?
A
Keratinocytes produce keratin which makes the skin tough and difficult to penetrate
- an effective barrier unless breached
13
Q
how may keratinised skin become infected?
A
if it is breached:
- Wounds/cuts can be infected e.g. C. tetani causes tetanus
- Bites from larger animals e.g. Rabies virus
- Most bites are caused by insects e.g. Dengue virus from mosquitos, plasmodium causing malaria from mosquitoes, deer ticks can transmit Borrelia bacteria which cause lime disease
- Some pathogens infect skin: Papilloma virus – causes warts, Microsporum – fungus causing athletes foot, trichophyton – fungi causing ringworm
14
Q
what mucosal surfaces exist in the body as barriers?
A
- Gastrointestinal tract - (300m2 surface area)
- Respiratory tract (100m2)
- Genitourinary tract - small surface area, but close contact so pathogens can be transmitted
15
Q
what pathogens may infect the GI tract?
A
- Salmonella - typhoid, Shigella – dysentery , Listeria – food poisoning, E. coli – food poisoning, Campylobacter – food poisoning from uncooked chicken
- Polio virus – polio from ingesting contaminated water, Rotavirus – diarrhoea and vomiting, Norovirus – winter vomiting
16
Q
what pathogens may infect the respiratory tract?
A
- S. pneumoniae - pneumonia
- Haemophilus influenzae – can cause meningitis, pneumonia
- Neisseria meningitidis – ¬meningitis
- Mycobacterium tuberculosis – TB (higher occurrence in HIV patients)
- Adenoviridae – colds, influenza virus, SARS-Cov-2
Can be spread via sneezing, coughing
17
Q
what pathogens may infect the GU tract?
A
Urinary tract infections (UTIs), most caused by E.coli, others if reaches kidneys can be life-threatening
Sexually transmitted:
- Treponema pallidum – spirochete causing syphilis
- Neisseria gonorrhoeae – gonorrhoea
- Chlamydia trachomatis – bacteria causing infertility
- HIV
- HSV
18
Q
what is the next defence if pathogens breach the barriers?
A
leukocytes
19
Q
where are leukocytes derived from?
A
they are derived from pluripotent haematopoietic stem cells, which give rise to 2 main lineages found in the bone marrow:
- Myeloid stem cells
- Lymphoid stem cells
20
Q
what do myeloid cells differentiate to?
A
- Neutrophils
- Eosinophils
- Monocytes which can become dendritic cells or macrophages
- Mast cells
21
Q
what do lymphoid cells differentiate to?
A
Lymphoid cells can differentiate to become lymphocytes, including:
- Natural killer cells
- Plasma cells (B cell)
- T cells
22
Q
which leukocytes are part of the innate immune system?
A
- Neutrophils
- Eosinophils
- Monocytes which can become dendritic cells or macrophages
- Mast cells
- NK cells
23
Q
what are phagocytes?
A
- Particularly important in the extracellular bacterial/fungal infections
- Present in blood and can move into tissues, or already resident in tissues
- can engulf pathogens
24
Q
what are the 2 main types of phagocytes?
A
- Neutrophils
- Mononuclear phagocytes e.g. macrophage
25
what are neutrophils?
- Main phagocyte in the blood
- Short-lived (live for 24 hours, longer in infection)
- fast-moving
- Specialised lysosome granules release enzymes, hydrogen peroxide
26
what are mononuclear phagocytes/macrophages?
- Long-lived (months-years)
- Undergo phagocytosis to engulf pathogens
- Help initiate adaptive responses
- These are present in a variety of tissues, seeded early in gestation and can self-renew:
o Brain = microglial cells
o Lungs = alveolar macrophages
o Liver = Kupffer cells
27
what are the 2 main forms of mononuclear phagocytes?
1. Monocyte = found in blood, move into tissues and differentiate into macrophages
2. Macrophage = resident in tissues and often the first to encounter pathogens
28
what are natural killer cells?
- Help to keep viral infection and intracellular pathogens in check until adaptive immunity develops
- Type of lymphocyte
- Distinct cytoplasmic granules
- Kill infected host cells to stop infection spreading
- Important in viral (e.g. Herpes) and certain intracellular bacterial (e.g. Listeria monocytogenes) and protozoal (e.g. Leishmania) infections
29
what soluble proteins are involved in innate immunity?
1. defensins
2. interferons
3. complement
30
what are defensins?
important in bacterial infections:
- Positively charged peptides made by neutrophils and epithelial cells
- Disrupt bacterial membranes, leading to bacterial lysis
31
what are interferons?
