L19- Autoimmune diseases

Question 1

Are auto-reactive T and B cell clones normal in the body?

Answer 1

Yes they are present in all normal healthy immune systems. However they are normally controlled by mechanisms of self-tolerance.

Question 2

What is an autoimmune response?

Answer 2

Immune response against one or more self-antigens. (also called auto-antigens).

Question 3

What is an autoimmune disease?

Answer 3

A disease caused by an autoimmune response.
Develops due to failure of self-tolerance.
Normal effector mechanisms are triggered, but targetted towards you!
Usually not possible to clear self antigen because it’s you, so results in a chronic response.

Question 4

What is the most common autoimmune disease?

Answer 4

Rheumatoid arthritis.

Question 5

What are the 2 main classifications of autoimmune diseases?

Answer 5

1. Based on whether one tissue (organ-specific) or multiple tissues affected (systemic).
2. Distribution of auto-antigens involved in response i.e. organ-specific and organ non-specific.

BUT some auto-antigens may not correspond to an organ.

Question 6

Give examples of organ specific autoimmune diseases?

where antigen is confined to affected organ

Answer 6

1. Hashimoto’s thyroditis- antigen=thyroglobulin

2. Grave’s disease- thyroid stimulating hormone receptor.

Question 7

Give examples of organ non-specific autoimmune diseases?

where antigen is widespread

Answer 7

Systemic Lupus Erythmatosis- anti-nuclear antigens (ANA)

Question 8

What do nearly all autoimmune disease involve generation of?

Answer 8

CD4+ T helper cells.

Because they are associated with antibody responses. Can’t have antibody responses unless you have T helper cells there.

Question 9

What are the 2 immunological features of autoimmune diseases?

Answer 9

-Auto-antibodies:
In the serum, deposited in tissues, contribute to formation of immune complexes.
-Cellular infiltrate:
T cells cd4 + cd8 & B cells.

Question 10

What pathology do you see of autoimmune diseases?

Answer 10

1. Primary pathology= a direct consequence of the autoimmune response.
2. Secondary pathology= arises as a consequence of the primary pathology.

Question 11

What are the mechanisms of auto-antibody mediated immune pathology?

Answer 11

1. Damage/destruction : e.g. complement mediated lysis, opsonisationa nd phagocytic removal.
2. Alteration of function: e.g. stimulation of receptors (agonist), inhibition of function
3. Deposition of immune complexes.
   (these are normal B cell, antibody jobs but against invaders normally.

Question 12

Describe the auto-antibody mediated damage or destruction-> complement mediated lysis.
e.g. autoimmune haemolytic anaemia

Answer 12

1. Auto-antibodies bind to the RBCs.

2. This causes complement to be fixed. Get generation of MAC. 3. That drives lysis of RBC.

Question 13

Describe the auto-antibody mediated damage or destruction-> opsonisation.
e,g, autoimmune thrombocytopenia, excessive bleeding.

Answer 13

1. Anti-platelet antibody binds to platelet.
2. Recruits macrophages (come eat me sign)
3. Macrophage phagocytoses platelets. Platelets destroyed. So hard to clot blood.

Question 14

Two example diseases where auto-antibodies mediate damage or destruction?

Answer 14

1. Autoimmune haemolytic anaemia (complement mediated lysis)

2. Autoimmune thrombocytopenis (opsonisation)

Question 15

Graves disease (hyper-thyroidism)

Answer 15

Stimulation of a receptor. (antibody mediated alteration of function)
Normally thyroid stimulating hormone acts at receptors at thyroid and you make thyroid hormone. Then neg. feedback on pituitary to inhibit thyroid stimulating hormone.
BUT IN GRAVES DISEASE:
Auto-immune B cells are making antibodys against the thyroid stimulating hormone receptors. That will stimulate thyroid production. Lose negative feedback loop completely. Now too much thyroid hormone!

Question 16

Summarise Graves disease briefly

Answer 16

Antibodies against thyriod stimulating hormone receptors.
So no negative feedback when thyroid hormone is released.
Get excessive thyroid hormone.

Question 17

Myasthenia gravis

Answer 17

Inhibition.
Auto-antibody blocks binding to receptor or it drives the internalisation and degradation of the receptors.
So lose the normal acetylcholine signal. So no Na+ influx so no muscle contraction.

Question 18

Pernicious anaemia.

