Immunology

Question 1

What does central tolerance consist of?

Answer 1

Positive Selection and Negative Selection

Question 2

What is Positive Selection?

Answer 2

Positive Selection is the selection of immature lymphocytes that expresses T cell receptors that binds moderately to MHC complexes on thymic cells.

They would receive “survival” signal, which allows them to continue their development.

Question 3

What happens to those immature lymphocytes which does not bind or bind minimally to MHC complexes?

Answer 3

They would undergo “death by neglect”

Question 4

What is Negative Selection?

Answer 4

Negative Selection is the selection of immature lymphocytes that expresses T cell receptors that binds too strongly to MHC complexes on thymic cells.
Because of this, they have a high likelihood of becoming self-reactive and attack own’s cells. They thus undergo apoptosis.

Question 5

Why is thymic tolerance important for the proper function of the immune system?

Answer 5

Thymic tolerance of T cells (central tolerance) is important so as to eradicate immature lymphocytes that has a potential to become self-reactive and attack its own cells. Hence, it is important to prevent autoimmunity.

Question 6

What are the 3 signals that naive T cells require to be activated?

Answer 6

1. T cell receptors binding peptide-MHC molecule
2. Co-stimulation
3. Cytokines

Question 7

What is co-stimulation?

Answer 7

Co-stimulation is the second signal expressed from APC to T cells to activate an immune response.

Co-stimulatory molecules on T cells will bind to Co-stimulatory molecules on APC

Question 8

Gives an example of co-stimulation.

Answer 8

CD28 on T cell receptors bind to B7.1 (CD80) and B7.2 (CD86) on dendritic cells.

This triggers the production of IL-2, which promotes the proliferation and differentiation of T helper cells (particular Th1)

Question 9

Describe how the requirement for costimulation during activation of naïve T cells promote self-tolerance in the absence / presence of infection.

Answer 9

In the presence of an infection, pathogens expresses pattern recognition receptors (e.g. pathogen-associated molecular patterns, PAMPs). This triggers the maturation of APC like dendritic cells, allowing more costimulation.

Question 10

Briefly describe the 3 mechanisms of peripheral tolerance.

Answer 10

1. Ignorance - when T cells receptors bind to peptide-MHC are too weak to cause an activation of mature T cells in the periphery.
2. Anergy - when T cells are functionally inactivated following an encounter with the antigen, but does not undergo apoptosis, or cell death. Instead, it remains in a prolonged state of unresponsiveness due to the lack of co-stimulation.
3. regulation - when T cells bind too strongly to self-antigen but not strong enough to attack it, are re-directed to regulatory function via the induction of transcription factor, FOXP3.

Question 11

List the 4 types of hypersensitivity reactions.

Answer 11

Mnemonics: ACID

A — allergy/atopic/anaphylactic (IgE antibody mediated reaction / immediate hypersensitivity) (type I)

C — cytotoxic (antibody-mediated reaction / cytotoxic hypersensitivity) (type II)

I — immune complexes (type III)

D — delayed (type IV)

Type I to Type III hypersensitivity are all antibody-mediated.
However, Type IV hypersensitivity is T-cell mediated.

Question 12

Describe the mechanism of Type I hypersensitivity reaction.

Answer 12

Type I Hypersensitivity is an immediate, IgE-antibody mediated reaction.
Genetic predisposition -> 2nd exposure to an allergen -> preformed IgE (sensitisation during the 1st exposure) will coats mast cells and basophils -> antigen (allergen) will bind to 2 IgE antibodies (known as crosslinking), resulting in the degranulation of the cells. This releases histamines and other mediators (e.g. prostaglandins, leukotrienes, and tryptase).

Question 13

Name the 3 tests that can be done to check for allergy.

Answer 13

1. Skin prick test
2. Scratch test
3. Intradermal test

Addition: Blood test to check for elevated tryptase (which is relatively specific for mast cell degranulation)

Question 14

What can be given to a patient with allergy?

Answer 14

2nd gen H1 receptor blockers (antihistamines) (e.g. cetirizine, fexofenadine)

Glucorticoids to suppress the immune reaction

Question 15

Give some examples of Type I Hypersensitivity reactions.

Answer 15

Mnemonics: 3As to be First

• Anaphylaxis
• Allergic (e.g. drugs, food)
• Atopic allergy (e.g. allergic rhinitis, asthma, eczema)

Question 16

Describe the mechanism of action of Type II Hypersensitivity Reaction.

