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Functional characterization of antigen repertoires in HLA-associated complex diseases to investigate antagonistic selection on HLA genes

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Arora,  Jatin
IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society;
Emmy Noether Research Group Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Max Planck Society;

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Citation

Arora, J. (2018). Functional characterization of antigen repertoires in HLA-associated complex diseases to investigate antagonistic selection on HLA genes. PhD Thesis, Max Planck Institute for Evolutionary Biology, Plön.


Cite as: https://hdl.handle.net/21.11116/0000-0003-B545-3
Abstract
The interaction between hosts and pathogens represents a major driver of their evolution,
and a core interest in the evolutionary biology. In vertebrate hosts, the classical genes of
Major Histocompatibility Complex (MHC) make a central component of their adaptive
immune system. The cell-surface molecules encoded by the MHC genes present peptide
fragments (derived from both self-antigens and pathogens) to T-cells, which upon
recognizing them as foreign, initiate a specific immune response. To explore the general
MHC evolution, I used humans as a study system where MHC is designated as Human
Leukocyte Antigen (HLA). Although a vast allelic diversity of HLA genes exists at the
population level, potentially maintained by pathogen-mediated balancing selection, only
a fraction of that is seen at the individual level in the form of a limited number of HLA
genes and their alleles. This setting has been proposed as an optimum between HLAconferred
resistance to pathogens and the risk of autoimmunity, which represent major
antagonistic selection forces on HLA genes. The fine-mapping of various HLA’s association
with different infectious and autoimmune diseases has suggested a major role of the
peptide-repertoire of HLA alleles in determining their specific effect on diseases.
However, the exact mechanisms that underlie HLA’s association with the diseases, and by
that modulate the antagonistic selection on HLA genes remain elusive.
In order to elucidate them, I started by investigating the functional basis of the previously
known protective effect of HLA heterozygosity at the HLA class-I genes on HIV-1
progression. I used a dataset of 6,311 HIV-1 infected individuals and predicted the HLAbound
peptides derived from HIV-1 proteome for each HLA allele represented in the
dataset. The individual-specific repertoire of HLA-bound peptides suggested that HLA
heterozygote advantage against HIV-1 could be mediated by both a broader array of HLAbound
peptides and a higher likelihood of carrying specific protective alleles in
heterozygotes compared to homozygotes. The comparison of the peptide-repertoire of
risk and protective alleles suggested that individual alleles could confer disease control
by binding either a large number of peptides or specific immunodominant peptides. The
separate analysis of the individual HLA genes indicated that different mechanism for the
heterozygote advantage might work at different genes, such as either T-cell or NK-cellmediated
immune attack on the virus, possibly resulting in different evolutionary
constraints on different HLA genes. Overall, the findings suggested that the pathogenmediated
selection might favor both HLA heterozygosity and individual alleles.
hypothesizing that not all HLA-bound peptides would be relevant for disease
control, we developed a new approach, named Peptidome-wide association study
(PepWAS), that can predict HLA-bound disease-associated epitopes from a given
peptidome. The PepWAS-predicted HIV-1-associated epitopes accounted for as much
variation (12%) in HIV-1 viral load as by the genetic variants in HLA class-I genes,
providing a functional basis for the association between HLA and HIV-1 control.
I then focused on the association between HLA class-II genes and Type 1 Diabetes (T1D).
Using a case-control dataset of 16,029 individuals, I first showed that heterozygosity at
the HLA class-II genes conferred T1D risk. To investigate functional basis of this HLA
heterozygote disadvantage, I predicted individual-specific repertoires of HLA-bound
peptides from 17 T1D-relevant human proteins. The comparison of individual-specific
peptide-repertoires between HLA heterozygous and homozygous individuals suggested
that both a broader array of HLA-bound self-peptides and higher odds of carrying risk
alleles might contribute to HLA heterozygote disadvantage. The characterization of the
allele-specific peptide-repertoire suggested that an allele might confer T1D risk due to its
low peptide-binding affinity possibly contributing to inefficient removal of autoreactive
T-cells in thymus and (or) by binding specific disease-causing peptides, e.g. posttranslationally
deamidated peptides. The PepWAS-predicted T1D-associated epitopes
accounted for even more deviance in T1D status than HLA class-II haplotypes (33.1 vs.
29.6%). Moreover, the sequence homology between predicted T1D-associated epitopes
and pathogenic peptides suggested pathogens as the potential trigger of autoimmunity.
Overall, the insights from this thesis shed light on different mechanisms that possibly
underlie the differential association of HLA genes with infectious and autoimmune
diseases, which, in turn, potentially shape the antagonistic selection on the classical HLA
genes.