- Can be made by any cell of the body if it is infected by a virus
- IFN-alpha and IFN-beta (transcribed by interferon-response genes)
- Induced by viral infection making several contribution to host defence
- They interfere with viral replication
32
what will interferons cause?
Interferons will:
- Induce resistance to viral replication in all cells that are uninfected
- Increase MHC class I expression and antigen presentation in all cells
- Initiate T-cell responses – interferons bring in adaptive immunity
- Activate NK cells to kill virus-infected cells
33
what is complement? what are the 3 ways in which it can be activated?
20 serum proteins found in blood, normally inert but can be activated in response to pathogens by innate mechanisms or when antibody binds to antigen (classical pathway)
3 pathways of complement activation:
1. classical pathway
2. MB-lectin pathway
3. alternative pathway
34
what is the process of the classical pathway activation of complement?
triggered when antibody binds to antigen
- Occurs in this order: C1, 4, 2, 3, 5, 6, 7, 8, 9
- C3 is most important in complement activation and is most abundant
- Many components have protease activity – each enzyme acts on the next component sequentially
- Begins with C1
35
what is the process of the MB-lectin pathway activation of complement?
- Mannose binding lectin binds to sugar residues called mannose found on surface of bacteria
- Uses MB-lectin instead of C1
36
what is the process of the alternative pathway activation of complement?
- Activated intrinsically by pathogen surfaces such as lipopolysaccharide
- Begins with C3 cleavage
37
what is the central event of all complement activation pathways?
C3 convertase cleaves C3 to generate peptide fragments: smaller C3a and larger C3b
- All pathways generate C3 convertase to cleave C3
38
what are the 3 major biological activities of complement?
1. Recruitment of inflammatory cells via phagocyte recruitment
2. opsonization
3. cell lysis - direct killing of pathogen (membrane attack complex)
39
how does complement activation lead to the recruitment of inflammatory cells via phagocyte recruitment?
C5 and C3 peptides are cleaved to form C5a and C3a which travel in bloodstream and act as chemoattractants
- They induce inflammatory mediator release
- Bind to C5a receptors on phagocytes so they move into tissues
- Bind to C5a receptors on mast cells so that they release histamine from their granules
40
what are chemoattractants?
Chemoattractants – chemical/molecule which induces movement of cells along a concentration gradient
41
what are anaphylatoxins?
Anaphylatoxins (e.g. wasp venom) – inducing inflammation by binding to mast cells and activate them to release inflammatory mediators e.g. histamine
42
what pathogen may inhibit complement recruitment of inflammatory cells?
S. aureus chemotaxis inhibitor protein (CHIPS) binds C5a receptor to resist this action of complement
43
How does complement trigger opsonisation?
- C3b coats bacterial surfaces and make them attractive to phagocytes
- C3b binds to pathogens which then are recognised by phagocytes which have C3b receptors on their surface
- Increased binding and phagocytosis
- Important in killing gram-positive bacteria
44
How may some pathogens evade opsonisation?
Some bacteria can evade opsonization by producing a thick capsule that envelopes C3b (S. pneumoniae, N. meningitides) so that the phagocytes cannot recognise ita
45
how does complement trigger cell lysis?
- Membrane Attack Complex (C5b-C9) – only occurs via full activation of the pathway
- C9 polymerises to form hollow cylinders, creating pores in bacterial membranes, which destabilises the bacterium and leads to lysis
46
which bacterial type (gram positive or negative) is the membrane attack complex effective against?
Important defence against gram-negative
- Good against gram-negative bacteria as they lack peptidoglycan layer, but less effective against gram-positive as their peptidoglycan layer is too thick to penetrate
- Gram-positive are resistant
47
what processes are triggered in inflammation?
- Mast cells, epithelial cells secrete vasoactive amines (histamine), activate complement
- Dilation of blood vessels – red appearance of skin
- Increased capillary permeability – tight junctions become leaky so fluid escapes into the tissues – swelling and pain
- Phagocytes migrate into tissues in response to chemoattractants such as C5a
48
what is inflammation?
important in bringing components of the immune system to where they are needed
- localised response
49
what is the fever response?
- Cytokines, LPS
- Induce synthesis of prostaglandin E2
- Acts on hypothalamus which controls body temperature
- Increase in temp can stop bacteria from replicating to slow the infection, and can activate adaptive immunity
50
how may phagocytes recognise pathogens?
1. can make use of elements of the adaptive immune system - e.g. when antibodies are bound to a pathogen, Fc receptors on phagocytes recognise Fc regions of antibodies, so they can then engulf the pathogen
2. can recognise complement bound to pathogen - e.g. C3b binds to pathogen and C3b receptors on phagocyte recognise the C3b and engulf the pathogen
3. they can use innate mechanisms
- Pattern Recognition Receptors (PRRs) can recognise Microbe-associated Molecular Patterns (MAMPs)
51
what are PRRs in the innate immune system?
