21. HLA and Disease

Question 1

What is the only way T cells can recognise antigens?

Answer 1

HLA presentation

Question 2

What do the MHC class 3 genes encode?

Answer 2

Immune proteins not involved in antigen presentation.

Question 3

Which are the most polymorphic HLA genes?

Answer 3

1. All HLA class 1genes
2. The ß chain of HLA-DR
3. The other HLA class 2 genes are somewhat polymorphic

Question 4

Where are the HLA allelic variations concentrated?

Answer 4

1. The anchor residues.
2. These are the amino acids that bind to the peptides.
3. These are very variable to present different antigens to different T cells.

Question 5

What does the codominance of HLA mean for expression?

Answer 5

All nucleated cells will express: 3 maternal HLA class 1 variants (HLA-A, HLA-B, HLA-C)
3 paternal HLA class 1 varients (HLA-A, HLA-B, HLA-C)

All Antigen presenting cells will express:
3 maternal HLA class 1 variants (HLA-A, HLA-B, HLA-C)
3 paternal HLA class 1 varients (HLA-A, HLA-B, HLA-C)
4 different HLA class 2 varients per allele making 12 types of HLA2 on the cell.

Question 6

Where does the 12 different HLA class 2 combinations come from?

Answer 6

For each HLA class 2 receptor: (HLA-DP, HLA-DQ, HLA-DR)
1. Maternal HLA2 a chain and ß chain.
2. Paternal HLA2 a chain and ß chain.
3. Maternal HLA2 a chain and paternal ß chain.
4. Paternal HLA2 a chain and maternal ß chain.

Question 7

What factors increase HLA diversity?

Answer 7

1. Polygeny
2. Polymorphism
3. codominance

Question 8

What does having thousands of different HLA molecules mean?

Answer 8

1. Each molecule can present hundreds of different peptides.
2. This allows the immune system to recognise a large range of pathogens.

Question 9

What does HLA diversity do?

Answer 9

1. Allows presentation of a broad range of antigens to maintain self tolerance and protection.
2. Allows use as a diagnostic tool for paternity testing and personal identification in forensics medicine

Question 10

What is a negative of HLA diversity?

Answer 10

Transplant rejection

Question 11

What is antigen presentation?

Answer 11

A continuous process

Question 12

What does MHC class 1 present?

Answer 12

intracellular antigens to CD8 T cells

Question 13

What does MHC class 2 present?

Answer 13

Extracellular antigens to CD4 T cells

Question 14

What are the 2 functions of MHC antigen presentation?

Answer 14

1. Self antigen presentation in the thymus.
2. T cell activation in the secondary lymphoid tissues and periphery.

Question 15

What is the role of MHC during the positive selection of T cells?

Answer 15

1. This makes sure all T cells that leave the thymus are MHC restricted and recognise the self MHC molecules.
2. This is important for T cell survival and determines phenotype.
3. A double positive CD4+ CD8+ T cell only exists in the thymus and will bind to an MHC complex during development.
4. If the cell binds an MHC1 it will become a CD8 T cell.
5. If the cell binds MHC2 it will become a CD4 T cell.

Question 16

What is the role of MHC during the negative selection of T cells?

Answer 16

1. This eliminates any self reactive T cells.
2. CD8 T cells will bind to an MHC1 presenting self antigens.
3. CD4 T cells will bind an MHC2 presenting self antigens.
4. If the T cell binds with high affinity they will be eliminated or become T reg cells.
5. If the T cell binds with low affinity it will be allowed to circulate and enter the periphery.

Question 17

What is doing the MHC antigen presentation in the thymus?

Answer 17

1. cortical epithelial cells in positive selection
2. medullary epithelial cells and dendritic cells in negative selection

Question 18

How does MHC activate T cells during infection?

Answer 18

1. Intracellular foreign antigens are presented on MHC1 as the pathogenic peptides are generated in the cytosol
2. Extracellular foreign antigens are presented on MHC2 as the pathogenic peptides are generated not in the cell but in the environment.
3. These peptides activate the APC which presents peptide fragments to the T cell.

Question 19

How does MHC activate T cells during cancer?

Answer 19

1. Mutated self-antigens called neoantigens are presented on MHC1 and MHC2.
2. They are self peptides but they look different so they are recognised by T cells.

Question 20

What is an autoimmune disease?

Answer 20

1. The immune system mistakenly targets and attacks healthy cells and tissues in the body.
2. This is mediated by auto reactive T and B cells.

