Image: Burnet Laboratory Head Dr Raffi Gugasyan
Burnet Institute research is providing new insights into autoimmune disease, with a particular focus on the gene NF-kB1, and its role in keeping inflammation in the body under control.
Autoimmune disease occurs when the immune system malfunctions and attacks the body’s own tissues, causing an autoimmune disorder such as rheumatoid arthritis, lupus or multiple sclerosis.
The causes are often not well understood so treatments are commonly aimed at relieving the symptoms.
A collaborative study led by Burnet Laboratory Head Dr Raffi Gugasyan and top PhD student Ms Elisha de Valle found that when NF-kB1 is lacking in immune cells called Follicular (Fo) B cells, the Fo B cells produce antibodies called autoantibodies that target and destroy vital organs.
More specifically, the research demonstrated that Fo B cells lacking NF-kB1 secrete large amounts of the pro-inflammatory factor Interleukin-6 (IL-6), which stimulates the production of autoantibodies by the Fo B cells.
“What we’ve identified for the first time is that NF-kB1 sits on the IL-6 gene and keeps it silent, that’s the key finding,” Dr Gugasyan said of the study published in the Journal of Experimental Medicine.
“NF-kB1 is like a brake and when you take it away, or if it doesn’t function, the brake is released and you get systemic inflammatory autoimmune disease.”
Dr Gugasyan said the problem is caused by a mutation in the NF-kB1 gene, and people who have the NF-kB1 mutation are susceptible to certain diseases, which tend to develop later in life.
Being able to identify individuals with the mutation sets up a new biomarker with the potential to assist in the establishment of treatment protocols.
“There are more and more papers coming out highlighting an association between mutations in NF-kB1 and various types of inflammatory autoimmune diseases, so it’s larger than we may think,” Dr Gugasyan said.
“These are diseases like Crohn’s disease, inflammatory bowel disease, and potentially there are links to gastric cancer.
“In those scenarios, there’s more work that needs to be developed, but there’s certainly a strong genetic link; it just hasn’t evolved in terms of proving a strong correlation.”
Dr Gugasyan said this latest study opens up new opportunities for further research.
One strategy is to develop drugs that will target, not NF-kB1, but a sister protein called RELA that drives the IL-6 gene when NF-kB1 is not functioning.
A second option is to investigate the efficacy of treating individuals with an antibody to IL-6.
“This research is very exciting for us,” Dr Gugasyan said.
“We hope that we can take this further, but we also realise that it’s opened the door for many people to follow on from.
“In the short term, I think the anti-IL-6 therapy for individuals who have the
NF-kB1 mutation is something that can be addressed quite quickly.
“But first we need to talk to our industry partners and see if we can get their support in order to take this further and ultimately to the clinic, of course.”