Known allelic frequencies for MHC Class I vs II?
Theory of how polymorphisms are driven for MHC?
MHC locus details
- The MHC locus contains multiple genes with _____ functions.
- Size: ~4 to 6 million base pairs (~200 genes in human MHC).
- Human MHC located on chromosome ___.
- Mouse MHC located on chromosome ___.
Genes found at the MHC locus include?
Genes found in the MHC include
- Classical MHC class I and II genes
- Non-classical MHC class I and II genes
- TAP1 and TAP2
- Tapasin
- LMP2 and LMP7 (proteasome components)
- TNF-a and -b
- Complement genes (C2, C4B)
Similarly conserved between human and mouse except A gene.
What’s important about the MHC locus?
The important genes tend to be clustered together and regulated together as well.
On diagram, Black and white = pseudogenes
There’s no such thing as “MHC class III molecules”
What is MHC restriction?
Cytotoxic T lymphocytes (CD8+):
–Virus-specific CTLs can kill cells - but only when the target cells also express the appropriate MHC molecule.
–For recognition, cells must express the restricting MHC class I molecule (ie. HLA-A*0201) bound to the specific viral peptide.
–Uninfected cells are not killed.
T-cell is seeing the combined MHC and peptide. NOT just the peptide molecule. This is the concept of MHC restriction.
How do you get a personalized immune response based on the MHC/HLA that you have?
Because you have different MHC molecules, they can all present peptides but may not be the same peptide.
Each have distinct peptide binding preferences…
Personalized immune response based on what MHC/HLA you have.
Discuss the different immunogencity of antigens
Why are transplants rejected?
- T cells undergo positive and negative selection in the thymus prior to entering the circulation (defines ‘self’):
- T cells that cannot recognize ‘self’ MHC are deleted in the thymus (useless for immunity).
- T cells that can moderately recognize ‘self’ MHC/peptide complexes are positively selected and can enter the blood.
- T cells that strongly recognize self MHC/peptide complexes are deleted (potentially self-reactive).
- As a result of these processes, individuals contain a high proportion of T cells (2 to 10%) that are capable of recognizing foreign MHC molecules, and thus can mediate rejection of grafts.
- T cells that moderately recognize self MHC would undergo positive selection, but these same T cells could then strongly recognize foreign MHC.
- Donors and recipients need to be matched at 5 or 6 out of six major loci for transplant success (HLA-A, -B, and -DR).
Some MHC alleles or haplotypes are associated with human disease. Give two examples.
- HLA-B27 is associated with the autoimmune disease ankylosing spondylitis.
- Certain HLA alleles are associated with HIV protection and/or susceptibility to developing AIDS:
How are MHC genes are co-ordinately co-regulated?
- MHC class I and class I-associated genes (TAP, tapasin, LMPs) are expressed constitutively, but all can be upregulated together by interferons (a, b, or g) and/or TNF.
- MHC class II and class II-associated genes (HLA-DM, invariant chain) are normally silent, but their expression can be upregulated by IFN-g, which then induces the synthesis of the class II transcription activator (CIITA).
MHC-encoded molecules and functions (diagram)
Non-MHC-encoded molecules and functions (diagram)
Recylcing of MHC molecules diagram
Discovery of MHC in mouse
Congenic mouse = everything is identical in genome except 1 locus.
The diagram = is strategy for creating a congenic mouse
To know that the gene mutation of interest is carried through generations = selection skin marker (e.g. skin graft rejection)