Question 21

What is the association of HLA with autoimmune disease?

Answer 21

1. Genetic and epidemiological studies have shown a strong association between certain HLA alleles and autoimmune disease.
2. This is due to genetic changes in either the HLA themselves or in other proteins in the pathway.
3. There are risk alleles that increase the risk of developing autoimmune disease compared to the general population.
4. There are protective alleles that decreased the risk of developing autoimmune disease compared to the general population.

Question 22

What is the Relative Risk?

Answer 22

1. The frequency of MHC alleles in patients with the disease compared to the frequency in the population.
2. High relative risk = risk alleles
3. Low relative risk = protective alleles

Question 23

What are most HLA-associated autoimmune diseases associated with?

Answer 23

1. MHC class 2 and therefore auto reactive CD4 T cells
2. A few are MHC1 mediated and associated with CD8 T cells.

Question 24

How does MHC TCR recognition normally work?

Answer 24

1. The peptide is tightly bound into the HLA peptide binding cleft and is stable.
2. The TCR binds to the a and/or ß chains of the antigen binding cleft.
3. The TCR needs to bind tightly and precisely to be stable.
4. When you have these 2 stable interactions, you will have high affinity activation of T cells in negative selection and T cell activation.

Question 25

What are the 2 risk associated MHC mechanisms with autoimmune disease?

Answer 25

1. Altered HLA/peptide/TCR binding orientation.
2. Low affinity peptide binding

Question 26

What happens when the HLA-peptide-TCR binding orientation is altered?

Answer 26

1. A change in amino acid sequence in the antigen binding cleft.
2. Changed orientation of binding so reduced stability of the binding.
3. This reduces the affinity of the TCR for the peptide-HLA complex.
4. The T cells escape negative selection and can cause an autoimmune response.

Question 27

What happens when the HLA-peptide binding affinity is lowered?

Answer 27

1. A change in amino acid sequence in the antigen binding cleft anchor residues.
2. The peptide does not bind in the peptide binding cleft correctly and stably.
3. Unstable HLA-peptide binding causing unstable TCR binding.
4. This causes low affinity T cell activation in negative selection and the T cells escape.
5. Autorective T cells enter circulating causing autoimmunity.

Question 28

How does presenting peptides in another binding register have a protective effect in autoimmunity?

Answer 28

1. A change in amino acid sequence in the antigen binding cleft.
2. The peptide binds differently like being flipped or inverted.
3. This means different parts of the peptide is bound or presented.
4. This increases the T cell repertoire.
5. This causes the deletion of auto reactive T cells and induction of more T regs.
6. This protects against autoimmunity.

Question 29

What is ankylosing spondylitis?

Answer 29

Chronic inflammatory arthritis of the axial skeleton. It can involve the fusion of the spinal vertebrae.

Question 30

What is the risk HLA allele for Ankylosing spondylitis?

Answer 30

HLA-B27 (MHC2)
A change in amino acid sequence leads to a changed binding orientation and thymic escape.

Question 31

How was the HLA risk allele for ankylosing spondylitis proved?

Answer 31

A HLA-B27 transgenic mouse developed spontaneous inflammatory disease.

Question 32

What is type 1 diabetes?

Answer 32

an autoimmune disease that results from the destruction of beta cells in the islets of Langerhans.

Question 33

What are the risk MHC alleles for type1 diabetes?

Answer 33

1. HLA-DQ2
2. HLA-DQ8
3. And some MHC1 alleles

Question 34

How do the MHC risk alleles increase the risk of diabetes?

Answer 34

1. A change of negative amino acid, aspartic acid, in position 57 to an uncharged amino acid.
2. This reduced the stability and affinity of MHC2 peptide binding causing weak T cell activation and thymic escape.

Question 35

How do different HLA risk alleles increase susceptibility to infections?

Answer 35

1. Don’t really know how
2. BUT something that impairs the stability of HLA-peptide-TCR binding leading to the decreased activation of T cells.
3. This impairs the elimination of pathogens and increases the severity of disease.

Question 36

How do different HLA protective alleles decrease susceptibility to infections?

Answer 36

1. Don’t really know how
2. BUT something that enhances the stability of HLA-peptide-TCR binding.
3. This inceases the recognition of antigens and T cell activation.
4. This leads to pathogen elimination and quicker recovery.

Question 37

How is HLA associated with malaria?

Answer 37

1. HLA-A30 has a change in the amino acid in position 77 leading to unstable peptide binding.
2. Decreased activation of T cells and elimination of malaria.