Block C Lecture 4: Tolerance

Question 1

What can the adaptive immune system generating a diverse range of antigen-specific cells potentially result in?

Answer 1

These cells recognising self-antigens
(Lecture 4, Slide 6 )

Question 2

How does the immune system prevent antigen-specific cells by recognising self-antigens?

Answer 2

Selection in the thymus
(Lecture 4, Slide 6)

Question 3

What is central tolerance?

Answer 3

Deletion of inappropriate T cells through positive and negative selection in the thymus
(Lecture 4, Slides 6 and 7)

Question 4

What is thymic selection dependant on?

Answer 4

The affinity of the TCR for MHC receptors
(Lecture 4, Slide 7)

Question 5

What occurs in positive selection in the thymus?

Answer 5

T cells which don’t have enough affinity for MHC receptors don’t receive a “survive signal” and undergo “death by neglect”
(Lecture 4, Slide 7)

Question 6

What does positive selection in the thymus select for and what does this ensure?

Answer 6

T cells with a TCR of moderate / high affinity for MHC, ensuring T cells can recognise MHC and antigens in the periphery
(Lecture 4, Slide 7)

Question 7

What does negative selection in the thymus removes and what does it ensure?

Answer 7

It removes T cells which bind too strongly, ensuring self-reactive T cells are clonally deleted
(Lecture 4, Slide 7)

Question 8

What happens to T cells that fail negative selection?

Answer 8

They undergo apoptosis
(Lecture 4, Slide 8)

Question 9

What is the problem with negative selection?

Answer 9

It ensures T cells do not have high affinity for self-antigens presented by MHC, but not all antigens are presented in the thymus, meaning some T cells which are self-reactive to antigens in other parts of the body could slip through
(Lecture 4, Slide 9)

Question 10

What is required on top of negative selection to ensure T cells are not self-reactive to any antigen in the body?

Answer 10

Peripheral tolerance mechanisms
(Lecture 4, Slide 9)

Question 11

What do peripheral tolerance mechanisms ensure?

Answer 11

That mature T cells don’t activate inappropriately (such as to self-antigens)
(Lecture 4, Slide 10)

Question 12

How do peripheral tolerance mechanisms ensure mature T cells don’t activate inappropiately?

Answer 12

T - cells need multiple signals to activate (recognition of antigen via TCR-MHC complex, presence of CD4, co-stimulatory molecules and eventually cytokines) and won’t activate without one of these signals being present
(Lecture 4, Slide 10)

Question 13

What can co-stimulatory molecules (such as B7.1) interact with, instead of interacting with CD28?

Answer 13

CTLA-4
(Lecture 4, Slide 11)

Question 14

What is CTLA-4?

Answer 14

An immune checkpoint
(Lecture 4, Slide 11)

Question 15

Why is the fact that CTLA-4 can bind more strongly with B7 than CD28 important?

Answer 15

As binding to CTLA-4 can turn off an activated T cell, whereas CD28 activates a T cell, so the turn off mechanism needs to be stronger than the turn on mechanism to prevent inappropriate immune responses
(Lecture 4, Slide 11)

Question 16

Other than T Cells needing multiple signals to become active, what is another peripheral tolerance mechanism?

Answer 16

Induction of Treg cells
(Lecture 4, Slide 12)

Question 17

How do regulatory T cells (Tregs) work?

Answer 17

By secreting Interleukin 10 (IL-10) and transforming growth factor beta (TGF-ß)
(Lecture 4, Slide 12)

Question 18

What do regulatory T (Treg) cells do to self-reactive T cells?

Answer 18

They inhibit them to prevent them from continuing to respond inappropriately
(Lecture 4, Slide 12)

Question 19

What do regulatory T (Treg) cells often play an important role in?

Answer 19

Regulating immune response after an infection has been cleared
(Lecture 4, Slide 12)

Question 20

What do central and peripheral tolerance do?

Answer 20

Central tolerance removes self-reactive T cells in the thymus
Peripheral tolerance mechanisms counteract cells which are responding inappropriately by turning these cells off - but not deleting them
(Lecture 4, Slide 13)

Question 21

What is antigen segregation?

Answer 21

Antigens being separated or distributed within different cellular or tissue compartments
(Lecture 4, Slide 15)

Question 22

What is an example of antigen segregation?

