MHC in Complex Disease

Question 0

Which genes found on HLA-I are associated with complex disease?

Answer 0

HLA-A, HLA-B and HLA-C

Question 1

What classes is the MHC made up of?

Answer 1

HLA class I
HLA class II
MHC class III

Question 2

What do HLA-A, B and C genes encode?

Answer 2

the major histocompatibility I molecule

Question 3

what is the MHC I molecule made up of?

Answer 3

an alpha chain made up of 3 immunoglobulin domains (encoded by HLA-I region on chromosome 6p21.3) and a B2-microglobulin (encoded on chromosome 15)

Question 4

Which cells express MHC I?

Answer 4

all nucleated cells (i.e. all cells except erythrocytes)

Question 5

which cells does MHC I present antigen to?

Answer 5

CD8 T cells (to kill virally infected cells)

Question 6

what are the features of the peptides presented by MHC I?

Answer 6

endogenous peptides of 8-9 amino acids

Question 7

what genes are present in the HLA-II region of the MHC?

Answer 7

HLA-DR(A/B), DB(A/B) and DQ(A/B)

Question 8

What do the HLA-II genes on the MHC encode?

Answer 8

the MHC II molecule

Question 9

what is the MHC II molecule made up of?

Answer 9

an alpha and a beta chain heterodimer, each made up on two immunoglobulin domains

Question 10

which cells express MHC II?

Answer 10

antigen presenting cells (dendritic cells and macrophages)

Question 11

which cells do MHC II molecules present peptide to?

Answer 11

CD4 T cells

Question 12

what are the features of the peptides presented by MHC II?

Answer 12

exogenous peptides of 13-21 amino acids

Question 13

why are so many diseases associated with the MHC region on chromosome 6p21.3?

Answer 13

encodes several genes key to the immune response

Question 14

why are so many diseases associated with the HLA-I/II regions on chromosome 6p21.3?

Answer 14

majority of HLA variations are functional and result in alterations to the peptide binding groove - i.e. alter the MHC molecule’s preference for peptide binding

Question 15

on what chromosome is the MHC region encoded?

Answer 15

chromosome 6p21.3

Question 16

the MHC is associated with more diseases than any other region of the genome: true or false?

Answer 16

true

Question 17

why is the MHC region especially associated with autoimmune and infectious diseases?

Answer 17

because the MHC region encodes genes key to the immune system

Question 18

what are four key features of the MHC region?

Answer 18

1 - high gene density
2 - high polymorphism
3 - clustering of genes with related functions
4 - highest degree of linkage disequilibrium

Question 19

Where does most positively selected for polymorphism occur in the MHC region?

Answer 19

in genes encoding the peptide binding groove of MHC I/II molecules

Question 20

polymorphically, how do genes of the MHC region differ from all other genes?

Answer 20

most genes have a small number of variants (2-3 major alleles) whereas MHC genes are very polymorphic
e.g. HLA-B has >2000 alleles

Question 21

most disease-associated variation within the MHC region is due to subtle effects of common alleles: true or false?

Answer 21

true

Question 22

what is Bare Lymphocyte Syndrome (I/II)?

Answer 22

a severe immunodeficiency disorder resulting from mutations in the MHC region resulting in no function MHC I/II molecules

Question 23

what is the major risk allele in ankylosing spondylitis?

Answer 23

the HLA-B27 allele

Question 24

how many subtypes of the HLA-B27 allele have been reported and how many are thought to be associated with ankylosing spondylitis?

Answer 24

130 HLA-B27 alleles have been reported, 11 of which are thought to occur with AS

Question 25

what is ankylosing spondylitis?

Answer 25

a form of chronic inflammatory arthritis mainly affecting the spine and the sacroiliac joints

Question 26

what are three examples providing evidence that most disease-associated variation within the MHC region is due to subtle effects of common alleles?

Answer 26

✅ ankylosing spondylitis - B27 allele in >95% sufferers and 9% healthy ✅ narcolepsy - DQ6 allele in >95% sufferers and 33% healthy ✅ IDDM - DQ8/DQ2 alleles in 81% sufferers and 23% healthy

Question 27

which allele has been found to be protective in IDDM?

