MHC genes
MHCI: B, C, A
MHCII: DP, DQ, DR
MHCIII: code for complement proteins
*Mice have only 2 MHCII and their MHCI loci are separated
MHC molecule structure
Class I: One alpha protein (3 subdomains) + stabilizing protein Beta-2-microgobulin, smaller binding groover can only fit smaller peptides 8-10 amino acids, anchor residues, bulge
Class II: one alpha and one beta protein with 2 subdomains each (both trans
Syngenic and congenic
Syngeneic - identical at all loci
Congenic - identical at all but one locus
MHC haplotypes
MHC alleles are codominant (every cell expresses ALL MHC alleles)
Mouse transplant experiment: The donor cannot give a foreign allele to the recipient
MHC diversity
Humans/mice have 3 MHCI loci and 2 alleles so there are 6 possibilities
Mice have 2 MHCII loci and humans have 3, and because 2 proteins there are 4 alleles so 8 possibilities for mice, 12 for humans
TONS of polymorphisms in the population, most of these
Expression of MHC
Some non "professional APCs" will present on MHC class II in certain conditions, called non-professional APCs
Some tumor and virally infected cells will have lowered expression of MHC
Relative risk of disease
Relative risk of a disease = Frequency of allele in disease group / frequency of allele in control group
MHC self-restriction (gp experiment)
Guinea pig Experiment:
1. Strain 2 and 13 of guinea pigs were grown and macrophages were isolated
2. Macrophages were pulsed with antigen ovalbumin so that they display it
3. Macrophages are injected into different strain 2 and 13 guine pigs
4. Lymph node
MHC self-restriction (mouse)
1. Spleen/T-cells were removed from a K-haplotype mouse
2. These cells were incubated 1. Normally, 2. With virus infected cells, k-haplotype 3. With virus infected cells, b-haplotype. Lysis detected by Chromium-51
Only if the haplotype matched was there l
Antigen processing
Experiment
1. APCs with MHC were fixed, didn't present full antigen, didn't activate T-cell
2. APCs were given antigen, then fixed, presented antigen, activated T-cell
3. APCs were fixed, given processed peptide, presented antigen, activated T-cell
Antige
Antigen processing Process
Proteins are ubiquitinated and broken down by proteasomes (specifically designed to cut to anchor residues)
Immunoproteosome - chops up proteins into peptides that can fit on MHC
Peptides are then loaded into the ER by TAP, then loaded into MHC class I
Endogenous Pathway
1. Chaperones aid in the folding and assembling of alpha and beta-2 microglobulin, localizing to be near TAP as peptides enter the ER
2. It's assembled and peptide is added within the RER lumen, it is then transported out through a vesicle to the golgi, t
Endocytic pathway
1. MHC is assembled and leaves ER bound to an invariant chain which blocks peptides from binding
2. As MHC travels toward the cell membrane, an antigen-receptor complex enters the cell via phagocytosis, an acidic endosome forms which breaks down the pepti
Cross presentation
Dendritic cell presents exogenous antigen (which could be intracellular from other peptides) on class II, if it needs to be presented on class I as well it processes it so that it can be. This allows for both Th cells and Tc cells to be activated at once
Non-peptide antigen
CD1 - very similar in structure to MHC class I, but with deeper binding pocket to allow for the presentation of longer lipids
More limited in terms of polymorphisms than MHC