Answer 22

T cells and dendritic cells not be able to cross the blood brain barrier (BBB) and therefore being unable to come into contact with antigens in the central nervous system (CNS)
(Lecture 4, Slide 15)

Question 23

Under what conditions can T cells and dendritic cells gain access through the blood brain barrier (BBB)?

Answer 23

Due to infection or injury in the brain
(Lecture 4, Slide 15)

Question 24

How can T cells and dendritic cells entering the blood brain barrier (BBB) end up being harmful?

Answer 24

By granting them access to self-antigens they could potentially react with
(Lecture 4, Slide 15)

Question 25

When can activation induced cell death via apoptosis occur?

Answer 25

When a large number of cells are activated simultaneously (Lecture 4, Slide 16)

Question 26

What protein may T cells increase the expression of following activation?

Answer 26

Fas proteins (Lecture 4, Slide 16)

Question 27

What are Fas proteins?

Answer 27

The target of a Fas ligand, an apoptotic mediator (Lecture 4, Slide 16)

Question 28

How can T cells cause allergy?

Answer 28

If a T cell escapes clonal deletion in the thymus and isn't tolerised in the periphery, it can become active to non-harmful antigens, causing allergy (Lecture 4, Slide 18)

Question 29

What is celiac disease?

Answer 29

When antibodies are produced against harmless gluten in wheat, with the resultant inflammatory response in the gut causing gut damage - known as "enteropathy" (Lecture 4, Slide 18)

Question 30

What 3 ways is the gut damaged in celiac disease?

Answer 30

Villi responsible for nutrient absorption are lost, the epithelium becomes leaky and there is an increased number of goblet cells which produce mucus (Lecture 4, Slide 18)

Question 31

What is asthma?

Answer 31

A decrease in the diameter of the airway caused by a build-up of immune cells and the increased muscle concentration that pinches the airway and restricts air flow (Lecture 4, Slide 19)

Question 32

What occurs when the body responds to self-antigens?

Answer 32

Autoimmunity (Lecture 4, Slide 20)

Question 33

How is autoimmunity usually categorised?

Answer 33

Into organ-specific or systematic categories (Lecture 4, Slide 20)

Question 34

What 3 things determines whether you generate an autoimmune or allergic response?

Answer 34

The right genes and environmental exposure and infection (Lecture 4, Slide 22)

Question 35

What percent of humans carry the gene that predisposes (makes us liable) to allergy and how many people develop these?

Answer 35

Around 40% of us carry this gene with few people developing it (Lecture 4, Slide 22)

Question 36

What is ankylosing spondylitis?

Answer 36

An autoimmune condition against MHC receptors (Lecture 4, Slide 22)

Question 37

Under what conditions is a person likely to develop ankylosing spondylitis?

Answer 37

A person harbouring the gene that makes a person liable to ankylosing spondylitis and them being infected with the bacterium shigella (Lecture 4, Slide 22)

Question 38

Why does a person harbouring the gene making them liable to ankylosing spondylitis and being infected with the shigella bacterium make them likely to develop ankylosing spondylitis?

Answer 38

It is likely due to the degree of cross-relativity by also because of innate activation triggers danger signals which triggers increased co-stim expression which can lead to more T-cell activation (Lecture 4, Slide 22)

Question 39

What percentage of T-cells are deleted in central tolerance as a result of failing either positive or negative selection?

Answer 39

95% (Lecture 4, Slide 23)

Question 40

Why does peripheral tolerance usually work?

Answer 40

As danger signals are lacking - no PAMPs or DAMPS resulting in no upregulation of costimulatory molecules - resulting in T cells being anergic - not reacting to antigens (their default state) (Lecture 4, Slide 23)

Question 41

What is a primary immunodeficiency?

Answer 41

A genetically acquired immunodeficiency (Lecture 4, Slide 24)

Question 42

What are 3 things that can result in secondary (non-genetically acquired) immunodeficiencies?

Answer 42

Infections (like HIV) Metabolic dysregulation Therapy (such as chemotherapy) (Lecture 4, Slide 24)

Question 43

How does the trypanosome parasite evade the immune system?

Answer 43

They have an antigen coat of them called the variant surface glycoprotein (VSG) and they have the ability to recombine these to produce many different forms of VSG, much like our immune system, and once our immune system recognises its VSG, they start to recombine them to make a new VSG, allowing the parasite to stay one step ahead of our immune system (Lecture 4, Slide 25)

Question 44

What 3 things are needed to achieve immunological homeostais?

Answer 44

The right response, at the right time, in the right place (Lecture 4, Slide 26)