Answer 27

the DQ6 allelic variant - it is found in <0.1% of IDDM sufferers and 33% of healthy controls

Question 28

give an example of a complex autoimmune disease associated with HLA-I genes

Answer 28

ankylosing spondylitis

Question 29

give an example of a complex autoimmune disease associated with HLA-II genes

Answer 29

IDDM

Question 30

give an example of a complex autoimmune disease associated with MHC-III genes

Answer 30

systemic lupus erythematosus

Question 31

what is the odds ratio of the association between the HLA-B27 allele and ankylosing spondylitis, as reported by Brown et al. (1996)?

Answer 31

OR = 171

Question 32

what is one theory explaining the HLA-B27 allele variant association with ankylosing spondylitis?

Answer 32

the molecular mimicry hypothesis - the MHC I molecule is able to present both foreign peptide and self peptide, leading to inflammation

Question 33

what allele variants increase susceptibility to IDDM?

Answer 33

DQ8 and DQ2 alleles

Question 34

why do the DQ8 and DQ2 allele variants produce increased susceptibility to IDDM?

Answer 34

both alleles produce an alanine in position 57 of the DQ beta chain = within pocket P9 of the PBG Asp ➡️ Ala switch = absence of a salt bridge within the peptide binding groove

Question 35

why is the DQ6 allele variant protective against IDDM?

Answer 35

it produces an aspartic acid variant at position 57 of the DQ beta chain, which interacts with argenine in position 79 to produce a salt bridge in the 9th binding pocket of the PGB

Question 36

what is systemic lupus erythematosus?

Answer 36

a systemic autoimmune disease characterised by non-clearance of immune complexes and affecting the brain, lungs, heart, blood vessels, liver and kidneys

Question 37

what allele variants are associated with increased susceptibility to SLE?

Answer 37

allele variants in any of the early components of the classical activation pathway of the complement system: C1q, C1r, C1s and C4

Question 38

Why is the C4A*Q0 allele variant associated with systemic lupus erythematosus?

Answer 38

the C4A*Q0 allele variant is a null allele associated with ⬇️ C4a levels and therefore decreased immunoclearance in the body

Question 39

what HLA genotypes have been found to increase susceptibility to coeliac disease?

Answer 39

DQ2 and DQ8

Question 40

what are autoantibodies generated against in SLE?

Answer 40

self nuclear and cytoplasmic antigens, producing immunological attack to body organs

Question 41

with relation to disease, what is the different between complement components C4a and C4b?

Answer 41

C4a proteins are more important in immunoclearance and and C4b proteins are more important in the defence against microbes

Question 42

broadly speaking which 3 categories of genes associated with SLE have been identified by candidate genes studies and GWAS?

Answer 42

1) immune complex recognition and clearance genes - e.g. complement components and FcY receptors 2) recognition of foreign microbial antigens - e.g. toll-like receptors and downstream signalling components - e.g. TRAF6 and IRFs 3) interferon signalling

Question 43

what is the DQ8 susceptibility allele for IDDM made up of?

Answer 43

DR4-DQB1*0302

Question 44

what is the DQ2 susceptibility allele for IDDM made up of?

Answer 44

DR3-DQB1*0201

Question 45

what non-MHC susceptibility alleles for TIID were identified with the WTCCC?

Answer 45

KCNJ11 E23K variant, PPARG Pro12Ala variant and SNPs in the TCF7L2 gene

Question 46

what non -MHC susceptibility alleles are associated with IDDM?

Answer 46

variations in the insulin promotor and a mutation in the PTPN22 gene

Question 47

how are VNTRs in the insulin gene promotor associated with IDDM?

Answer 47

⬇️ VNTRs ("short alleles") = susceptibility | ⬆️ VNTRs ("long alleles") = protection

Question 48

what insulin gene promotor SNP is associated with susceptibility to IDDM?

Answer 48

-23HphI

Question 49

after HLA-associated genes, variations in the insulin gene are the strongest associations with IDDM susceptibility: true or false?

Answer 49

true

Question 50

the -23HphI SNP within the insulin gene promotor was found to have the highest OR (2.38) for IDDM in the T1DGC GWAS: true or false?

Answer 50

false - it was found to have the 2nd highest

Question 51

how is the PTPN22 gene associated with susceptibility to IDDM?

Answer 51

a gain of function mutation within the PTPN22 gene (involved in immune system down regulation) increases susceptibility to IDDM

Question 52

the DR8/DRQ susceptibility alleles are found in ___% IDDM sufferers and ___% healthy population

Answer 52

81% IDDM sufferers and 23% healthy population