Immunological Tolerance and Autoimmune Disease

Question 1

Who has autoantibodies?

Answer 1

Everyone

Question 2

How many people get autoimmune disease at some point in their life?

Answer 2

5%

Question 3

Why do small number of autoantibodies suddenly turn into autoimmune diseases?

Answer 3

Increase in number, class switch, T cell proliferation

Question 4

How do we prevent undesirable autoimmune responses?

Answer 4

Specific immunological tolerance

Question 5

What types of immunological tolerance are there? Where?

Answer 5

Central and Peripheral
Central is in bone marrow and thymus as lymphocytes develop
Peripheral is everywhere else

Question 6

Where is most effort put into when tolerising? why?

Answer 6

T cells, needed to make high affinity B cells, and produce IFNy to activate macrophages

Question 7

What is tolerising T cells called?

Answer 7

Thymic education

Question 8

Two stages of thymic education are: where?

Answer 8

Positive selection (mostly cortex of thymus)
Negative Selection - mostly medulla

Question 9

Describe positive selection from when T cells enter thymus:

Answer 9

They enter the thymus as double -ve T cells, then become double +ve.
They are destined to die.
If they recognise Self MHC on Thymic epithelial cells (both MHC I and MHCII on them) - they are saved (signal sent in to save them)
If they don’t they die from apoptosis by neglect

Question 10

Describe negative selection:

Answer 10

There are macrophages and dendritic cells there too. If the T cells have a high affinity for self MHC and self proteins then they are killed - induced apoptosis

Question 11

How do double +ve T cells become single +ve?

Answer 11

If they recognise MHCII, CD8 is switched off

If recognise MHCI, CD4 is switched off

Question 12

Why do a lot of T cells die in the thymus?

Answer 12

Genetic recombination isn’t specific

Question 13

How do the T cells become tolerant to tissue specific antigens?2

Answer 13

The AIRE transcription factor switches alot of them on in the thymus.
We also have peripheral tolerance

Question 14

What happens if you are AIRE deficient?

Answer 14

Lots of autoreactivity

Question 15

2 types of central tolerance for B cells:

Answer 15

Clonal deletion and receptor editing

Question 16

Where does peripheral tolerance occur and what does it deal with?

Answer 16

Outside thymus or bone marrow

deals with self reactive lymphocytes that escape central tolerance

Question 17

2 main mechanisms of peripheral tolerance are:

Answer 17

Clonal anergy and suppression

Question 18

Describe anergy in peripheral tolerance

Answer 18

Inactivate the lymphocyte if only Ag recognised in the absence of co stimulators like VCAM1, ICAM, B7 (so only CD4 and TCR active).
This is because pathogens upregulate the costimulators but self antigens don’t.
Lymphocyte can be reactivated though

Question 19

What are natural and induced Tregs and how do they do peripheral tolerance?

Answer 19

So natural T regs are FOXP3 and CD25+ when leave thymus
Induce Tregs begin expressing these after meeting antigen
They all produce anti inflammatory cytokines like TGFB and IL10

Question 20

4 things that Tregs do:

Answer 20

Produce mainly immunosuppressive cytokines like TGFB and IL10
Have lots of IL2 receptors and mop up IL2 from vicinity
CTLA4 grabs and internalises B7 from APCs
Release cytotoxic granules

Question 21

Why does Autoimmune occur? two types:

Answer 21

Break down of immune tolerance
Primary (born with it)
or breaks down later in life

Question 22

5 Organ specific autoimmune diseases:

Answer 22

Brain - MS
Thyroid - Hashimotos thyroditis
Stomach - pernicious anemia
Adrenal - addisons 
Pancreas - type I diabetes

Question 23

4 non organ spec autoimmune:

Answer 23

Muscle - dermatomyosis
Kidney SLE
Skin - SLE and scleroderma
Joints -RA

Question 24

Why does SLE affect kidney?

Answer 24

Large immune complexes get trapped in glomeruli

Question 25

What are rheumatoid factors?

Answer 25

IgG recognises Fc bit of another IgG

Question 26

What are 3 genetic factors associated with autoimmunity?

Answer 26

MHC issues, CTLA4 issues, female

Question 27

How does infection cause autoimmunity?

Answer 27

B cells respond to microbial agent that cross reacts with self - eg rheumatic fever from group a strep
Ag is similar to cardiac myosine

Question 28

Hashimotos is:

Answer 28

Ab against thyroglobulin and thyroid peroxide