As the hub for a network of interdisciplinary collaborators in the HOPE Research Program, we are revealing how immune tolerance checkpoints break down in the 100 different autoimmune diseases.
These diseases include rheumatoid arthritis, psoriatic and other autoimmune arthritis, Sjögren’s syndrome, systemic lupus erythematosus, scleroderma, autoimmune anaemia/thrombocytopenia/neutropenia, vasculitis, kidney glomerulonephritis, arteritis, demyelinating neuropathies including Guillain-Barré syndrome and MAG neuropathy, myasthenia gravis, multiple sclerosis, myositis, celiac disease, inflammatory bowel disease, thyroiditis and type 1 diabetes.
The HOPE Research Program is pioneering genomic technologies and computational tools for single cell molecular analysis, to reveal specific changes in the DNA sequence of individual cells among thousands of cells in patient samples. With these new tools, our interdisciplinary team has successfully identified DNA mutations affecting gene expression into RNA and protein activity in rare immune cells that form a ‘rogue clone’: a multiplying family of sibling cells that are no longer controlled by immune tolerance checkpoints. In a growing number of autoimmune diseases, the team has shown that these mutant rogue clones are the root cause of the person’s disease. This sets the stage for a next phase of research: investigating treatments that selectively target cells with these specific DNA abnormalities.
The same mutations also drive the rogue clones responsible for common blood cancers such as chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of unknown significance and T cell large granular lymphocytic leukaemia. The HOPE Research Program is thus revealing that the root cause of some autoimmune diseases is also the benign stage of cancer. This surprising connection opens up strategies to improve treatment of autoimmune disease and of early-stage cancer with new targeted therapies that are currently being developed for late-stage cancer.
The HOPE Research Program is also revealing how inherited gene differences, epigenetic abnormalities and environmental triggers, such as common infections (e.g. hepatitis C virus, Campylobacter jejuni, Epstein-Barr virus) or diet (e.g. gluten) also drive the development of rogue clones, leading to autoimmune disease.
The philanthropic support of The Bill and Patricia Ritchie Foundation has been a key driver in establishing HOPE Research. In addition to getting HOPE Research off the ground, The Bill and Patricia Ritchie Foundation is paving the way for the additional community funding needed to realise the project’s mission.
The program has also received support from numerous other generous sources, including The Ferris Foundation Fellowship awarded to Dr Manu Singh and NHMRC Investigator Grants awarded to Professor Chris Goodnow and Dr Manu Singh.
Autoimmune diseases occur when rare cells in our immune system evade normal checkpoints to turn their destructive mechanisms on normal parts of our body, instead of fighting infectious invaders.
There are more than 100 different autoimmune diseases. Ten percent of people will develop an autoimmune disease, sometimes very early in childhood like type 1 diabetes, celiac disease in teenage years, lupus that most commonly develops in early adult years and rheumatoid arthritis that is most common in women over 60. Autoimmune diseases are a major cause of chronic disease in the community, imposing a large social, health and economic burden. Without effective intervention, many result in irreversible complications or death.
Doctors currently don’t know why patients have autoimmune diseases, making treatment a trial-and-error process often focused on ameliorating the effects without targeting the root cause. HOPE Research is changing the direction of science and medicine by revealing the root cause of human autoimmune disease, opening a new chapter where treatment is targeted at eradicating the rogue clones.
Since 2017, the HOPE Research team has learned a great deal about the genomic pathogenesis of autoimmune diseases. In 2017, HOPE researchers selected 42 different autoimmune diseases to study over five-to-seven years. In these diseases, we aimed to test a hypothesis developed by Professor Chris Goodnow in 1995 and fully elaborated in 2007: that the root cause of some or all autoimmune diseases was the evasion of immune tolerance checkpoints by ‘rogue clones’ with somatic mutations in their DNA.
Somatic mutations are errors in the normal DNA sequence that arise in individual cells of our body as we grow and age. Most are of no consequence but through the HOPE Research Program, the Immunogenomics Lab has pioneered new technologies to identify mutations that corrupt immune cells to evade normal checkpoints.
To test the rogue clones hypothesis, there were two huge challenges we had to tackle. First, we needed to identify corrupting mutations in single cells with high accuracy, even if the rogue cells were as rare as one in ten thousand cells in blood or tissue samples from someone with autoimmune disease. A needle in a haystack problem.
Second, when rogue clones with somatic mutations were found, we needed ways to test whether these rare cells were causing the person’s autoimmune disease or were simply an effect of chronic immune disease. It wasn’t enough just to find a needle, we needed to show it was upsetting the haystack.
The HOPE Research team published its first landmark success in 2020, in the prestigious international journal Cell. This study focused on the autoimmune disease Sjögren’s syndrome, a complex and common disease damaging the salivary and tear glands that sometimes spreads to inflammatory damage of joints, kidneys, skin and nerves. The spread of this disease to other organs was known to be caused by a particular type of antibody, called a ‘monoclonal rheumatoid factor cryoglobulin’, that directly damages small blood vessels. In blood samples from a series of patients, the HOPE Research team successfully identified the rogue clone making the damaging antibody in each patient and identified a series of somatic mutations that had allowed the rogue cells to evade immune checkpoints and secrete a rogue antibody that damaged small blood vessels.
The team has now discovered rogue clones with somatic mutations in other autoimmune diseases, including small blood vessel inflammation in people with chronic hepatitis C virus infection, in people with chronic demyelinating nerve disease and in people with coeliac disease triggered by chronic ingestion of gluten.
In November 2022, the HOPE Research team published in the most highly cited immunology journal, Immunity, research analysing rogue clones of killer T cells with mutations in the STAT3 gene. The study showed that these rogue T cell clones are a cause – and not a consequence – of a range of chronic autoimmune diseases (rheumatoid arthritis, aplastic anaemia and neutropenia) previously correlated with an indolent form of leukaemia called T cell large granular lymphocytic leukaemia. By analysing mouse ‘avatars’ with the same T cell mutations, the team deduced how the STAT3 mutation drives rogue killer cell accumulation.
The discovery of rogue clones sets the stage for the next phase of HOPE Research, investigating treatments that selectively target cells with these specific DNA abnormalities.
Our interdisciplinary network of collaborating researchers is working to pinpoint rogue clones in patients with many other autoimmune diseases. We have identified unique characteristics that distinguish these rogue cells and may offer new ways to target them with immunotherapy.To understand and eventually eliminate rogue clones from the immune system, we need a collaborative, large-scale approach, leveraging the best research technology and expertise. We can only achieve this with your support.
Senior Research Fellows and team leaders
Research Fellows and PhD Scholars
Research team – external:
- Jennifer Chen – Visiting Student
- Raymond Louie – Visiting Scientist
- Associate Professor Fabio Luciani, UNSW Kirby Institute
- Associate Professor Stuart Turville, UNSW Kirby Institute
- Dr Joanne Reed, Westmead Institute
HOPE Research can’t continue its activities without additional financial support. The research team requires $20 million over five years to make radical change in diagnosing and treating autoimmune disease. This means:
- $500,000 to fund the team’s work analysing rogue clones in one autoimmune disease, or
- $12,500 to fund the team’s work analysing rogue clones in one patient.
Please invest in the future health of your family, and all families affected by autoimmune diseases. You can help us by:
- Investing in HOPE Research analysis in one autoimmune disease
- Funding participants in HOPE Research
- Creating a Named Fellowship for a key researcher
- Making a donation.
Supporting HOPE Research is the best way to find new treatments and, we believe, an eventual cure for autoimmune disease. Any donation, no matter how large or small, helps us realise our mission.