PRRs recognise broad categories of MAMP molecules commonly found on many pathogens
52
what are MAMPs?
molecules commonly found on pathogens, such as LPS, lipoteichoic acid, chitin, dsRNA
- conserved molecules shared by microbes
- MAMPs are distinct from self molecules
- MAMPs are critical for the survival/function of pathogens, so are unlikely to be mutated as they are essential
53
give examples of PRRs in phagocytosis?
- LPS receptor (CD14)
- Mannose receptor – binds to mannose residues found commonly on bacteria
- Glucan receptor
- Scavenger receptor
54
what does PRR binding to a MAMP trigger?
Receptor binding may initiate phagocytosis, chemotaxis or signalling to induce expression of new genes within the infected cell
55
what are PRR chemotactic receptors?
chemotactic receptors recognise chemoattractants:
- E.g. C5a receptor binds C5a
- E.g. f-met-leu-phe receptor on phagocytes which recognises N-formylated peptides produced by bacteria
56
what are toll-like receptors (PRRs)?
Toll-like receptors (TLRs) are sensors that signal the presence of microbes
- Not directly involved in phagocytosis, but when they bind to a MAMP they act as signalling molecules for the phagocyte to express new genes
- There are 11 TLRs in humans, each recognising a distinct MAMP
- They usually act as dimers and are found on cell surfaces (extracellular infection) or endosomes (intracellular infection)
57
what are the different toll-like receptors and what ligands do they recognise?
TLR-1 dimer and TLR2/TLR6 dimer recognise peptidoglycan, lipoproteins, zymosan (yeast)
TLR-3 - recognises dsRNA
TLR-4 dimer (plus CD14) recognises LPS in gram-negative bacteria
TLR-5 recognises flagellin
TLR-9 recognises unmethylated GpG DNA
58
what is the structure of a toll-like receptor?
- Hook-like structure protruding from membrane which recognises the MAMP
- Hook is made up of beta-sheets
-Transmembrane proteins
- Cytoplasmic region contains signalling domain
- To function, they normally have to dimerise: Can form hybrid TLRs e.g. TLR-2 and TLR-6 dimerise to recognise MAMPs
59
what does Toll-like receptor signalling trigger?
TLR signalling induces expression of new genes which may code for inflammatory cytokines and interferons
60
what is the process of phagocytosis?
1. Adherence: phagocyte binds to bacterium using a PRR e.g. mannose-binding protein
2. Phagocyte extends out pseudopods which gradually surround the bacterium
3. Tips of the pseudopods fuse so that the bacterium is enclosed in a vesicle (phagosome) inside the phagocyte so that it is trapped
4. Specialised lysosomes in the phagocyte fuse with the phagosome to form a phagolysosome
- Lysosome contains agents which make the environment of the phagolysosome inhospitable for bacteria
5. Leads to destruction of bacterium and release of debris out of the phagocyte
61
what phagocyte bactericidal/bacteriostatic agents are released into the phagosome by lysosomes?
1. Lysosome contains acidic proteins which makes the pH inside the phagolysosome 3.5-4 -This will kill the bacteria or inhibit their growt
- Bacteriostatic or bactericidal
2. When phagocytes take up pathogens, they undergo a respiratory burst – an increase in metabolism of oxygen
- Respiratory burst results in production of oxygen-free radicals such as superoxide, hydrogen peroxide - These ROS are very reactive and bind to pathogen proteins and cause damage
3. Production of toxic nitric oxide which is toxic to bacteria
4. Lysosomes contain antimicrobial peptides such as defensins and cationic proteins which can disrupt the membranes of bacteria
5. Lysozymes dissolve the cell walls of gram-positive bacteria
6. Acid hydrolases further digest bacteria in the acidic environment
7. Competitor proteins such as lactoferrin binds iron, vitamin-b12 binding proteins to mop up key substrates that bacteria may need to survive
- Bacteriostatic
62
what are the most important killing mechanisms of phagocytes?
- Reactive intermediates produced through respiratory burst – ROS, nitrogen oxides
- These free radicals are short-lived and are contained in the phagosome so that they do not damage the phagocyte
- Used by monocytes, macrophages and neutrophils
63
what are neutrophil NETs?
Neutrophils throw neutrophil extracellular traps (NETs) around bacteria
- Occurs following NETosis
- Net is made of DNA (chromatin) impregnated with antimicrobial compounds such as defensins to kill the bacteria
- This process happens when the neutrophil is dying (it is short-lived) so it kills the bacteria with it
64
how do NK cells recognise infected host cells? how is this regulated?