Answer 16

Type II hypersensitivity is a cytotoxic, antibody-mediated reaction. It is often limited to a particular tissue type. This is because antibody are specific to the tissues (antigens).

Activation of complement system: IgG and IgM bind to tissue-specific antigens, which activates the complement cascade, and result in phagocytosis and lysis of cells
Opsonisation, and phagocytosis of cells with C3b
ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity): NK cells bind to the Fc region of antibody-antigen complex -> release perforins, granzymes, and granulysin -> apoptic cell death
Antibody-mediated cellular dysfunction (only non-cytotoxic mechanism)

Question 17

Give some examples of Type II Hypersensitivity reaction.

Answer 17

Type II hypersensitivity have a few different mechanisms, and thus can be classified under

Destruction of cells
Inflammatory
Impaired cellular function

Some examples include:

Destruction of cells:
Autoimmune haemolytic anemia
Acute haemolytic transfusion reaction

Inflammatory
Goodpasture syndrome
Rheumatic Fever

Cellular dysfunction
Graves (TSH receptors autoantibodies that acts like TSH, and promotes the thyroid gland to produce more thyroid hormones)
Myasthenia gravis (autoantibodies against postsynaptic acetylcholine receptors)

Question 18

Describe the mechanisms of Type III Hypersensitivity

Answer 18

Type III hypersensitivity is a immune complex, antibody-mediated reaction.

Antigens bind to IgG antibodies, forming a antigen-antibody complex. This immune complex then deposit in tissues (esp. blood vessels) and results in the initiation / activation of the complement cascade, which triggers the neutrophils to release lysosomal enzymes (e.g. perforins, granzymes). This leads to lysis and cell death.

Question 19

List a few examples of Type III Hypersensitivity reaction.

Answer 19

Rheumatoid arthritis
Arthus reaction (vaccination against tetanus and diphtheria)
Serum sickness
Systemic Lupus Erythematosus (SLE)
Lupus nephritis

Question 20

Describe the mechanism of Type IV Hypersensitivity.

Answer 20

Type IV Hypersensitivity is a delayed, cell-mediated reaction.

The nickel penetrates the skin of Mr L. → Langerhans cells (APC) takes up the antigen and migrates to the lymph nodes. This results in the formation of sensitised T lymphocytes.
The repeated contact with the antigen results in presensitised T cells response.
CD4+ T cells → recognise antigen on APC → release inflammatory lymphokines cytokines (IFN-y and TNF-a) → activates the macrophages → phagocytosis of target cells
CD8+ T cells → recognise antigen on somatic cells → cell-mediated cytotoxicity → direct cell destruction

Question 21

Why is Type IV Hypersensitivity delayed?

Answer 21

Because T-cell mediated (delayed) reaction requires a pre-sensitised T cells and takes 2-3 days to be activated.

Question 22

Give some examples of type IV hypersensitivity.

Answer 22

Contact dermatitis (e.g. metal stuff like nickel; poison ivy; rubber gloves)
GVHD (Graft-vs-Host Disease)
Mantoux tuberculin skin test

Question 23

What is HLA?

Answer 23

Human Leukocyte Antigen (HLA) is a gene cluster found on chromosome 6 that encodes for major histocompatibility complex (MHC) molecules.

Question 24

What is MHC?

Answer 24

Major Histocompatibility Complex (MHC) are peptides found on the surface of all cells that display antigenic peptides as a normal physiological function, so that they can be recognised by T cells as either self- or non-self antigens.

Question 25

Which part of the HLA loci is MHC matching at?

Answer 25

MHC matching is at HLA-DR, HLA-A and HLA-B

Question 26

Why is HLA typing important for transplantation.

Answer 26

Because allogenic T cell responses are primarily directed at foreign HLA peptide, and this reaction is very strong.
Activation of T cell by a foreign HLA peptide will result in clonal expansion of that T cell, leading to transplant rejection.

Question 27

Why is ABO compatibility screening important for transplantation?

Answer 27

Because, ABO incompatibility can lead to acute intravascular hemolysis of the transfused donor RBCs.

Question 28

Briefly describe the 3 different types of graft-rejection, subdivided by their time line following rejection.

Answer 28

Hyperacute Rejection (<48 hours)
Acute Rejection (<6 months)
Chronic Rejection (>6 months)

Question 29

What are the 2 groups of targets (i.e. antigen) in graft rejection?

Answer 29

ABO antigens

HLA / MHC antigens

Question 30

What would you screen for to minimise graft rejection complications?

Answer 30

Cross-matching (recipient serum is match with donors’ preformed antibodies)

ABO compatibility
Histocomptibility

Question 31

What are the effectors for the complement pathway?

