Immunology

Question 1

How does the immune system recognise pathogens?

Answer 1

Fc receptors can bind Fc regions of antibodies bound to pathogens. Pattern Recognition Receptors (PRRs) bind Microbe-Associated Molecular Patterns (MAMPs). Complement components such as C3b can bind to pathogens.

Question 2

Give some examples of MAMPs

Answer 2

LPS, Lipoteichoic acid, Chitin, dsRNA

Question 3

What are the key features of MAMPs?

Answer 3

They are shared by many microbes, they are distinct from self, thy are critical to function/survival.

Question 4

What can PRR binding lead to?

Answer 4

Phagocytosis, chemotaxis, other signalling pathways

Question 5

Give some examples of PRRs (not TLRs)

Answer 5

CD14 binds LPS.
Mannose receptors bind mannose
Glucan receptors
Scavenger receptors
Chemotactic receptors bind chemoattractants
C5a receptors bind C5a
f-met-leu-phe receptor recognises N-formylated polypeptides produced by bacteria

Question 6

Give some examples of Toll-Like-Receptors

Answer 6

They are cell-surface or endosomal, there are 11 in humans.
TLR-1 dimers, TLR-2 & TLR-6 recognise peptidoglycan, Lipoproteins, Lipoarabinomannan (Mycobacterium), GPI (T. cruzi), Zymosan (Yeast).
TLR-3 binds dsRNA.
TLR-4 (and CD14) bind LPS
TLR-5 binds flagellin
TLR-9 binds unmethylated CpG DNA

Question 7

Tell me about TLR structure

Answer 7

They have hook-like structures which protrude from the membrane. Signalling domain is usually in the cytoplasm and they often function as dimers. MAMP bind leads to a change in gene expression, usually inducing the expression of cytokines and interferons.
Contain leucine-rich repeats

Question 8

Describe the process of phagocytosis

Answer 8

1. Bacterium binds to surface of phagocyte. (Aided by complement and antibodies)
2. Phagocyte pseudopods extend and engluf organism
3. Invagination of phagocyte membrane traps organism in a phagosome
4. Lysosome fuses with phagosome creating a phagolysosome. Enzymes cleave macromolecules generating reactive oxygen species, destroying the organism
5. Release of microbial debris or presentation of antigen

Question 9

What pH are phagolyosomes?

Answer 9

3.5-4.0

Question 10

Which oxygen-derived products and nitrogen products are generated in phagolysosomes?

Answer 10

Superoxides, hydrogen peroxide, singlet oxygen, hydroxide radical, hypochlorite. Nitric oxide.

Question 11

Which antimicrobial peptides and enzymes and competitors are present in phagolysosomes?

Answer 11

Defensins & cationic proteins. Lysozyme which dissolves cell walls, and acid hydrolases.
Lactoferrin binds Fe and Vitamin B12 binding protein.

Question 12

What are NETs?

Answer 12

Neutrophil extracellular traps. A dying neutrophil will throw out a trap. Net made of DNA and chromatin impregnated with antimicrobial compounds such as defensins.

Question 13

Tell me about the recognition of infected cells by NK cells

Answer 13

Natural Killer cells can recognise the ‘altered self’. Normally, MHCI protein expressed is recognised by NK inhibitory receptors preventing the NK cell attacking self-cells.
When a virus infects a cell, MHCI is downregulated. Reduced expression leads to a lesser inhibitory signal in NK cells leading them to attack the infected cell.

Question 14

How do NK cells kill infected cells?

Answer 14

They secrete perforin which pokes pores into the infected cell and secrete granules containing granzyme into the cell. Granzyme are proteases that induce the Caspase pathway which leads to apoptosis leading to a clean cell death rather than apoptosis. Macrophages clear up the shrivelled cell corpses.

Question 15

What are cytokines?

Answer 15

Cytokines are the hormones of the immune system. They regulate cell behaviour by changing gene expression and can act locally or systemically. They are small 5-20kDa proteins acting on cells with the appropriate cytokine receptors. Over 100 cytokines have been identified

Question 16

Give some examples of cytokines

Answer 16

Interleukins: IL-1 -> IL-38, usually produced by T cells
Interferons: IFN-α, IFN-β, respond to viral infections. IFN-γ induces the activation of T cells, monocytes and macrophages
Chemokines: induce cell movement (chemotaxis). One example is IL-8 (CXCL8)
Tumour Necrosis Factors (TNFs): pro-inflammatory, can kill some cells but are very toxic to the host

Question 17

Define antigen

Answer 17

Molecules which induce the production of antibodies (antibody generating material)

Question 18

What is clonal selection hypothesis?