They detect signals/molecules on the infected host cell which causes the cell to become ‘altered self’ because of the infection
Killing by NK cells is regulated by receptors on the NK cell surface which either tell it to kill or inhibit it from killing
- Activating or inhibitory receptors
65
how is it ensured that NK cells do not attack healthy self cells?
Inhibitory receptors recognise MHC1 (self) proteins present on all nucleated cells:
- If a NK cell recognises these receptors on a healthy cell, it is inhibited from killing that cell
66
what triggers NK cells to attack infected host cells?
When viruses infect host cells, they cause downregulation of MHC1 proteins
- If level of MHC1 proteins on a cell is low, the NK cell is activated to kill that infected cell
- Alterations in expression of MHC1 proteins prevents inhibitory signalling and induce killing
67
what is the process of NK cells killing infected host cells?
1. Activated NK cells produce perforin protein, which inserts into the membrane of the target cell
- This doesn’t cause cell lysis itself, but it enables a channel to form through which the NK cells can secrete degradative enzymes into the infected target cell to kill it
2. Once the target cell has been perforated, the cytoplasmic granules in the NK cell become polarised and move towards the perforin channel
3. Through this channel, the granules secrete granzymes into the target cell
4. The granzymes activate the apoptotic pathway in the target cell
- Clean form of cell death and no release of bacteria/viruses inside
- Granzymes can enter intracellular bacteria and kill them directly
68
what are cytokines?
- Cytokines regulate immune responses by changing cell behaviour or gene expression
- Small proteins 5-20kDa, over 100 cytokines identified
- Most act locally, but can have systemic effects e.g. when they act on hypothalamus to induce fever - Can be dangerous if they act body wide for long time
- Short-lived activity – avoids cytokine storm and toxicity
- Can be produced by many cell types in response to immune activation, mostly leukocytes
- Act on cells bearing specific cytokine receptors
69
how do cytokines work?
1. Stimulus e.g. MAMP on surface of bacterium is recognised by a cell which can produce cytokines
2. This triggers expression of cytokine genes and translation of cytokines which are then released from the cell
3. Cytokines bind to a cytokine receptor on a target cell
4. This causes the target cell to change its behaviour/express new genes which will help overcome the infection
70
what are the main groups of cytokines?
1. Interleukins (IL-1 to IL-38) – usually made by T cells and act between white blood cells
2. Interferons (IFNs) – viral infections e.g. IFN-alpha, IFN-beta which can be made by any cell in response to a viral infection
- IFN-gamma is produced by monocytes, macrophages and T-cells and is involved in activation of these leukocytes
3. Chemokines – cytokines which induce cell movement/chemotaxis e.g. IL-8 (CXCL8) which induces neutrophils to move out of the bloodstream
4. Tumour necrosis factors (TNFs) – toxic cytokine which is pro-inflammatory and can kill tumour cells in vitro, but also kills healthy cells
71
what is adaptive immunity?
- Isn’t developed when we are born, it is acquired over lifetime based on the pathogens we encounter
- Learned by experience – adapts
- Confers pathogen-specific immunity
- B and T lymphocytes recognise antigen
- Enhanced by second exposure – memory
72
what are the 2 arms of adaptive immunity?
1. humoural (antibody) immunity - B cells
2. cell-mediated immunity - T cells
73
what is humoral immunity?
B cells:
- B lymphocytes recognise antigen and differentiate into plasma cells that secrete soluble antibody that bind to and label antigen
- Antibody receptors exist on the B cell surface and recognise antigen
- Antibody receptors are acquired in the bone marrow
74
what is cell-mediated immunity?
T cells and innate cells
- T lymphocytes recognise antigen through T cell receptors
- T cell receptors are acquired in the thymus
- T cells then differentiate into cytotoxic T cells that kill infected host cells or helper T cells that control the immune response
- Cytotoxic T cells kill infected host cells specifically by recognising particular pathogens
- Helper T cells make cytokines which control the immune response
75
what is the role of cytotoxic T cells and helper T cells in cell-mediated immunity?
Cytotoxic T cells kill infected host cells specifically by recognising particular pathogens
Helper T cells make cytokines which control the immune response
76
what is an antigen?
An antigen is a molecule (protein, carbohydrate etc) that induces the production of antibodies
- Antibody generating material
- Both B cells and T cells can recognise antigens
- A single antibody molecule is specific in that it normally binds to only one antigen
77
what is B cell clonal selection?
