STAT3 gene highlights delicate immune balance

The immune system runs on a knife edge balance between defending from pathogens and attacking the body’s own healthy cells. Tip too far in one direction and diseases can result.

Now researchers at Sydney’s Garvan Institute have revealed the role of a key gene in immune function and how it manages this balance.

This raises the prospect for new therapies that could restore the balance, thus aiding individuals with immunodeficient or autoimmune disorders, as well as possibly treating other diseases such as cancer.

The researchers, led by Dr Cindy Ma and Associate Professor Stuart Tangye, found that patients with mutations in the STAT3 gene had an impaired ability to produce IL-21, which is essential to the development of T follicular helper (Tfh).

Tfh cells, in turn, enable B cells to make long-lived high-potency antibodies. These antibodies fight current infections, but Memory B cells created in the process instantly recognise the same invaders in the future.

“This is the first study to demonstrate the critical nature of the STAT3 gene in T-cell dependent antibody-mediated immune responses in people,” said Tangye.

“STAT3 enables a chain of other events, including activation of complex signalling pathways, without which our T cells can’t help our B cells do their job.

“Robust antibody responses are critical for our health. When they’re absent or defective, people suffer from crippling and recurrent infections. When they’re exaggerated, people can develop autoimmune diseases such as lupus, Type 1 diabetes or rheumatoid arthritis.

“Anti-cancer drugs already exist that inhibit the function of STAT3. In the case of autoimmunity, where the body attacks its own tissues, the immune system is on overdrive, working too hard and making mistakes. We need to find a way to wind that back – and we believe that blocking the STAT3 gene, or its effects, might do just that.

“While these are early findings, we believe their potential is evident.”

The paper was published in Blood on March 8 and is available online today.