Tolerance and Autoimmunity

Question 1

What type of immune response is involved in autoimmunity?

Answer 1

Adaptive immune response

Question 2

Which cell type is always involved in autoimmunity?

Answer 2

Lymphocytes

Question 3

What proportion of people has lymphocytes with the capability of recognising self-antigens?

Answer 3

ALL of us – this is normal autoimmunity

Question 4

What are the 3 main factors that affect the transition from normal autoimmunity to autoimmune disease?

Answer 4

Genetic susceptibility
Infections- causes inflammatory environment
Environmental factors such as diet

Question 5

Why are autoimmune conditions chronic?

Answer 5

Because self-tissue is always present

Question 6

The effector mechanisms in autoimmunity resemble those of which type of immune reaction?

Answer 6

Hypersensitivity reactions (types 2, 3 and 4)

Question 7

What proportion of people affected by autoimmune disease isfemale?

Answer 7

75% overall (this changes between diseases)

Question 8

What is a possible reason for the increase in incidence of autoimmune disease?

Answer 8

Hygiene hypothesis

Question 9

Describe the pathophysiology of autoimmune haemolytic anaemia.

Answer 9

There are autoantibodies against red blood cells, which bind to red blood cells and activate complement
This results in clearance and complement-mediated lysis of the autologous erythrocytes

Question 10

What is a type II hypersensitivity reaction?

Answer 10

Antibody response against cellular or ECM antigens (insoluble antigens)

Question 11

What is a type III hypersensitivity reaction?

Answer 11

Immune complex formation by antibody against soluble antigen

Question 12

What is a type IV hypersensitivity reaction?

Answer 12

T cell mediated disease – delayed type hypersensitivity

Question 13

What is Goodpasture’s syndrome?

Answer 13

Type 2 hypersensitivity reaction in which there are IgG antibodies against a type IV collagen found on the basement membrane in the glomerulus
This results in deposition of autoantibodies in the renal corpuscle and activation of complement leading to infiltration of inflammatory cells and kidney damage
NOTE: the inflammatory cells (e.g. neutrophils) bind to the Fc portion of antibodies via their own Fc receptors

Question 14

How do type II and type III immune reactions recruit inflammatory cells?

Answer 14

Inflammatory cells are recruited via the binding of inflammatory cells to the Fc portion of antibodies via their Fc receptors

Question 15

What is the main difference between type II and type III hypersensitivity reactions?

Answer 15

Type II – insoluble antigens

Type III – soluble antigens

Question 16

Other than antigen-TCR binding, what else is required for the activation of naïve T cells?

Answer 16

Costimulation

Question 17

What is the dominant genetic factor affecting susceptibility to autoimmune disease?

Answer 17

HLA (class II in particular)

Question 18

What did the freemartin cattle experiment show about tolerance?

Answer 18

It showed that early exposure to foreign antigens allows the development of tolerance to those antigens

Question 19

Define immunological tolerance.

Answer 19

The acquired inability to respond to an antigenic stimulus

Question 20

What are the main features of immunological tolerance?

Answer 20

It is acquired
It is antigen specific
It is an active process in neonates

Question 21

What are the two types of immunological tolerance?

Answer 21

Central Tolerance = happens during lymphocyte development

Peripheral Tolerance = once we’ve developed mature lymphocytes, there are mechanisms to develop tolerance

Question 22

What are the three main mechanisms of peripheral tolerance?

Answer 22

Anergy
Ignorance
Regulation

Question 23

What are the three outcomes for T cells based on how stronglythey bind to MHC in the thymus?

Answer 23

Useless –don’t recognise MHC at all – die by apoptosis
Useful – associate weakly with MHC
Dangerous – associate too strongly with MHC – die by apoptosis

Question 24

What percentage of thymocytes survives selection?

Answer 24

5%

Question 25

What class of immunoglobulin are the B cell surface receptors?

Answer 25

IgD and IgM

Question 26

What happens to B cells that recognise soluble autoantigens?

Answer 26

They will migrate to the periphery but they do not express normal levels of IgM and they are anergic (they are not very responsive)

Question 27

What is the role of the AIRE transcription factor?

Answer 27

It is important for the low-level expression of a large variety of self-peptides in the thymus, against which the T cells are selected

Question 28

What is APECED caused by?

Answer 28

Mutation in the AIRE transcription factor This mutation means that the T cells can’t be selected against a wide range of self-peptides so lots of self-reactive T cells get released into the circulation and can cause autoimmune disease

Question 29

What is anergy caused by?

Answer 29

The presentation of an antigen in the absence of costimulation such as CD80-CD28 – this makes the lymphocytes enter a refractory state

Question 30

What is immunological ignorance caused by?

Answer 30

Occurs when the antigen concentration is too low It can be due to the absence of antigen presenting molecules It occurs at immunologically privileged sites where the immune cells don’t normally penetrate This is ignorance – the T cells never see their antigen

Question 31

Give an example of a failure of ignorance.

Answer 31

Sympathetic ophthalmia Damage to the eye can release eye antigens into the lymphatics and lymph nodes These antigens are recognised by T cells, which become activated against the eye antigens The T cells then go back to both eyes and cause damage

Question 32

What are the main receptors expressed by Tregs?

Answer 32

CD4 CD25 –IL-2 receptor, which is an important growth factor for T cells CTLA-4 – binds to B7 and sends a negative signal FOXP3 – essential transcription factor for Treg development

Question 33

What is IPEX caused by?

Answer 33

Mutation in FOXP3 FOXP3 encodes a transcription factor that is critical for the development of T regs A mutation in FOXP3 leads to the accumulation of autoreactive T cells

Question 34

What are the two types of Treg?

Answer 34

``` Natural Tregs (nTregs) – these are generated in the thymus Inducible Tregs (iTregs) – these are produced as part of the normal T cell response as a mechanism of dampening down an immune response after it has happened ```

Question 35

Criteria for disease to be autoimmune

Answer 35

Evidence of disease specific adaptive immune response in affected tissue Passive transfer of autoreactive or antibodies replicating the disease Elimination of autoimmune response modifies disease History of autoimmune disease in family Genetic MHC associations

Question 36

Examples of type IV automimmune dieases

Answer 36

T1DM Rheumatoid arthritis MS