Functional genomics in the regulation of the immune response
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Date
02/09/2022Author
Parkinson, Nicholas J.
Metadata
Abstract
Genetics contribute substantially to the ability of the immune system to respond
appropriately to a challenge. Consequently, many infectious and inflammatory
diseases have a heritable component. As genome-wide association studies
provide increasing data linking genetic variants to disease, we can leverage
this information to gain insights into disease biology if we can elucidate the
mechanisms underlying an observed association. Data-driven bioinformatic approaches, in vitro mechanistic studies and whole-organism approaches to study
integrated pathophysiological systems provide complementary information to
help establish causal links between specific variants and their effects on a target gene, and between that gene and disease pathogenesis.
Cells of the mononuclear phagocyte system play key roles in regulation of innate and adaptive immune responses, either via secreted mediators or through
direct cell-to-cell contacts. To advance understanding of how these regulatory
processes, and genetic variations therein, shape the course of disease, I have
combined experimental and bioinformatic approaches to explore novel genetic
associations between genes for macrophage surface receptors and human disease.
Specifically, functional follow-up of an association between adhesion G-protein-coupled receptor CD97 and severe influenza showed, using a mouse model,
that deficiency of this receptor reduces the efficiency of the CD8+ T-lymphocyte
response, a process critical to clearance of infected cells. Secondly, I addressed
the question of how to identify causal variants in a disease-associated linkage
disequilibrium block, for an association between macrophage regulatory receptor SIRPα and schizophrenia. To achieve this, I developed novel methodology
for targeted locus screening using CRISPR/Cas9 mutagenesis, and identified
a number of plausible causal regulatory variants that could affect expression of
this receptor.
Combining variant-level information with gene-level studies of disease pathophysiology can provide valuable insights into genetic causation of immune dys-regulation leading to disease, which may be harnessed for improved personalised disease risk prediction, or to identify therapeutically targetable pathways.