Answer 31

All three pathways culminate in the formation of the convertases, which in turn generate the major effectors of the complement system:

1. anaphylatoxins (C4a/C3a/C5a) — pro-inflammatory polypeptides generated after proteolytic cleavage of C3 , C4, and C5 in response to complement activation. Their well appreciated effector functions includechemotaxis and activation of granulocytes, mast cells and macrophages.
2. the membrane attack complex (MAC) (C5b, C6, C7, C8 and many C9) — complex of proteins typically formed on the surface ofpathogencell membranesas a result of the activation of the host’scomplement system
3. opsonins (e.g., C3b) — a substanceto react with bacteria and make them more susceptible to ingestion by phagocytes.

Question 32

What is graft-vs-host disease (GVHD)?

Answer 32

Damage to host as a result of systemic inflammatory reaction induced by T cells present in the graft.

Question 33

Describe the pathophysiology of acute GVHD.

Answer 33

Donor T lymphocytes triggers a type IV hypersensitivity reaction in the host organs, resulting in severe organ damage.
It happens < 100 days after transplantation.

Chronic is >100 days after.

Question 34

Name 3 aims from vaccination.

Answer 34

1. Herd Immunity
2. Eradication of a disease
3. Lower incidence and associated risk

Question 35

How are adjuvants useful when administered together with an inactivated vaccine?

Answer 35

Adjuvant helps to enhance the immune response, as an inactivated vaccine (heat-killed vaccine construct) generate a weaker immune response compared to live attenuated vaccine. It also requires multiple periodic “boost” dose to sustain a high antibody titres as the antibodies level falls overtime.

Adjuvant employ the following mechanism to elict immune response:
allow sustained release of antigen at the site of injection (depot effect)
upregulate cytokines & chemokines
cellular recruitment at site of injection
increase antigen uptake & presentation to APC
activation & maturation of APC (increase MHC class II and co-stimulatory molecular expression) and migration to lymph nodes
activation of inflammasomes

Question 36

Describe the advantages of using a live attenuated version of the viral pathogen as a vaccine construct.

Answer 36

Live attenuated vaccine are modified functioning virus or bacterium that is able to replicate in the patient’s body but does not cause disease.


It is able to induce a cellular and humoral immune response, and form specific B cells against the antigen, providing potent, and lifelong immune response.
It does not require adjuvants, and generate immunological memory.


Question 37

Describe the disadvantages and/or risks of using a live attenuated version of the viral pathogen as a vaccine construct.

Answer 37

Live attenuated vaccine. can cause a mild form of the disease (usually caused by replication of the attenuated vaccine strain)
Very rarely, live attenuated vaccine may become virulent again, and are thus often contraindicated in immunodeficient individuals and pregnant women (observed in polio vaccine
It is contraindicated in children <9 months old
Ensure absence of contamination of culture
May be a hazard to personeel
Require refrigeration temperatures / cold chain
Possible that live virus will be shed in urine/feces thus impact the environment

Question 38

Describe the advantages and disadvantages of using a heat-killed version of the viral pathogen as a vaccine construct. (4 marks)

Answer 38


Disadvantages:
first dose usually does not confer immunity and requires periodic “boost” to ensure sufficiently high antibody titers
number of antibodies decreases overtime
causes a weaker immune response
expensive
need to ensure mode of killing is successful

Advantages:
considered safer than live vaccines
possible to combine multiple strains of the same pathogen in the vaccine

Question 39

Explain what is Herd Immunity.

Answer 39

Once a certain percentage of the population has received immunisation, non-vaccinated individuals (e.g. children too young to receive immunisation) will also be protected.

Question 40

What does Anti-PD1 targets?

Answer 40

1. Exhausted T cells
2. Chronically activated T cells
3. Regulatory T cells
4. Tumour infiltrated T cells

Question 41

What does anti-PDL1 targets?

Answer 41

Tumour cells

Question 42

Briefly explain why when given anti-PDL1 cancer therapy may results in autoreactivity?

Answer 42

PD-1 receptors that are expressed on exhausted T cells / chronically activated T cells / regulatory T cells / tumour infiltrated T cells will bind to PD-L1 receptors on the antigen-presenting cells (APC). This binding results in the inhibition of activation signal (signal 1) and co-stimulatory signal (signal 2) of the T lymphocytes.

Hence, when given anti-PD-L1, it inhibits the binding of PD-L1 and PD-1, resulting in the loss of peripheral tolerance. This In turn results in autoreactivity.