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What is HLA？
HLA stands for Human Leukocyte Antigen, and is the human equivalent of MHC (major histocompatibility complex)
What is MHC?
The major histocompatibility complex are immune genes that code for proteins involved in recognition of peptides, whether it be foreign (antigenic peptides) or non-foreign (self peptides)
There are 2 main classes of MHC:
- Class I: found in most cells, recognises intracellular peptides- e.g. antigens from viruses
- Class II: found in antigen presenting cells (e.g. macrophages, B cells, dendritic cells), recognises extracellular peptides eg from bacteria and fungi.
MHC class II (MHCII)
For MHC class II, extracellular antigens are engulfed and processed (broken down) by antigen presenting cells into smaller antigenic peptides. A certain MHC II protein (determined by the MHCII allele/gene) can recognise specific peptides, bind it, and then present it on the surface of the cell. This is often called the PMHC (peptide + MHC) complex, which will bind to the T cell receptor and trigger the adaptive immune response.
MHC genes are one of the most diverse (polymorphic) genes- what has driven this diversity?
There are numerous proposed mechanisms that work together or non-exclusively to drive MHC/HLA diversity, including:
- Heterozygote advantage (overdominant selection: individuals heterozygous at MHC/HLA respond to more antigens (due to co-dominant expression of 2 MHC/HLA genes) = higher fitness compared to homozygotes
- Negative frequency dependent selection (rare allele advantage): selection may drive pathogens to be resistant to common MHC alleles, while newly emerging alleles (rare alleles) offer new protection and thus are selected for. This cycle continues (protective allele becomes common over time and then pathogen becomes resistant, so new alleles can offer protection) = co-evolutionary race between host and pathogen
- Fluctuating selection: where MHC/HLA diversity is maintained by allelic selection across time and/or space in response to different levels and types of pathogens.
In my research, I am interested in further studying some of these mechanisms, focusing on overdominant selection and an adaptation of this called divergent allele advantage.
Divergent allele advantage (DAA)
Individuals with more diverse MHC alleles could respond to a larger range of antigens, leading to maintenance of highly divergent alleles in the population.
Many studies have provided support for the divergent allele advantage (DAA) model
In our study, we follow on from the previous computer-based prediction research by Lenz (2011),
Lenz (2011) used computer binding prediction programs (NetMHCIIpan and ProPred):
- The programs will predict whether a specific HLA allele will bind a input protein sequence
- Input sequences: several antigen proteins from human pathogens
- Compiled all possible pairs of HLA alleles (i.e. heterozygotes) and compared the sequence difference between the allele pair VS the number of peptides the allele pair can recognise
- Results: With increase sequence difference, there was increase in total number of peptides bound by the allele pair (UNION) and decrease in overlapping number of peptides bound by the allele pair (JOINT)
We explore whether there is a limit to the DAA model
i.e. sequence divergence between MHC alleles should reach a threshold, when 'over-divergence' would result in no increase in fitness.
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