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Genetic variants impact immune cell function

Researchers have harnessed the power of genome-wide sequencing and functional profiling of immune cells to understand how genetic variants can impact disease.

Immune cells

Neutrophils are the most abundant circulating leukocytes in human blood. They comprise up to 80% of the white blood cell population. They are also the body’s first line of defence against invading pathogens. As they are inflammatory cells, they respond to chemotactic signals and migrate to the site of infection to protect the body from insults. They are phagocytes and therefore envelope and consume microbial invaders. In addition, they have a host of antimicrobial properties, making them highly cytotoxic to invaders.

Due to their ability to secrete cytotoxic molecules, neutrophils can irritate and damage surrounding tissues. As a result, they contribute to many inflammatory and autoimmune diseases. However, researchers’ understanding of how much aberrations to neutrophil function drives immune disorders remains unknown. Moreover, pinpointing the causal cell types in these disorders is difficult due to crosstalk between immune cells.

PU.1 (encoded by the SPI1 gene) is a master transcription factor that controls myeloid development. Deficiency of this transcription factor has profound effects on neutrophil maturation and function. While researchers have found that PU.1 is required for modulating mouse neutrophil response to infection, its role in complex diseases is limited to other cell types.

Functional analysis of neutrophils

In this study, published in Nature Communications, researchers built upon a previous study called BLUEPRINT, which revealed how variants in blood cells can affect risk of developing complex diseases. The team specifically combined previous GWAS data with in-depth functional analysis of neutrophils to profile the binding of PU.1 in primary neutrophils.

They found that genetic variants that were associated with an increased risk of autoimmune disease also had an impact on the binding of PU.1 in neutrophils. For example, some variants made PU.1 unable to bind to DNA within neutrophils, thus altering gene expression and neutrophil behaviour.

Overall, this research provides evidence for the functional role of PU.1 in neutrophils in immune disease aetiology. It also provides insights into the effects of non-coding DNA within health and pathological immune traits.

Dr Biola-Maria Javierre, co-senior author, stated:

“It is crucial to understand the mechanisms in the cell if we are to fully understand the impact of these on disease. In this case, how the genetic variants affect the ability of PU.1 binding, which goes on to modulate gene expression in neutrophils, could be vital in understanding the role that neutrophils play in certain autoimmune diseases.”

Image credit: By Science Photo Library –