- If infected with a bacterium with an antigen on its surface, a B cell is capable of recognising that antigen via its antibody receptor
- When the antibody of the B cell binds to the antigen, it triggers the B cell to start dividing and differentiating
- A single B cell gives rise to a clone of identical daughter cells - Number of B cells expands from 1 to thousands
- The B cells may differentiate to plasma cells or memory cells
78
what 2 fates may B cells differentiate into? what is the role of these differentiated cells?
1. plasma cells - secrete soluble antibody which can travel through fluids and bind to specific the antigen recognsied by the original B cell
2. memory cells - long-lived cells which survive after initial infection and can respond quickly by dividing and differentiating to plasma cells to deal with future infections by the same pathogen
79
where do B cells acquire their antibody receptors?
B cells acquire their antibody receptors on their surface independently of antigen in the primary lymphoid tissue - bone marrow
80
where do B cells respond to antigen?
B cells respond to antigen in secondary lymphoid tissue such as lymph nodes, spleen etc – this is where clonal expansion occurs
- the appropriate B cell to differentiate is selected by antigen recognition
81
what are antibodies?
- bind specifically to particular antigens
- have 2 Fab arms which recognise and bind antigen - these are the variable regions and are specific to certain antigens
- have an Fc region which is constant and involved in the innate immune system to help eliminate the antigen e.g. complement, Fc receptors on phagocytes
82
what kind of infections are antibodies important in tackling?
Antibody arm of the immune response is important extracellular bacterial infections and intracellular pathogens
83
what is the 4 chain structure of antibodies?
4 polypeptide chains: 2 light, 2 heavy
- Light (L) chain = 25kDa
- Heavy (H) chain = 50kDa
- Immunoglobulin G = L2H2 = 150kDa
- Light chains are identical to each other
- Heavy chains are identical to each other
- Chains are joined by disulphide bonds
84
what makes up the polypeptide chains of the antibody?
Each chain is made up of compact immunoglobulin domains:
- Light chains have 2 domains
- Heavy chains have 4 domains
85
what is important about the Fab arms of the antibody that allow them to perform their function?
In IgG, there is a hinge region with proline residues to allow the Fab arms to be flexible and move relative to one another
86
which parts of the antibody are the variable regions?
The N-terminal domains of the heavy and light chains are variable in sequence
- These come together to form site which interacts directly with antigen
- It is these domains that allow antibody to target specific antigens
87
what regions make up the Fab arms of the antibody?
Fab regions are made up of both constant and variable regions of both light and heavy chains
88
what regions make up the Fc region of the antibody?
Fc region is made up of only constant regions of just the heavy chains
89
what are the variable regions of the antibody?
Variable regions: part of antibody which binds to antigen. Differs between antibodies with different specificities for antigens
90
what are the constant regions of the antibody?
Constant regions: same for antibodies of a given heavy chain class or light chain type
91
how are variable and constant regions of the antibody encoded ?
Variable and constant regions are encoded by separate exons/genes – cuts down amount of DNA needed to encode these domains
92
what is somatic recombinaion?
Multiple variable region exons in the genome can recombine at random during early B cell differentiation – somatic recombination:
- This increases the number of antibodies that can be produced
- Somatic recombination is unique to B cells and T cells
- Allows B and T cells to respond to quickly mutating pathogens
- They mutate to match the rate of pathogen mutation
- Inprecise process to increase variability
93
how are immunoglobulins classified?
Differ in the amino acid sequence of the constant regions of their heavy chains
94
what are the 5 immunoglobulin classes?
1. IgG (γ) – main class in serum (blood) and tissues, important in secondary responses (memory)
2. IgM (μ) – important in primary responses
3. IgA (α) – in serum and secretions (e.g. GI tract, milk, saliva), protects mucosal surfaces
4. IgD (δ) – present in small amounts in serum, possibly important in respiratory infections
5. IgE (ε) – present at very low levels, involved in allergy and protection against large parasites
95
what are the 2 light chain immunoglobulin types?
There are also 2 light chain types: kappa (κ) and lambda (λ)
- These are not class restricted – can have IgGκ or IgGλ
96
which immunoglobulins appear as a single Y-shaped molecule?
IgG,
IgA (monomer),
IgD
IgE
97
which immunoglobulin may be found as a dimer?
IgA (dimer): found in secretions as a dimer of 2 antibodies linked end-to-end:
- In serum/blood, IgA is a monomer
- When secreted, IgA occurs as a dimer
- J-chain joins the 2 antibodies
- Secretory component protein wraps around the IgA and is important in protecting IgA from digestion by enzymes
98
which immunoglobulin is found as a pentamer?
IgM (pentamer) – found in serum as a pentamer, where 5 Y-shaped antibodies are bound together by disulphide bonds in the Fc region:
- Important in primary immune response as can bind to multiple antigens at once
- J-chain is important in catalysing pentamer formation
99
what is the primary immune response?
