1. MHC
March 24, 2009
11:00-12:00

2. MHC CLASS I AND CLASS II ARE LINKED
MHC class I, II, and III are located in a cluster
The cluster is called HLA for human leukocyte antigen

3. MHC GENES ARE POLYGENIC
There are 3 “classical” class I genes: A,B,C
There are multiple class II genes
Class II genes are organized in clusters: DP, DQ, DR
In general, clusters have genes for both a and b chains

4. MHC GENES ARE POLYMORPHIC
There are multiple forms (alleles) of each class II chain in the population
There are multiple alleles for each class I gene
The combination of alleles on an individuals’ chromosome = haplotype

5. Figure 3-23 DEGREE OF POLYMORPHISM RELATES TO FUNCTION
Highly polymorphic molecules are responsible for presenting peptides

6. POLYGENIC VS POLYMORPHIC
Polygenic = multiple genes
Result: Each individual expresses multiple proteins
Polymorphic = multiple alleles or forms within a population
Result: Different individuals express different
sets of HLA proteins

7. EXPRESSION OF MHC ALLELES IS CODOMINANT
Every individual expresses the haplotypes of both parents:
6 Class I proteins (A,B, and C from each parent)
8 or more Class II proteins

8. MHC EXPRESSION C6 C3
C10 C9 7 C6
C10
C10 C6
C10 C3 C9 1 C9 C3 C3

9. POLYGENY AND POLYMORPHISM CREATE DIVERSITY
Extensive polymorphism means that homozygotes
are rare
Polygeny overcomes the limits imposed by
the ability to express only two alleles
The combination of polymorphism and polygeny
leads to a high degree of diversity

10. MECHANISMS RESPONSIBLE FOR POLYMORPHISM
Point mutations
Acquisition of a region of another allele
for the same gene
Acquisition of a region of
another gene

11. MHC DIVERSITY AFFECTS PEPTIDE BINDING
Peptides only contact MHC at anchor residues
Each type of MHC interacts with a distinct set of peptides with
the correct anchor residues

12. ALLELIC VARIATION IS LIMITED TO SPECIFIC SITES
Allelic variation occurs in regions that contact peptide or TCR

13. THE IMPACT OF MHC EXPRESSION ON DIVERSITY OF PEPTIDES PRESENTED1 C9 C3 C3
Each child has 6 class I proteins
The class I of each child can bind 6 different types of peptide restricted
by anchor residues

14. ADVANTAGES OF DIVERSITY
Individuals
Co-dominance and heterozygosity mean that the vast
majority of people can present two sets of peptides
Populations
“Survival of the fittest”-- individuals whose MHC bind
immunogenic peptides will survive an infection. Their
alleles will be passed on and occur in higher frequency
in a population

15. DISADVANTAGE OF DIVERSITY: ALLOREACTIVITY
1-10% of T cells recognize differences in structure of MHC
Responses against proteins from a different allele are called alloreactivity
Mothers make alloantibodies against the fetus
The basis for alloreactivity is not clear
Possible explanations
for alloreactivity

16. MHC COMPLEX CONTAINS OTHER PROTEINS INVOLVED IN IMMUNITY
TAP, tapasin, and DM in class II region are involved in antigen processing
Cytokines TNFa, lymphotoxin a and b are in class III region
Several complement components are in the class III region

17. OTHER PROTEINS IN MHC COMPLEX
MICA and MICB:
Limited expression--fibroblasts and epithelium in intestine
Increase in response to stress
Lots of speculation about their role..could be important in
inflammatory conditions,cancer
Nonclassical Class I:
HLA-E,F,G. Limited polymorphism and cell type expression.
HLA-E may be involved in modulating NK cell activity

18. Sergei and Natasha recently emigrated to the US and were unable to obtain their
medical records before leaving. Two of their 5 children suffer from chronic viral
infections. The parents were informed that the children have a genetic defect
that causes them to be unable to make a response toviral infections. They don’t
know the nature of the defect, but they know it is genetic and recessive.
(cf family tree Sergei and Natasha)
The inability to respond to viruses suggests a defect in which cell population?
How would you prove your theory.
MHC expression is required for both development and activation of CD4
and CD8 cells. If you HLA typed the affected children, which HLA alleles
(A,B,C,D) would you expect to be absent on their cells?
3. What are some potential causes for the inability express MHC class I?