Answer 18

Antibodies & antigens are highly specific, if a B cell with a specific antigen receptor recognises an antigen the B cell undergoes proliferation producing plasma cells which secrete identical antibodies and memory cells which can remain in the blood for long periods of time

Question 19

Where do B cells acquire their antigen receptors, and where do B cells respond to antigen?

Answer 19

B cells acquire their antigen receptors in the primary lymphoid tissue (bone marrow) independent of antigen presence.
B cells respond to antigens in secondary lymphoid tissue (lymph nodes, spleen)

Question 20

Describe the structure of an antibody

Answer 20

Contains heavy and light chains connected by disulphide bridges and hinge regions. There is a variable region which is specific to a single antigen and is highly variable across antibodies and a constant region. The Fab region contains the Fab arms, and the Fc region contains the ‘tail’ of the antibody which binds to Fc receptors on immune cells.
The heavy chain is 50kDa and Light chain 25kDa, in total, an antibody is 150kDa. Each immunoglobulin domain is about 12.5kDa

Question 21

What is somatic recombination?

Answer 21

During early B-cell development, V-gene exons recombine to generate a unique V-region.

Question 22

What is IgG and where is it found?

Answer 22

IgG (γ), is the main class of antibody in serum and extracellular fluids, important in the secondary response. It can cross the placenta and is a monomer.

Question 23

What is IgM and where is it found?

Answer 23

IgM (µ) is a pentamer which is important in the primary response and class-switching of the secondary response. It is usually restricted to serum.

Question 24

What is IgA and where is it found?

Answer 24

IgA (α) is found in serum and secretions. Monomeric IgA is found in serum & extracellular fluids. Dimeric IgA is found in mucosal secretions, tears, saliva and breastmilk. It has a role in protecting mucosal surfaces.

Question 25

What is IgD?

Answer 25

IgD (δ) has a largely unknown function.

Question 26

What is IgE and where is it found?

Answer 26

IgE (ε) is present at very low levels and normally involved in allergic responses & parasite responses

Question 27

What are the variations in the heavy chain?

Answer 27

There are lamda (λ) and kappa (κ) heavy chains, they are not restricted by class.

Question 28

Tell me about J-chains and secretory components

Answer 28

J-chains are required for antibodies to form polymers. In IgA, secretory components wrap around the Fc regions of antibodies to allow transport to and along mucosal surfaces.

Question 29

What is the primary response?

Answer 29

If it is the first time you’ve had that infection, there is a slow response with a significant delay time. You have increased IgM levels than increased IgG levels.

Question 30

What is the secondary response?

Answer 30

If you encounter a pathogen for the second time, memory cells create a much larger and faster antibody response. IgM levels are similar to a primary response but IgG levels are much higher. IgM undergoes class switching to either IgG, IgA or IgE depending on the type of infection.

Question 31

What is class switching?

Answer 31

Occurs at the B-cell level after stimulation by antigen in lymph nodes or the spleen. Same V-region genes combine with different C-region genes. This allows the same antigen specificity to be paired with an Fc region that has a different distribution in the body.

Question 32

What is affinity maturation?

Answer 32

During an immune response, affinity to antigen increases. As antigen levels decrease, there is more selective pressure on antibodies/antigen receptors with even greater affinity for the antigen. Somatic hypermutation involves the enzyme activation-induced cytidine deaminase which introduces mutations in the V-regions. This allows B-cells to keep up with the antigen mutation rates.

Question 33

What are the functions of antibodies?

Answer 33

Block adherence onto cells: IgA, IgG, IgM
Neutralise toxins: IgG, IgA
Agglutination of bacteria to inhibit movement: IgM, dimeric IgA
Blocking uptake of nutrients: IgG
Interacting with the complement system to activate the classical pathway
Enhancement of phagocytosis via opsonization
Enhanced killing of infected cells via NK cells

Question 34

Tell me about antibodies interaction with the complement system

Answer 34

C1q has to bind to at least 2 Fc regions to be activate the classical pathway leading to opsonization, inflammation and complemented-mediated cell lysis.
IgM is a much more efficient activator of the complement system than IgG due to it’s multiple Fc regions

Question 35

Tell me about the enhancement of phagocytosis by antibodies

Answer 35

IgG and monomeric IgA bind to bacteria exposing their Fc regions to phagocytes (opsonization).
Bacteria have evolved Fc receptors which bind to antibody Fc regions removing local antibodies, a form of immune evasion. Staph A has Protein A and Streptococcus sp. has Protein G.