- The first time we encounter antigen, there is some lag/delay as the B cells undergo clonal selection
- 3-7 days antibody appears in blood, usually IgM
- After few more days IgG levels increase, but levels are generally low
antibody levels are lower and the response is less specific, hence more IgM than IgG as it can bind to multiple antigens at once
slower and less-specific response
100
which immunoglobulin is more present in the primary immune response?
IgM as it can bind to up to 10 antigens
101
what is the secondary immune repsonse?
- If we come across the same pathogen later, there is an initial rapid IgM response, but level doesn’t increase
- In memory response, there are extremely high levels of IgG in the blood
increased levels of IgG and rapid, specific response
102
what immunoglobulin is more present in secondary immune responses?
IgG as it is more specific
103
what is class switching?
Occurs at the level of individual B cells and is unique to B cells:
- All B cells begin by making IgM but they can switch to IgG, IgA or IgE after antigen stimulation
- Only occurs if B cell has been stimulated by antigen in secondary lymphoid tissue
- The same variable region gene of the heavy chain recombines with different constant region genes
- This allows the same antigen specificity to be linked to different Fc functions/locations
- Gives flexibility to the immune response – different antibodies have different functions depending on the infection
104
how are the different immunoglobulin classes distributed around the body?
- IgG – present in blood (serum), extracellular fluid, only class that can cross the placenta to protect newborn against
- IgM – restricted to blood as it is so large, but under inflammation IgM can enter tissues as the blood vessels become leaky
- IgA monomer – blood, extracellular fluid
- IgA dimer – mucosal secretions, tears, saliva, breast milk
- IgE – mainly associated with mast cells beneath epithelial surfaces (respiratory tract, GI tract, skin)
105
what is affinity maturation?
During an immune response, the affinity of antibody increases, so antibody can bind more tightly to antigens the longer an infection goes on:
- This is unique to B cells and occurs via mutation of the genes in the variable regions that interact directly with antigen
- the mutations occur by somatic hypermutation
- the mutations that result in increased antibody binding affinity are selected
- B cells need to bind to antigen to survive
- As antigen levels decrease during immune response, only the B cells that are bound tightly to antigen will survive – natural selection
106
what is somatic hypermutation?
somatic hypermutation is the mutation of variable region genes in B cells responding to antigen
- Helps the body deal with fast mutating pathogens
- Mutations that increase binding affinity are selected
- B cells need to bind to antigen to survive
107
what effects do the Fab regions of antibodies have on pathogens?
- Block pathogen adherence to host cells: IgM, IgG, IgA
- Neutralise toxins: IgG, IgA
- Cause agglutination of motile bacteria to inhibit their movement: IgM, dimeric IgA
- Block uptake of nutrients needed for bacterial survival: IgG
108
what effects do the Fc effector regions of antibodies have on pathogens?
- Complement-mediated lysis (bacteria and enveloped tissues)
- Enhancement of phagocytosis (opsonisation)
- Enhancement of killing of infected cells by NK cells
109
what region of the antibody allows it to direct innate immune components?
Fc effector regions
110
how can antibodies activate complement?
- Occurs following the interaction between C1 and antibodies bound to foreign antigen
- Globular heads of C1q activate with the Fc regions of 2 adjacent IgG molecules
- Activation can lead to opsonisation, inflammation and cell lysis (membrane attack complex)
111
which immunoglobulin is the more efficient activator of complement?
- IgM is the more efficient activator than IgG as it is a pentamer, hence why it is used in primary responses
- Easier for C1q to find 2 Fc regions to interact with on the pentamer
112
how are healthy cells protected from the membrane attack complex?
Healthy cells have a protein on cell surface called CD59/MAC-inhibitory protein which sequesters membrane attack complex to protect the cells from complement lysis
113
how can antibodies enhance phagocytes?
some classes of antibodies can act as opsonins by binding to Fc receptors on phagocytes
- The antibodies trigger phagocytosis
- IgG and monomer IgA are important in triggering this
114
how may bacteria evade antibody-mediated phagocytosis?
Bacterial Fc receptors – bind IgG/IgA
- Some bacteria have evolved Fc receptors to mop up IgG/IgA and sequester it from binding to phagocytes and thus prevents phagocytosis activation
- Staph. Aureus have Protein A
- Streptococcus sp. have protein G
115
how are antibodies involved in aiding NK cells?
antibody dependent cell-mediated cytotoxicity (ADCC):
- infected host cells may express foreign proteins on their cell surface e.g. virus envelope proteins for recognition
- If IgG antibodies have been previously made against these viral proteins, then that can aid the recognition of the infected cells by NK cells
- NK cells have Fc receptors that recognise the Fc region of IgG
- This allows NK cells to recognise infected cells more specifically
- NK cells can then kill the infected cells by secreting perforin and enzymes to trigger apoptosis
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which immunoglobulins are important in complement activation?
