Since he was six months old, Patient P has been very sick.
Skin rashes, gut pain, type 1 diabetes, and diarrhea burden him and severely diminish his quality of life.
His condition is called Immune Dysregulation Syndrome (IDS), and it’s a severe form of autoimmunity or immunity against oneself.
IDS occurs when the network of immune cells, which is meant to protect the body, turn on it.
“Think about the worst mosquito bite you ever had and how red and swollen it was. Under that bite, your immune cells were protecting you,” said Cynthia Turnbull, a PhD student studying autoimmunity and Patient P’s condition.
“Now imagine if those cells turned on you… that bite would never go away and instead spread all over your body.”
And that resembles what happened to Patient P.
Self as foreign
While it’s fundamental for our immune cells to be able to distinguish between self and foreign, they can sometimes get confused and start attacking innocent cells they exist to protect, treating them as intruders.
In Patient P, such confusion and self-targeting are perpetual.
In the Humoral Immunity and Autoimmunity Group at JCSMR, Cynthia is looking into why this happens at a genetic level.
By reading the DNA sequence of Patient P’s genome, she found a mutation in a gene called CTLA4, which impairs the function of his regulatory T cells (Tregs).
Tregs are one of the critical ‘bouncers’ of our immune system. Their job is to keep the self-reactive ‘drunk’ immune cells that could attack healthy cells in line.
Patient P’s mutation limits the suppressive role of his Tregs, making him more vulnerable to autoimmunity than those with an intact CTLA4.
In fact, other individuals with CTLA4 deficiency also present with type 1 diabetes and other symptoms displayed by Patient P.
“I thought this mutation could explain his disease and be a way we could treat him,” said Cynthia
But the reality, as always, was far more complicated.
Patient P has other symptoms that are not associated with CTLA4 deficiency, and that one mutation “just couldn’t explain the severity of his disease”.
Cynthia needed a new hypothesis.
A second mutation
“Every day, we have to come up with ways to test our ideas, analyse the results, create new theories, then test them and so on.”
To Cynthia, refining hypotheses is but one part of “a beautiful cycle of discovery and creativity”—and a must-do to understand the complex diseases of Patient P and others like him.
It turned out that not all people who carry a copy of the CTLA4 mutation identical to Patient P’s share his suffering.
His mother, for example, has the same mutation but is, overall, healthy.
This phenomenon, known as ‘incomplete penetrance’ in genetics, suggests there may be other modifiers affecting the physical traits of CTLA4 mutation carriers. They could be something hidden in Patient P’s genetic codes, gene expression patterns, or the environment in which he lives.
Searching through the 3 billion letters of Patient P’s DNA strand, Cynthia found another mutation on a gene that encodes a protein called DECTIN-1, which stops his DECTIN-1 from working.
In mammals, DECTIN-1 recognises dangerous pathogens responsible for bacterial and fungal diseases, including tuberculosis and salmonella infections, with which Patient P presented.
The protein quickly grabbed Cynthia’s attention.
By isolating immune cells from healthy blood donors, she started to investigate the function of DECTIN-1 in T cells, which had never been looked at before.
While the role of DECTIN-1 in turning on the immune system to fight infections had been well established, Cynthia’s work suggests the protein could also help suppress autoimmunity.
“When I turned DECTIN-1 on, it induced more Tregs,” said Cynthia.
That may explain why Patient P’s mother, who has functional DECTIN-1, remains relatively healthy even though she has weakened Tregs, whereas Patient P is severely sick.
The mutated DECTIN-1 may have worsened the performance of his Tregs, which already function poorly due to his first CTLA4 mutation.
Will the presence of these two mutations be the actual cause of Patient P’s disease? To figure it out, Cynthia has developed an animal model which lacks both CTLA4 and DECTIN-1 to mimic Patient P’s condition.
“Understanding how the genes which have these mutations regulate the immune system will tell us why the immune system protects the body in most people but turns on the body in others.”
Her ultimate ambition is to find a way to switch elements of the immune system on and off according to the patients’ needs. That way, Patient P and others like him will be able to “see autoimmunity as a memory and not a disease, just like that pesky mosquito bite”.
Along the way
Cynthia became interested in biology when she was in Year 11.
“My mother was diagnosed with breast cancer, and my nana had been placed in a nursing home due to her dementia around that time,” she said.
“Biology was a way to explain what was happening to them, deal with their pain, and marvel at their recovery and ability.”
Later, Professor Carola Vinuesa, Joint Director of the Centre of Personalised Immunology (CPI), turned out to be the catalyst of Cynthia’s passion for immunology.
“Her vision at the CPI was revolutionary to me and where I felt my research could help patients directly,” recalled Cynthia.
Since she started her Honours project in Professor Vinuesa’s lab in 2018, Cynthia has been “in love with immunology”.
Now a PhD student, Cynthia also finds herself engaged in other aspects of science outside the lab. She’s actively involved in fundraising events for biomedical research and is very passionate about science communication.
Her talk on her research journey on Patient P, for instance, led her to compete in ANU Three Minute Thesis (3MT) Final and win the 2021 CHARM 3MT competition.
“To share our vision for the treatment of autoimmunity brings me a lot of pride,” said Cynthia.
“I hope that my research and the many other projects at the CPI will change the lives of our patients.”