Applying functional genomics to identify causal cell states across autoimmune diseases

The immune system is a complex network of interacting cell types that are constantly and rapidly changing and reacting to their surroundings.

However, while such agility favours a fast and sophisticated response to any environmental encounter, such as a viral infection, this same immune response can also have detrimental consequences for people who have inherited a genetic susceptibility to one or more autoimmune disease.

This project aims to capitalise on the wealth of genetic data that has already been collected, and has been made publicly available, for many thousands of patients, across multiple autoimmune diseases, yet remains out of reach from clinical use due to an inability to translate the full biological consequence of these findings.

Autoimmune diseases with this readily available data include, multiple sclerosis (MS), celiac disease, rheumatoid arthritis (RA), inflammatory bowel disease( IBD), type 1 diabetes (T1D), and Crohn's disease.

Together, these encompass hundreds of genetic risk factors that are found across the human genome, many of which are shared across these diseases.

However, unlocking the full potential of such valuable data first relies on finding the immune cells, as well as what affects them (e.g., exposure to an infection), that are regulated by these genetic risk factors.

To achieve this, blood samples from both healthy individuals as well as from patients with two different autoimmune diseases (MS and IBD), will be used to map and categorise individual immune cells into one of two categories: Causal (i.e. contains and is actively using genetic risk factors associated with disease risk), or non-causal (i.e. no evidence of involvement in disease processes).

Single cell technologies can be used to separate different cell populations based on which regions of the genome they are using and can be mapped against the known regions of the genome that harbour genetic risk, thereby highlighting those cells which are contributing to disease.

As immune cells that are found in a blood sample represent a large proportion of the immune system of that person, the information contained within them provides a clinically appropriate platform in which to understand the underlying pathways that are associated with disease.

In the first instance, cells from healthy individuals will be stimulated the lab with infectious agents or with biological products that are produced in response cells becoming infected, with the aim to reflect the environmental influence on immune cells as closely as possible.

These findings will then be tested against against immune cell signatures from peripheral blood samples from patients who either have MS or IBD, to determine how causal cell populations change by disease course, disease type or in response to therapy.

This one year study will establish the framework needed to understand the clinical implications of our research strategy, with the aim that our findings are not exclusive to only MS and IBD patients, but can be applied across all autoimmune diseases when there is an underlying genetic component.