Answer 18

Blocking- aleration of function.
Usually make intrinsic factor enabling vitamin b12 to be absorbed.
In pernicious anaemia you make autoantibodies to the intrinsic factor. Block ligand receptor interaction. So the B12 is not absorbed.

Question 19

Systemic lupus erythematosus

Answer 19

Deposition of immune complexes.
These deposit in small blood vessel walls and initiate inflammatory reaction.
possible symptoms: arthritis, rash, vasculitis

Question 20

Are there just autoimmune diseases caused by antibodies?

Answer 20

No. Also destruction by undefined mechanisms.

e. g. -CD8 cytotoxic T cell function
- Macrophage mediated destruction
- Inflammatory response
e. g. type I diabetes, rheumatoid arthritis.

Question 21

What’s the concordance of most autoimmune diseases?

Answer 21

Concordance in identical twins is more than non-identical twins.
BUT concordance in identical twins is less than 50%. So tells us that genetics plays a role but environment also important.

Question 22

What are the possible environmental influences in autoimmune disease?

Answer 22

1. microbial agents-may resemble self-antigens
2. drugs- may bind to self-Ag and then Ag appears foreign
3. toxins
4. diet-not really clear link
5. hygeine-no worms (inflammatory bowel disease improved with worms)

Question 23

Why are most autoimmune diseases not the result of single gene mutations?

Answer 23

Multiple genes contribute!
Because..
Many genes are polymorphic (present in population in more than one form e.g. MHC)

So different forms of protein are made- structural polymorphism e.g. MHC.
Or altered protein activity ro protein levels- non-structural polymorphism.

Question 24

What is susceptibility to autoimmunity due to?

Answer 24

Expression of different gene alleles i.e. POLYMORPHISMS and not mutations.
The degree to which an allele of a gene increases susceptibility is called the RELATIVE RISK. (RR).

Question 25

Which genes are the susceptibility genes in autoimmune diseases?

Answer 25

MHC genes- 
especially MHC class II. Accounts for ~50% of the total genetic risk.

Non-MHC-
CTLA-4
Sex-related genes

Question 26

Give example of autoimmune disease caused by sex related genes?

Answer 26

Hashimoto’s thyroiditis is 50 times more likely in women.
SLE = x10 more likely.
May be due to action fo sex hormones on immune system

Question 27

Give example of MHC gene causing autoimmune disease?

Answer 27

HLA-DR2 has RR of 16 for Goodpasture’s syndrome.

relative risk

Question 28

Describe the sex link with autoimmune diseases?

Answer 28

75% autoimmune diseases are in women
Usually arises in child-bearing years.
Usually gets a bit better during pregnancy.

Question 29

Genetic risk of autoimmune diseases?

Answer 29

Genes identified as risk factor only account for small proportion of genetic risk. It is the combination of these genes that substantially enhances risk of developing a particular disease. (multiple polymorphisms)

Question 30

Autoimmune disease is due to a loss of tolerance to self.

Why does this mean bypassing t cells?

Answer 30

Autoimmune disease caused by production of high affinity auto-antibodies or generation of autoreactive T cells.
Everyone has B ceels that are autoreactive but normally don’t make antibody due to lack of antigen-specific T cell help.
So must either lose T cell tolerance/get T cell help or bypass need for T cell help.

Question 31

How can B cells bypass the need for T cells?

Answer 31

Some B mitogens stimulate B cells without T help.
Bacterial products like LPS can directly stimulate B cells to differentiate to plasma cells.
This is NOT antigen-specific.
The bacterial product is acting as a mitogen.
Because any B cell can be stimulated, this may activate autoreactive B cells.
Transient-should stop if bacterial product removed.

Question 32

How can you gain T help?

Answer 32

May be because antigens on pathogens are similar to our own ones.
Could have had infections/drugs/environmental chemicals that caused this.

Question 33

What’s an example where microbial agents cause autoimmune disease?

Answer 33

Rheumatic fever.

Make antibodies against streptococcal M-antigen, react against heart myosin, joints and kidney.

Question 34

If drugs or infections are finite, how does this cause autoimmune diseases that last forrrreverrr?

Answer 34

Normally it is transient when the stimuli ends. However in genetically susceptible people this triggers Th cells for self-antigen and autoimmunity.

Question 35

What is molecule mimicry?

Answer 35

This idea that you have foreign antigen that looks remarkably like a self-antigen. Generates T cell agents that can cross react against the foreign antigen also against self antigen.