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Genetics of Complex Disease > MHC in Complex Disease > Flashcards

MHC in Complex Disease Flashcards

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0
Q

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

A

HLA-A, HLA-B and HLA-C

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1
Q

What classes is the MHC made up of?

A 
HLA class I
HLA class II
MHC class III
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2
Q

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

A

the major histocompatibility I molecule

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3
Q

what is the MHC I molecule made up of?

A

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)

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4
Q

Which cells express MHC I?

A

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

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5
Q

which cells does MHC I present antigen to?

A

CD8 T cells (to kill virally infected cells)

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6
Q

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

A

endogenous peptides of 8-9 amino acids

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7
Q

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

A

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

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8
Q

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

A

the MHC II molecule

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9
Q

what is the MHC II molecule made up of?

A

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

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10
Q

which cells express MHC II?

A

antigen presenting cells (dendritic cells and macrophages)

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11
Q

which cells do MHC II molecules present peptide to?

A

CD4 T cells

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12
Q

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

A

exogenous peptides of 13-21 amino acids

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13
Q

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

A

encodes several genes key to the immune response

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14
Q

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

A

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

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15
Q

on what chromosome is the MHC region encoded?

A

chromosome 6p21.3

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16
Q

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

A

true

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17
Q

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

A

because the MHC region encodes genes key to the immune system

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18
Q

what are four key features of the MHC region?

A

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

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19
Q

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

A

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

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20
Q

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

A

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

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21
Q

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

A

true

22
Q

what is Bare Lymphocyte Syndrome (I/II)?

A

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

23
Q

what is the major risk allele in ankylosing spondylitis?

A

the HLA-B27 allele

24
Q

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

A

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

25
Q

what is ankylosing spondylitis?

A

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

26
Q

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

A

✅ 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

27
Q

which allele has been found to be protective in IDDM?

A

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

28
Q

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

A

ankylosing spondylitis

29
Q

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

A

IDDM

30
Q

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

A

systemic lupus erythematosus

31
Q

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

A

OR = 171

32
Q

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

A

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

33
Q

what allele variants increase susceptibility to IDDM?

A

DQ8 and DQ2 alleles

34
Q

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

A

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

35
Q

why is the DQ6 allele variant protective against IDDM?

A

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

36
Q

what is systemic lupus erythematosus?

A

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

37
Q

what allele variants are associated with increased susceptibility to SLE?

A

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

38
Q

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

A

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

39
Q

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

A

DQ2 and DQ8

40
Q

what are autoantibodies generated against in SLE?

A

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

41
Q

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

A

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

42
Q

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

A

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

43
Q

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

A

DR4-DQB1*0302

44
Q

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

A

DR3-DQB1*0201

45
Q

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

A

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

46
Q

what non -MHC susceptibility alleles are associated with IDDM?

A

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

47
Q

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

A

⬇️ VNTRs (“short alleles”) = susceptibility

⬆️ VNTRs (“long alleles”) = protection

48
Q

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

A

-23HphI

49
Q

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

A

true

50
Q

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?

A

false - it was found to have the 2nd highest

51
Q

how is the PTPN22 gene associated with susceptibility to IDDM?

A

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

52
Q

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

A

81% IDDM sufferers and 23% healthy population

Genetics of Complex Disease (6 decks)

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