Allergy, tolerance and immune regulation

Question 1

What is the definition of allergy?

Answer 1

An excessive immune response to harmless antigens (allergens) in the environment.

Question 2

Example of type 1 hypersensitivity and how it’s mediated

Answer 2

Asthma- IgE mediated

Question 3

What is phase 1 of an allergic reaction?

Answer 3

Sensitisation: Production of Ag specific IgE

Question 4

What are the steps in sensitisation?

Answer 4

1. Exposure to allergens leads to stimulation of Th2- specialise in making IL4 and helping B cells produce IgE.
2. B cells produce IgE that recognise the allergen.
3. IgE circulates in the blood and associates with Mast cells in mucosal and connective tissues via FcεR- Mast cells specialise in releasing mediators of inflammation

Question 5

What is phase 2 of an allergic reaction?

Answer 5

Re-Exposure and Activation of inflammatory response

Question 6

What are the steps in phase 2 of an allergic reaction?

Answer 6

• Allergen bind to IgE on Mast cells located in skin, airways, GI tract
• IgE signals to the Mast cell to release its chemical arsenal: Histamines, Cytokines, Prostaglandins, Leukotrienes
• Results in increased vascular permeability, inflammation, muscle contraction, immune cell recruitment, swelling, redness, blistering, itching

Question 7

What are some of the other types of hypersensitivities and what are they mediated by? Give examples of each.

Answer 7

Type 2: IgG - mediated e.g. Foetal haemolytic syndrome
Type 3: IgG – mediated e.g. Serum sickness
Type 4: Delayed-type (DTH) e.g. Poison Ivy

Question 8

Process of serum sickness

Answer 8

Animal serum stimulates strong antibody response.
If receive 2nd dose of serum, antibodies bind to the serum proteins forming immune complexes
Complexes are deposited in blood vessels eg skin, kidney and joints
Causes fever, rash, arthritis, kidney disorder

Question 9

What cells does type 4 hypersensitivity involve?

Answer 9

Th, Tc and macrophages

Question 10

Which types of responses are effective at eliminating parasites?

Answer 10

Th2 & Mast cells; IgE-associated responses

Question 11

What is the aim of central tolerance?

Answer 11

Prevent harm generated in the first place.

Question 12

What is the aim of peripheral tolerance?

Answer 12

Make sure everything stays under control.

Question 13

What is the compromise in establishing protection against autoimmunity?

Answer 13

Have to remove dangerous self-reactivity but without impairing the capacity for broad recognition and effective defence.

Question 14

What do mechanisms of tolerance do?

Answer 14

• Limit the production of self-reactive T and B cell clones.

- Prevent unwanted destructive responses by any clones that are produced.

Question 15

Define self-tolerance.

Answer 15

Failure to respond to intrinsic self-antigens.

Question 16

Is tolerance antigen specific?

Answer 16

Yes

Question 17

Apart from being tolerant to intrinsic self-antigens, what else can you develop tolerance to?

Answer 17

External antigens such as:

• Harmless non-self antigens
• Therapeutically relevant antigens

Question 18

Is self tolerance acquired or inherited?

Answer 18

Acquired

Question 19

What is clonal deletion?

Answer 19

As cells are maturing, if they saw and bound to self-antigen they would be deleted.

Question 20

What mechanisms contribute to tolerance?

Answer 20

• Inactivation of potentially self-reactive clones (death, editing, anergy)
• Immune regulation (suppression, functional deviation)
• Self-epitopes not available for recognition (ignorance, sequestration, immune privilege)

Question 21

Where do central and peripheral tolerance mainly act and what do they do there?

Answer 21

Central tolerance: primary lymphoid organs (bone marrow, thymus). remove highly self-reactive clones during lymphocyte development.

Peripheral tolerance: peripheral organs and tissues and secondary lymphoid organs (LNs, spleen). Multiple mechanisms limit reactivity against self and harmless antigens in the periphery.

Question 22

What is the strength of interaction of B cell with self-antigen influenced by?

Answer 22

• The concentration of the antigen

- It’s ability to cross-link surface receptors.

Question 23

What two immunoglobulins does a mature B cell express?

Answer 23

IgM and IgD.

Question 24

T cell stages of development

Answer 24

Early thymocyte-> double negative thymocytes-> double positive thymocytes-> single positive thymocytes.

Question 25

Which 2 types of t cell/TCR are useless?

Answer 25

• T cells that fail to make a functional TCR

- TCR that cannot recognise self-MHC molecules.

Question 26

Which type of TCR is harmful?

Answer 26

TCR that recognises self-MHC: self-antigens too strongly.

Question 27

Which type of TCR is useful?

Answer 27

TCR that recognises self-MHC and does not bind self-antigens too strongly.

Question 28

What is the first quality checkpoint of TCR and what does it mean?

Answer 28

Has TCR beta gene rearrangement resulted in a functional pre TCR expression?
-Failure to receive a survival signal makes it useless as the cell is deleted by apoptosis. This would be because it failed to make pre-TCR so failed to make a beta-chain which makes it useless.

Question 29

What is the second quality checkpoint of TCR and what does it mean?

Answer 29

Can the rearranged aB-TCR recognise self-MHC?
If it can then they survive and move to the medulla as single positive CD4 or CD8 cells.
If they cannot then the receptor may be edited and if it still cannot then it dies by apoptosis.

Question 30

What is the third quality checkpoint of TCR and what does it mean?

Answer 30

Does the aB-TCR recognise self MHC+self peptide too strongly?
DCs and medullary epithelial cells present antigens to the thymocytes. Medullary epithelial cells express a transcription factor AIRE. If you don’t have AIRE then there’s autoimmune disease.

Question 31

How are B cells tolerant to self antigens?

Answer 31

They don’t receive T cell help so the B cells is not activated.

Question 32

What are the immunologically privileged sites?

Answer 32

Brain, eye, testis, uterus

Question 33

What are the properties of immunologically privileged sites?

Answer 33

• enclosed by a physical barrier
• low MHCI
• rich in suppressive cytokines e.g. TGFb
• express FasL

Question 34

Example of breaking the immune privilege.

Answer 34

Sympathetic ophthalmia:

• Trauma to one eye results in release of sequestered intraocular protein antigens.
• The released antigen is carried to the lymph node and activates a T cell.
• Effector T cells return and encounter antigen in both eyes.