Core Concepts- L13-MHC and HLA genes(MHC genetics)

discuss the MHC I structure vs MHC II

• alpha chain- alpha1/2/3 domains

• beta 2 microglibulin- non covalently associated

• peptide binding groove formed by alpha 1/ 2 and sits on beta sheet floor and flanked by alpha helices

• a3 domain interacts with CD8

• 1 alpha chain alpha 1 and alpha 2

• 1 beta chain beta 1 and beta 2

discuss MHC- what it stands for, what gene is it on etc

region of genome encoding MHC proteins and other AP machinery

• major histocompatibility complex

• 200 genes for humans- on chromosome 6

• chromosome 17 on mice

• includes genes for MHC I/II, TAP, tapasin

why are mice not great to study for MHC studies- advantages vs disadvantages

• as scientific mice are inbred- not genetically diverse and so have genetically identical clonsed

• advantages- easy to study effects of knockouts or knocking of genes

• disadvantages- lack of diversity, poor model for human diversity.

types of HLA genes- discuss how many etc

1. class I- HLA A/B/C- present endogenous peptides from proteins to CD8- make 2 of each(6)

2. class II- HLA DR, DQ, DP-present to CD4

3. Class III- genes for complement proteins, TNF, stress antigens like MICA

2 copies of each gene one from each parent

talk about the class II HLA genes

• HLA DR, DQ, DP

• presents exogenous peptides to CD4

• DP- 1 alpha and 1 beta gene- combine to make heterodimer

• DQ- 1 alpha and 1 beta gene- heterodimer

• DR- 1 alpha and 1 beta gene normally but has extra beta gene- alpha can bind to either beta chain- 2 different DR can be made per chromosome and more diversity

everyone makes 6-8 class II chains at cell surface based on DP, DQ, DR. 6-8 class II and 6 class I- make 12-14 MHC molecules per cell

discuss conserved vs polymorphic genes in relation to HLA/MHC

1 conserved- little variation and encode critical proteins where a mutation would be harmful. ie genes for DNA replication

2. polymorphic genes- eye colour, HLA etc- very polymorphic and have many alleles at each locus like HLA-A/B/C. makes diverse peptide binding capabilities so better immune defense

describe difference between haplotype vs genotype

genotype- full set of alleles an individual carries at a locus from both parents ie HLA A, alpha and beta.

haploytpe- set of alleles on a single chromosome that are inherited together as a unit. ie a gene A8-B7-C2- you inherit these as a UNIT

how can MHC cause graft rejection?

• as MHC molecules are polymorphic, each person expresses different combinations. this is why even related donors cant donate as they don’t match perfectly

• parents segratete chromosome 6 randomly- high variability so host T cell may recognise donor MHC as foreign

where does MHC diversity come from? why are they polymorphic

1. point mutations- single nucleotide change in the MHC gene and change one amino acid- can alter peptide binding specificity

2. gene conervsion- misalignment of chromosomes during meiosis. piece of DNA from one gene is copies into another gene and the original gene stays the same mostly but other one gets new DNA. new combo of DNA makes different MHC

3. recombination

discuss class I HLA gene organisation and HLA II

• HLA A/B/C - polymorphic- have 2 alleles of each- 6 proteins

• HLA DP: 1 alpha, 1 beta

• HLA DQ: 1 alpha 1 beta

• HLA DR: 1 alpha 2 beta- alpha binds to either- make 6-8 proteins

all together- 12-14 MHC molecules

how do MHC alleles influence disease susceptibility or advantages?

• if you have a mutation that’s advantegeous- will increase- ie gene that helps fight malaria. in west Africa HLA B-B53 allele

• negative- autoimmune disease- triggered by antigens- HLA association as it presents this. HLA DR4 in rheumatoid arthritis