IgG and IgM
- IgM is the more efficient activator of complement
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which immunoglobulins are important in triggering phagocytosis?
IgG and monomer IgA
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which immunoglobulin is important in aiding NK cells?
IgG
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why is IgG important in secondary immune responses and foetal immunity?
IgG has a long half-life (21 days) so survives for a long time in serum:
- This is why it is important in secondary responses as it is not broken down quickly
- Also why it is important in protecting the foetus as it provides long protection
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where do T cells acquire their receptors?
- T cells acquire their receptors in the thymus
- An organism without a thymus is incapable of making T cells, but still have an innate immune system
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what are thymus-independent antigens?
- some microbial agents can induce B cell responses in the absence of T cells
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what are thymus-dependent antigens?
B cell responses to most protein antigens require T cell help
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how do T cells aid B cell processes?
B cell class switching and somatic hypermutation requires T cells:
- Organisms without a thymus can make IgM antibody via innate immunity, but not the immunoglobulin classes
- Organisms without a thymus cannot undergo somatic hypermutation so cannot produce antibodies that bind tightly to antigen
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where do T cells initially develop?
bone marrow
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where do T cells mature?
thymus - acquire T cell receptors
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how do T cells recognise antigen?
T cell bind antigen via specific T cell receptors
when they recognise antigen, they undergo clonal selection and expansion
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what are the 2 major subpopulations of T cells?
1. T helper cells: CD4+ve
2. Cytotoxic T cells: CD8+ve
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what is the role of T helper cells?
- Help B cells make antibody - Mice that lack T cells have issues with B cell antibody production
- Activate macrophages and natural killer cells – aid innate immune system
- Help development of cytotoxic T cells
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what is the role of cytotoxic T cells?
Recognise and kill infected host cells – specifically targets cells infected with particular pathogen
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what is the structure of the T cell receptor (TCR)?
- 2 chains – alpha chain and beta-chain
- Contain constant domains ad variable domains
- Hinge disulphide region
- Hydrophobic domain to sit in plasma membrane lipid bilayer
- Only expressed as a membrane receptor, never secreted
- TCR structure is similar to the Fab arm of an antibody.
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what codes for the variable and constant regions of the TCRs?
- V and C regions encoded by separate exons
- Many variable exons, limited number of constant exons
- Multiple V region exons can RECOMBINE during early T cell differentiation (SOMATIC RECOMBINATION)
- Variable region is made of up to 3 different exons which can recombine at random
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which domain of the TCR recognises antigen?
the variable domain
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do TCRs undergo somatic hypermutation?
no, the genes for TCRs do not undergo this process
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what type of antigen do T cells recognise?
Unlike B cells, T cells can only recognize host cell-associated, processed antigen
- Antigen-presenting cell (APC)
- Processed antigen = antigen protein is degraded to 8-24 amino acids long in the host cell
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what are MHCs and what are their roles?
Major Histocompatibility proteins (MHC) transport processed antigen (peptides) to the surface of host cells
- Main role of MHCs is antigen presentation
- T cell can recognise the MHC and the processed antigen
- MHCs are polymorphic and responsible for graft rejection
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what are the two types of MHCs?
1. MHC I
2. MHC II
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what are MHC I proteins?
- expressed by all nucleated cells – also recognised by NK cells
- MHC I displays endogenous antigen to CD8+ve (cytotoxic) T cells
- Endogenous – protein has been synthesised inside the APC
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what are MHC II proteins?
- MHC II displays exogenous antigen to CD4+ve (helper) T cells
- Exogenous – APC has taken something up from environment (e.g. bacterium, protein) which it digests, and then transports peptides from the external antigen to its cell surface
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how do cytotoxic T cells recognise antigen?
Cytotoxic T cell receptor recognises peptide bound to MHCI:
- CD8 interacts with MHCI
- Virus-infected cell produces viral proteins, some of which broken down in cytosol (proteosomes) into peptides
- Peptides transported to ER, bind MHCI and migrate to cell surface to be recognised by cytotoxic T cell
- CD8 helps stabilise the interaction between MHC I and the TCR to facilitate signalling
- Activated cytotoxic T cells kill the infected cell by inducing apoptosis – clean death
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how do T helper cells recognise antigen?
