Immune cells linked to leukaemia drive autoimmune diseases

Gene variants associated with leukaemia can produce ‘rogue’ immune cells that drive autoimmune diseases, according to a new study from the Garvan Institute of Medical Research.

Scientists had previously noticed that leukaemia patients were also likely to develop an autoimmune disease, such as rheumatoid arthritis or aplastic anaemia. Research into this link revealed that immune cells called killer T cells — responsible for destroying harmful cells and pathogens — were a key player.

The new research, published in the journal Immunity, provides insight into the role these killer T cells play in leukaemia and autoimmune disease. Gene variations affecting a protein that controls the growth of killer T cells can turn them rogue, the researchers found.

“We showed that these rogue killer T cells are driving the autoimmunity. They’re probably one of the cell types most directly contributing to autoimmune disease,” said Dr Etienne Masle-Farquhar, a postdoctoral researcher at Garvan.

“Our research also narrows down a few pathways that might be helpful in targeting these cells for future treatments.”

Cancers can grow when tumour cells are not identified or destroyed by the immune system. Autoimmune diseases occur when the immune system attacks the body’s own cells, mistaking them for harmful or foreign cells.

“We knew that people with various autoimmune diseases acquire these rogue killer T cells over time, but also that inflammation can cause immune cells to proliferate and develop mutations. We set out to discover whether the rogue T cells were causing these autoimmune conditions or simply associated with them,” Masle-Farquhar said.

The researchers used high-resolution screening methods to look at blood from children with rare inherited autoimmune diseases. They then used CRISPR/Cas9, a genome-editing tool, in mouse models to find out what happens when the protein STAT3 is genetically altered.

STAT3 is found throughout the body and is critical for various cell functions, including controlling the immune system’s B cells and T cells. The team found that if these proteins are altered, they can cause rogue killer T cells to grow unchecked, resulting in enlarged cells that bypass immune checkpoints to attack the body’s own cells. Even just 1–2% of a person’s T cells going rogue could cause autoimmune disease.

“It’s never been clear what the connection between leukaemia and autoimmune disease is — whether the altered STAT3 protein is driving disease or whether leukaemic cells are dividing and acquiring this mutation just as a by-product. It’s a real chicken-and-egg question, which Dr Masle-Farquhar’s work has been able to solve,” said Professor Chris Goodnow, Head of the Immunogenomics Lab at Garvan.

“This gives some really good cracks in the coalface of where we might do better in terms of stopping these diseases, which are sometimes life-threatening.”

Future applications could include better targeting of medication, like already TGA-approved JAK inhibitors, based on the presence of these mutations. Goodnow explained, “We can now go and look for T cells with STAT3 variations. That’s a big step forward in defining who’s the bad guy.”

The study also identified two specific receptor systems — ways for cells to talk to one another — that are linked to stress. Goodnow noted, “Part of what’s driving these rogue cells to expand as killer T cells is the stress-sensing pathways. There is a lot of correlation between stress, damage and aging. Now we have tangible evidence of how that’s connected to autoimmunity.”

The team’s work may help develop screening technologies that clinicians could use to sequence the complete genome of every cell in a blood sample, to identify which cells might turn rogue and cause disease. Further research is now needed to determine whether rogue killer T cells are involved in all autoimmune diseases, and what proportion of people with rheumatoid arthritis and other autoimmune conditions have rogue cells and STAT3 variations.

Image caption: Hands of an individual with rheumatoid arthritis.

Please follow us and share on Twitter and Facebook. You can also subscribe for FREE to our weekly newsletters and bimonthly magazine.