Non-MHC Immune Response Genes in Complex Disease Flashcards
which interactions mediate suppression of T cell activity?
interaction between CTLA-4 molecule expressed on T cells and B7 on antigen presenting cells
Which molecular interactions mediate T cell activation?
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”
which CTLA4 gene polymorphism is associated with IDDM and Grave’s disease?
CT60 polymorphism
on what chromosome is the CTLA4 gene encoded?
chromosome 2q31-q33
what variant, encoded on the haplotype containing the CT60 allele, was originally thought to have significant association with IDDM and Grave’s disease?
an A+49G SNP encoded in an exon of the CTLA4 gene
why is the CT60 allele associated with Grave’s disease and IDDM?
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
what is Grave’s disease?
an autoimmune disease commonly associated with hyperthyroidism
is the association between the CT60 allele and IDDM/Grave’s disease very significant?
not really -
CT60 OR for GD is 1.59
CT60 relative risk in IDDM is 1.15
what disease has been found to be associated with IL-1 and helicobacter pylori?
gastric cancer
what connects gastric cancer, IL-1 and helicobacter pylori?
gastric cancer and helicobacter pylori are associated with hypochloridia (low stomach acid levels) and IL-1B is a potent inhibitor of gastric acid secretion
IL-1B gene polymorphisms are associated with a wide variety of diseases, especially… ?
cancer
which polymorphisms in the IL1B promoter are associated with which cancers?
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
which pro-inflammatory cytokine inhibits the expression of gastrin?
IL-1B
what is gastrin?
a peptide hormone that stimulates secretion of gastric acid by parietal cells in the stomach
what is the result of the IL1B-31C/T promoter polymorphism?
the T/C variation produces two different promotors with different transcriptional capacities capable of differential expression of the IL-1B protein
what is the IL1B-31C promotor variant associated with?
weaker ILB1 promotor activity, less IL-1B expression and less gastrin inhibition
how is gastrin inhibition by IL-1B thoughts to be brought about?
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
what is the IL1B-31T promotor variant associated with?
stronger ILB1 promotor activity, increased IL-1B expression and greater gastrin inhibition
(when compared to IL1B-31C)
what is the function of IL-23?
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
what diseases are associated with SNPs in the IL-23R gene on chromosome 1?
ankylosing spondylitis Crohn's disease psoriasis inflammatory bowel disease rheumatoid arthritis
what is the function of the ARTS1 protein?
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
which non-MHC genes are linked to ankylosing spondylitis?
the IL-1 gene cluster, the IL-23R and the three genes encoding the ARTS1 protein
what three pieces of evidence support the association between the IL-1 gene cluster and ankylosing spondylitis?
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
what two susceptibility genes for ankylosing spondylitis were identified with the WTCCC?
IL-23R and ARTS1