Helper T cell receptor recognises peptide bound to MHCII:
- CD4 interacts with MHCII
- Macrophage/dendritic cell/B cell internalises and breaks down foreign material in a phagolysosome into peptides
- Peptides bind to MHC II in endosomes and migrate to cell surface to be recognised by a helper T cell
- CD4 helps stabilise interaction between MHC II and TCR to facilitate signalling
- Activated T helper cells help B cells make antibody, produce cytokines that activate/regulate other leukocytes
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where do T helper cells encounter antigen?
T helper cells encounter APCs in lymph nodes
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how can naive T helper cells develop?
- Naïve T helper cells can develop into different SUBSETS that differ in the CYTOKINES they produce.
- Naïve CD4 T cell which recognises peptide-bound MHCII is called a TH0 cell, which can differentiate to many subsets
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what subsets can naive T helper cells (TH0) develop into?
1. TH1 makes IFN-gamma, IL-2, TNF
2. TH2 makes IL-4
3. T-regulatory cells make IL-10 – downregulates immune responses (inhibitory)
4. TH17 makes IL-17
5. TFH (follicular) makes IL-21
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how is naive TH0 cell development induced?
- Subsets are induced by different types of pathogen and orchestrate different immune functions, to generate pathogen-appropriate responses
- Specific cytokines are appropriate for particular types of pathogen
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what are Th1 CD4 cells?
- Produce interferon-γ, IL-2 and TNF
- IFN-gamma is important in activating cells, IL-2 important for development of cytotoxic T cells, TNF activates cells
- Activate macrophages, cause inflammation
- Induce B cells to make IgG (opsonizing) antibodies to enhance phagocytosis
- Induce production of cytotoxic (CD8+ve) T cells via IL-2
- Deal with extracellular bacteria, microbes that persist in macrophage vesicles (e.g. mycobacteria, Leishmania donovani), viruses.
- More TH1 cells than TH2 cells in body (60:40 ratio)
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what are TH2 CD4 cells?
- Produce IL-4, IL-5 and IL-13
- IL-4 allows B cells to switch from IgM to IgE
- IL-4 triggers mast cells
- Activate mast cells, eosinophils
- Induce B cells to make IgE – allergen and large parasite immunoglobulin
(Helminths, allergens)
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what are TH17 CD4 cells?
- Produce IL-17, IL-22
- Found under mucosal surfaces
- Activates epithelial cells e.g. to make antimicrobial peptides
- recruits neutrophils to induce inflammation
- Pro-inflammatory, especially at mucosal surfaces.
- Important against extracellular bacteria (e.g. Klebsiella pneumoniae), fungi (e.g. Candida albicans).
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what are TFH CD4 cells (follicular cells)?
Follicular helper T cells
- Produce IL-21
- Help B cells recognise antigen
- Found in sections of lymph nodes called follicles, which are close to B cells
- Induce B cell differentiation, class switching and affinity maturation
- Switch from IgM to other antibodies, help differentiate to plasma cells, aid somatic hypermutation
- Important against most microbes – helps formation of antibodies with high affinity
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what are Treg CD4 cells (regulatory T cells?
- Produce IL-10 and TGF-β
- Helps inactivate the immune response to prevent damage to the body
- Downregulate T helper cells
- Heterogeneous group
- Suppress inflammation by acting on other T cell subsets, B cells etc.
- Downregulate immune responses once infection dealt with
- Prevent responses against self- and microbiome-derived (flora) antigens
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what is the function of CD8+ve cytotoxic T cells?
- Kill infected host cells, not pathogens themselves (similar to NK cells)
- Once activated, cytotoxic T cells bind specifically to infected target cells and induce the target cell to undergo APOPTOSIS
- Produces perforin to penetrate the infected host cell membrane and form a channel
- Granzymes (proteases) from cytotoxic T cell enter target cell via perforin channel
- Granzymes activate caspase cascade to induce apoptosis
- A single cytotoxic T cell can kill 100s of infected targets – very efficient
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how is adaptive immunity activated in the draining lymph node?
1. infection in skin via cut so bacteria can enter
2. Resident tissue macrophages and dendritic cells respond first, as they travel from the skin, through the lymphatics, to the nearest drain lymph node
3. The lymph node will contain naïve T and B cells
- If there is infection, T and B cells stay in the lymph node, if not they travel through lymphatics
4. T cells become activated by macrophage which presents processed antigen on its surface
5. Active T cells interact with B cells, helping them to differentiate into plasma cells which can produce soluble antibody
- T follicular helper cells are found particularly in the lymph node to aid the B cells
6. Memory B cells will also be produced in the lymph node
7. Activated T cells leave the lymph node via lymphatics to go to infected tissue site to further deal with infection
