L20 - HLA and disease Flashcards
(28 cards)
name the 3 MHC-1 genes
HLA-A HLA-B HLA-c
what are allotyopes in terms of HLA
some HLA genes have thousands of alleles/variants
= not all alleles produce functional proteins (null)
only a subset code for distinct functional protein varinats = allotypes
where are allelic variations concentrated
antigen binding cleft
= anchor residues in peptide bind to this
name the 3 qualities that allow HLA diversity to allow presentation of hundreds of thousands of peptides
Polygenic:
multiple different HLA genes = pick and choose
Polymorphic:
variations of the different genes
Co-dominant expression:
6 MHC-1 and 12 MHC-2 genes = 50% from maternal and 50% from paternal
= both are expressed equally
name 3 qualities/uses allowed by the HLA diversity
- broad range of antigens preseneted
- use as diagnostic tool in paternity testing –> compare childs HLA alleles to maternal/paternal
- problems with transplants –> rejection due to difference in MHc moleulces between donor + recipient
what type of proscess is antigen proscessing and presentation
continous proscess
= multiple molecules involved in pathways; proteases,chaperones and transporters
how long are peptides boun by MHC-1
8-10 amino acids
how long are amino acids presented by MHC-2
13-25 amino acids
= or longer
= peptide binding cleft is open and allows bound fragment to extend beyond cleft
bame 2 roles of MHC molecukes in primary lymph tissues
in thymus
= positive/negative selction for T cells
what is positive slection in the thymus for T-cels
proscess of selcting T cells that recognise self-MHC in cortex of thymus
= produces ‘MHC restricted’ T-cells –> only recognise and arre activated by antigens presented by MHC
describe positive slection for MHC-restricted T-cells in thymus
- Double-posititive T cells for CD4 and CD8 bind ‘weakly’ to self-peptides on MHC molecules
- MHC presented by cortical epithelial cells in thymyus –> depending which MHC type depends which T-cell it becomes
= MHC-1 –> CD8+
- succesfull weak binding to MHC = T cell recives survival signal
= esnures that T-cells later on can only bind to MHC-retsricted antigens but not at TOO HIGh of an affinity
what is negative slection of T-cells in thymus
proscess of eliminating self-reactive T-cells in meddula of thymus
= Ensures that T cells don’t react strongly to self-antigens –> preventing autoimmune disease
describe the method of negative selction in the thymus
- single positiove T-cells following positive slection migrate to medulla
- TCR is tested AGAIN by self-peptides being presented AGAIN by MHC molecules on mTEC and DC cells
= Medullary thymic epithelial cells and Dendritic cells
- if TCR binds too strongly, the T cell is considered dangerous — it might attack the body’s own tissues. ❌
= T cell receives a signal to undergo apoptosis
what type of affinity do the surving T cells in both positive and negative slection have to the self-peptides
weak binding
= too strong and it coould cause autoimmune
= too weak and insuffiecient T-cell activation
what do the different MHC classes do in infection
MHC-1:
intracellular –> viruses
= activate CD8+ T cells to lyse infected cells
MHC-2:
extracellula –> bacteria and fungi
= activate CD4+ T cells to producre cytokines and activate macrophages, B cells and CD8+ T-cells
are both MHC classes important in cancer
yes
= recognise and present neoantigens –> mutated self antigens
= either intracellular produced and put on 1 or extracellular taken in and presented on 2
what are risk and protective alleles
an allele which increases risk to develop autoimmune disease
protective decreases risk
= can be in HLA or non-HLA genes
= genes tha code for the antigen proscessingf and presentation on chromosome 6
describe a normal and stable peptide-HLA interaction
HLA has pcokets in antigen-binding cleft that bind to anchor residues
TCR binds to HLA/antigen complex and interacts with BOTH molcules seperately AND together
= high affinity T cell activation
how might a risk allele cause disease/problems
changes in amino acids in antigen-binding cleft pockets
= unstable HLA-peptide complex
= unstable/loose TCR binding
low-affinity T-cell activation
what is ankylosing spondylitis
inflammatory arthritis of axial skeleton
= fusion of the spinal vertebrae
what is the risk allele asociated with Ankylosing spondylitis
HLA-B27
= HLA-B is a gene for MHC-1 molecules
= relative risk of 87.4
whats the relative risk of the HLA-B27 allele
87.4
= there is a 87.4x increased rusk to a normal person to get Ankylosing spindylitis autoimmune disease
what happens in Ankylosing spondylitis
HLA-B27 isnt fully understood in its effects but scientists think it might:
= present self-peptides that mimic pathogen ones –> autoreactive CD8+ T cells attack joint tissues.
what does the HLA-DQ8 risk allele increase the chance of
Type 1 diabetes
