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

Arora, Jatin ORCID

The cell-surface molecules encoded by the genes of Human Leukocyte Antigen (HLA) present peptides to T-cells, which upon recognizing them as foreign, initiate a specific immune response. HLA genes have been associated with a variety of infectious and autoimmune diseases. However, the exact mechanisms that underlie this association, and by that, modulate the antagonistic selection on HLA genes remain elusive. In order to elucidate them in my thesis, I started by investigating the basis of HLA heterozygote advantage against HIV-1 progression using a dataset of 6,311 HIV-1 infected individuals. The individual-specific HLA-bound HIV-1 peptide repertoires suggested that HLA heterozygote advantage could be mediated by a broader array of HLA- bound peptides. The comparison of 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. Overall, the findings suggested that the pathogen-mediated selection might favor both HLA heterozygosity and individual alleles. Further, focusing on the association between HLA genes and Type 1 Diabetes (T1D) and using a case-control dataset of 16,029 individuals, I showed that heterozygosity at the HLA class-II genes conferred T1D risk. The comparison of HLA-bound peptide-repertoire between HLA hetero- and homozygous individuals suggested that a broader array of HLA-bound self-peptides underlie 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 by binding specific disease-causing peptides e.g. deamidated peptides. The insights from my 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.

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Arora, Jatin: Functional characterization of antigen repertoires inHLA-associated complex diseases to investigate antagonistic selection on HLA genes. 2019.

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