Question 36

What are TD antigens?

Answer 36

Thymus-dependent antigens are antigens that bind to B cells, the B cell then requires T cell help to function properly such as in class switching & somatic hypermutation.

Question 37

What are TI antigens?

Answer 37

If a B-cell binds to a thymus-independent antigen, it does not require T cell help to function properly.

Question 38

What is ADCC?

Answer 38

ADCC is antigen-dependent cell-mediated cytotoxicity. It is a state that NK cells induce in viral infected cells to trigger apoptosis.
When cells are infected with viruses they can present viral protein at their cell surface (particularly common if it’s an enveloped virus as their envelope joins the cell membrane). NK Cell Fc receptors bind to antibodies bound to presented viral protein, if the MHCI is downregulated and NK cell inhibitory pathway is off then NK cells induce ADCC.

Question 39

Describe TCR structure

Answer 39

TCR, T-cell Receptors are very similar to the Fab arm of antibodies. They are made of two chains anchored into the membrane via a hydrophobic domain. Each chain has a variable region and constant region immunoglobulin, in total a TCR is ~50kDa. Like B cells, the V-gene undergoes somatic recombination to ensure variation

Question 40

Which T cells express CD4 and what are their functions?

Answer 40

T helper cells express CD4 at their cell surface.
They help B cells produce antibodies, activate macrophages and NK cells.
They help to activate Cytotoxic T cells

Question 41

Which T cells express CD8 and what are their functions?

Answer 41

Cytotoxic T cells express CD8 at their cell surface. They recognise and kill infected cells with a much greater specificity than NK cells.

Question 42

What is a processed antigen?

Answer 42

Processed antigens are short peptides 8-24 amino acids long. They are presented on the cell surface by Major Histocompatibility complexes

Question 43

Which cells express MHCI and what does it present?

Answer 43

MHCI is expressed by all nucleated ‘self’ cells. It displays endogenous antigen to CD8 +ve cytotoxic T cells

Question 44

Which cells express MHCII and what does it present?

Answer 44

MHCII is expressed by macrophages, dendritic cells and B cells. It displays exogenous antigen to CD4 +ve T helper cells.

Question 45

Describe cytotoxic T cell recognition of processed antigen

Answer 45

Viral proteins are broken down in cells via proteasomes and transferred to the ER. In the ER, peptides are bound to MHCI and transported to the cell surface via endosomes. Cytotoxic T cell CD8 co-receptor proteins interact with MHCI to stabilise the CD8-MHC1/antigen interaction & facilitate signalling. After which, Cytotoxic T cells are activated and trigger ADCC.

Question 46

What are TH1 cells?

Answer 46

T helper 1 cells produce IFN-γ, IL-2 and TNF. They are activated by APC macrophages and lead to:
Further activation of macrophages & inflammatory response, induce B cells to make IgG, Induce Cytotoxic T cell proliferation.
They deal with extracellular pathogens which can survive in macrophage vesicles such as Mycobacteria and Leishmania donovani

Question 47

What are TH2 cells?

Answer 47

T helper 2 cells produce IL-4, IL-5 and IL-13. They induce the production of IgE in B cells, activate mast cells to release histamine (IL-4), activate eosinophils.
They are key in parasitic infections such as that of helminths and activate in response to allergens.
Theorized that the increasing allergy levels in the west are due to increasing numbers of TH2 compared to TH1 cells.

Question 48

What are TH7 cells?

Answer 48

T helper 7 cells produce IL-17, IL-22. They activate neutrophils and induce inflammation by activating epithelial cells to secrete AMP which recruits neutrophils.
Deal with extracellular bacteria and fungi such as Klebsiella pneumoniae and Candida albicans.

Question 49

What are TFH cells?

Answer 49

T Follicular helper cells produce IL-21. They are found in the lymph node follicles close to B cells. They induce B-cell differentiation, class switching and affinity maturation.
They are involved in responses to most microbial infections.

Question 50

What are T reg cells?

Answer 50

T regulatory cells produce IL-10 and TGF-β. They suppress inflammation and downregulate the immune response by acting on other T cells and B cells.
Involved in suppressing responses to ‘self’ cells and self microbiome antigens.
A lack of T reg cells significantly increase the likelihood of autoimmune diseases.