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

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

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

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

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

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

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

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

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

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

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

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

THE IMPACT OF MHC EXPRESSION ON DIVERSITY OF PEPTIDES PRESENTED 1 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

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

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

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

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

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?