Non-MHC Immune Response Genes in Complex Disease

Question 0

which interactions mediate suppression of T cell activity?

Answer 0

interaction between CTLA-4 molecule expressed on T cells and B7 on antigen presenting cells

Question 1

Which molecular interactions mediate T cell activation?

Answer 1

TCR and CD28 on CD4 T cells interacting with MHC-peptide complex and B7 on antigen presenting cells (primary and secondary activating signals)
i.e. “COSTIMULATION”

Question 2

which CTLA4 gene polymorphism is associated with IDDM and Grave’s disease?

Answer 2

CT60 polymorphism

Question 3

on what chromosome is the CTLA4 gene encoded?

Answer 3

chromosome 2q31-q33

Question 4

what variant, encoded on the haplotype containing the CT60 allele, was originally thought to have significant association with IDDM and Grave’s disease?

Answer 4

an A+49G SNP encoded in an exon of the CTLA4 gene

Question 5

why is the CT60 allele associated with Grave’s disease and IDDM?

Answer 5

the CT60 allele encodes and spliced variant/isoform of the CTLA4 protein and is therefore associated with lower levels of CTLA4 production and reduced T cell suppression

Question 6

what is Grave’s disease?

Answer 6

an autoimmune disease commonly associated with hyperthyroidism

Question 7

is the association between the CT60 allele and IDDM/Grave’s disease very significant?

Answer 7

not really -
CT60 OR for GD is 1.59
CT60 relative risk in IDDM is 1.15

Question 8

what disease has been found to be associated with IL-1 and helicobacter pylori?

Answer 8

gastric cancer

Question 9

what connects gastric cancer, IL-1 and helicobacter pylori?

Answer 9

gastric cancer and helicobacter pylori are associated with hypochloridia (low stomach acid levels) and IL-1B is a potent inhibitor of gastric acid secretion

Question 10

IL-1B gene polymorphisms are associated with a wide variety of diseases, especially… ?

Answer 10

cancer

Question 11

which polymorphisms in the IL1B promoter are associated with which cancers?

Answer 11

IL1B-511C/T and IL1B-31C/T are associated with lung cancer, prostate cancer and gastric cancer

IL1B-511T/T has been associated with a lower risk for chronic lymphocytic lymphoma and cervical cancer

Question 12

which pro-inflammatory cytokine inhibits the expression of gastrin?

Answer 12

IL-1B

Question 13

what is gastrin?

Answer 13

a peptide hormone that stimulates secretion of gastric acid by parietal cells in the stomach

Question 14

what is the result of the IL1B-31C/T promoter polymorphism?

Answer 14

the T/C variation produces two different promotors with different transcriptional capacities capable of differential expression of the IL-1B protein

Question 15

what is the IL1B-31C promotor variant associated with?

Answer 15

weaker ILB1 promotor activity, less IL-1B expression and less gastrin inhibition

Question 16

how is gastrin inhibition by IL-1B thoughts to be brought about?

Answer 16

in response to IL-1B stimulation, transcriptional repression of the gastrin gene is induced by NFkB through recruitment of a transcription repressor to the gastrin promotor

Question 17

what is the IL1B-31T promotor variant associated with?

Answer 17

stronger ILB1 promotor activity, increased IL-1B expression and greater gastrin inhibition
(when compared to IL1B-31C)

Question 18

what is the function of IL-23?

Answer 18

a potent pro-inflammatory cytokine that stimulates the generation of Th17 cells as well as the production of other cytokines -
TNF-a, IL-6, IL-17, IL-22

Question 19

what diseases are associated with SNPs in the IL-23R gene on chromosome 1?

Answer 19

ankylosing spondylitis
Crohn's disease
psoriasis
inflammatory bowel disease
rheumatoid arthritis

Question 20

what is the function of the ARTS1 protein?

Answer 20

aminopeptidase regulator of TNF receptor shedding 1 = aminopeptidase enzyme in the ER responsible for cleaving cytokine receptors (TNF-a, IL-6 and IL-1) and trimming of antigenic peptides before presentation on MHC I

Question 21

which non-MHC genes are linked to ankylosing spondylitis?

Answer 21

the IL-1 gene cluster, the IL-23R and the three genes encoding the ARTS1 protein

Question 22

what three pieces of evidence support the association between the IL-1 gene cluster and ankylosing spondylitis?

Answer 22

1 - ⬆️ VNTRs within intron 2 of IL-1RN gene of AS sufferes
2 - 2 SNPs in exon 6 of IL-1RN associated with AS
3 - 14 SNPs in IL1A and IL1B genes show significant association with AS

Question 23

what two susceptibility genes for ankylosing spondylitis were identified with the WTCCC?

Answer 23

IL-23R and ARTS1

Question 24

how many SNPs in the IL-23R gene show significant associTion with ankylosing spondylitis?

Answer 24

7

Question 25

how many SNPs within genes encoding for the ARTS1 protein showed significant association with ankylosing spondylitis in the WTCCC?

Answer 25

5

Question 26

what diseases are associated with IL-1?

Answer 26

ankylosing spondylitis
gastric cancer
prostate and lung cancer
chronic lymphocytic lymphoma and cervical cancer

Question 27

the ARTS1 genes are associated with increased susceptibility to IBD: true or false?

Answer 27

false - unlike the IL-23R gene,the ARTS1 genes are not associated with IBD