HTHSCI 1DT3 Lecture Notes - Lecture 21: Immunoglobulin A, Liver Transplantation, Transforming Growth Factor Beta
23 Jun 2018
School
Department
Course
Professor
HLA
HLA haplotypes are groups of HLA genes inherited together
This is the proven mode of HLA inheritance, because of strong linkage disequilibrium i.e. certain
HLA genes being inherited together in excess of statistical expectation
It is thought the high degree of polymorphism is maintained by allelic diversity conferring
survival advantages by allowing response to wide degree of mutating pathogens
HLA DQA1*0501 / DQB1*0201 = HLA DQ2.5 can be inherited in cis or trans form
10% of coeliacs are HLA DQ8
HLA DQ2.5 homozygotes have five times the risk of developing CD that heterozygotes do; this is
because they will bind more peptides hence have increased chance of reaching the threshold for
T cell activation
the bond formed with gliadin is stable because of a tyrosine at position 22, which forms a
hydrogen bond with the gliadin peptide in the MHC pocket
Account for approximately 35% of Coeliac disease susceptibility
GWAS show 39 different non-HLA genes which confer small risks, generally giving an odds ratio
of 0.5; these collectively comprise a further 14% of Coeliac
Many of these are related to other disease e.g. T1DM, Graves’s disease and RA
They are typically involved with:
1) Dendritic cell activation
2) T cell stimulation
3) Gluten-specific Th1 cell function
4) Recruitment of B cells and Ab production
5) Cross-talk between CD8 cells and GI epithelial cells
Immunology of Coeliac disease
HLA DQ2.5 and DQ8 bind readily to modified gluten peptide; DQ8 can also bind native gluten
peptides
The more HLAs expressed by APCs the stronger the T cell response is: gene-dose effect
HLA DQ2.5 is stable, lasting 4 days; this allows time for APCs to bind the expressed peptide in
the mucosa and migrate to mesenteric LN and stimulate T cells
HLA-DQ2.5 and HLA-DQ8 binding to cognate TCR encourages the recruitment of cross-reactive T
cell immune responses to gluten polypeptides
There are at least 15 different gluten T cell epitopes that bind TCRs in the context of HLADQ2.5 /
DQ8
One T cell epitope is 33 amino acid polypeptide at position 55-78 within alpha-2-gliadin (33mer
immuno-dominant peptide)
This contains at least 6 HLA-DQ2 binding and T cell stimulatory epitopes, that are resistant to
intestinal proteases
Infusion of the p55-78 gliadin peptide into the duodenal mucosa of patients with stable CD
provokes an inflammatory response that is similar to that seen in untreated patients with CD
DC-derived cytokines like IFN-gamma and IL-15 stimulate Th1 cell differentiation antigen-
specific CD4 T cell generation
- IFN-gamma also activates CD8+ IELs and induces DC maturation
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Hla haplotypes are groups of hla genes inherited together. This is the proven mode of hla inheritance, because of strong linkage disequilibrium i. e. certain. Hla genes being inherited together in excess of statistical expectation. It is thought the high degree of polymorphism is maintained by allelic diversity conferring survival advantages by allowing response to wide degree of mutating pathogens. Hla dqa1*0501 / dqb1*0201 = hla dq2. 5 can be inherited in cis or trans form. Hla dq2. 5 homozygotes have five times the risk of developing cd that heterozygotes do; this is because they will bind more peptides hence have increased chance of reaching the threshold for. T cell activation the bond formed with gliadin is stable because of a tyrosine at position 22, which forms a hydrogen bond with the gliadin peptide in the mhc pocket. Account for approximately 35% of coeliac disease susceptibility.
