6. MHC Flashcards
How do B and T cells differ in their recognition of antigen?
B cells recognise native proteins
T cells recognise degraded proteins bound by major histocompatibility complex (MHC) molecules
What is the major histocompatibility complex (MHC)?
Cluster of genes on the short arm of human chromosome 6
- encoding a set of polymorphic membrane glycoproteins called MHC molecules
- function = presentation of short peptide antigens on T cells
What are class I MHC molecules?
Present peptide antigens derived from pathogens that replicate inside the cell (viruses and some bacteria)
What are class II MHC molecules?
Present peptides from pathogens and antigens that are present outside the cell and taken up by endocytic vesicles of phagocytic cells
How are the different classes of MHC molecules expressed on cells?
MHC class I = nucleated cells MHC class II = antigen presenting cells (dendritic cells, macrophages and B-cells)
What is the structure of a MHC class I molecule?
Made up of a heavy chain, non covalently linked to 𝛃2 microglobulin (𝛃2m)
- heavy chain has three domains (𝛂1,𝛂2,𝛂3)
Peptide binding site formed by the folding of 𝛂1 + 𝛂2
Peptide binding groove is supported by the Ig-like 𝛂3 domain and 𝛃2m
- gene encoding 𝛃2m located outside the MHC
What is the structure of a MHC class II molecule?
Consists of two non-identical transmembrane chains (𝛂&𝛃) - each chain contributes one domain to peptide binding site and one Ig - like supporting domain
- both molecules have a similar 3D structure
- two domains farthest from the membrane form the peptide binding site - 𝛂2 and 𝛃2 are both Ig - like domains
How do the MHC molecules bind to peptide-peptide binding groove?
Peptide binding site can bind many different peptides Vast majority of peptides that bind MHC class I molecules are 8,9,10 amino acids long vast majority of peptides that bind MHC class II molecules are 13-25 amino acids long
What are genetic properties of MHC?
Polygenic so contains several different MHC class I and class II genes, every individual possesses a set of MHC molecules with different ranges of peptide binding specificities - Human; HLA (human leukocyte antigen) 3 MHC class I genes (alleles) A,B,C 3 MHC class II genes (alleles) DR,DQ,DP Dog: DLA (dog leukocyte antigen) - MHC class I genes - MHC class II genes
What is polymorphism?
Multiple variants of each gene within a population
Describe the variability of MHC class I
Most variability in amino acids at different positions along the 𝛂 chain of MHC class I molecules occurs in the 𝛂1 + 𝛂2 regions Greatest polymorphism found in the amino acids that line the wall and floor of the groove that binds peptides Variability in these residues together with the number of different MHC provides the ability to bind to a different range of antigens that the body will encounter
Describe the variability of MHC class II
Greatest polymorphism for MHC class II is found for those amino acids in the 𝛃2 regions that line the wall and floor of the groove that binds the peptide
How are MHC molecules expressed?
Co-dominantly (polygenic)
Why do we need MHC polymorphism?
Polymorphism of the MHC has evolved to outflank the evasive strategies of the pathogens
In large outbred populations polymorphism at each locus can double the number of different MHC molecules expressed - enhances the number of peptides to be presented and the likelihood of responding to a pathogen
In any population, individuals will show different susceptabilities to any given pathogen, not all will become ill and the spread of the pathogen will be limited
What problems does a lack of MHC diversity lead too?
Infection - poor gene pool of MHC molecules can lead to increased susceptibility to immune disease
Immune mediated disease - certain MHC molecules are associated with a higher risk of allergy and autoimmunity
e.g. cheetahs - highly susceptible to viral infections - limited MHC polymorphism, could be due to bottleneck breeding in recent past
