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An Australian Discovery Reveals a Dysregulated Immune Pathway in Acute Rheumatic Fever

How a common bacterial infection can trigger persistent inflammation and lifelong heart-valve damage

⏱ In 30 Seconds

✓ Acute rheumatic fever can develop after infection with Group A Streptococcus and may eventually cause permanent heart-valve damage.
✓ Australian researchers identified a dysregulated IL-1β–GM-CSF immune pathway in cells from people with acute rheumatic fever.
✓ IL-1β promoted the expansion of inflammatory GM-CSF-producing CD4 T cells, offering a possible explanation for persistent immune activation.
✓ The study also showed that hydroxychloroquine could suppress this response in laboratory experiments, suggesting a potential direction for future immune-targeted therapies.

Every year, hundreds of millions of people are infected with Group A Streptococcus, commonly known as GAS. For most people, the infection causes a sore throat or skin infection and disappears within days.

But for a small number of people, the most serious illness begins only after the bacteria have gone. Their immune system remains activated, inflammation spreads through the body and the heart valves can become targets of immune-mediated injury.

Repeated episodes of this illness, known as acute rheumatic fever, can eventually cause permanent valve damage called rheumatic heart disease.

For decades, molecular mimicry provided the leading explanation for this disease. Yet one question remained unresolved:

Why does inflammation persist in only some people after the original infection has already been cleared?

For years, researchers searched for the missing link. A landmark study published in Circulation in 2018 identified a dysregulated inflammatory pathway that offered an important new piece of the puzzle.

Molecular Mimicry: When an Immune Defence Turns Against the Heart

The immune system normally protects the body by recognising molecules produced by invading microorganisms. During a GAS infection, antibodies and T cells are generated to identify and eliminate the bacteria.

The problem is that some GAS proteins resemble molecules found in human tissues, including proteins associated with heart valves, cardiac muscle and joints. This resemblance can confuse the immune system, allowing immune responses initially directed against the bacteria to begin reacting with the body’s own tissues.

This phenomenon is known as molecular mimicry. It helps explain how a bacterial infection can trigger an autoimmune-like inflammatory disease after the microorganism itself has disappeared.

However, molecular mimicry alone could not explain why the inflammatory response becomes unusually strong or persistent in only a minority of people. Something else appeared to be amplifying the response.

Beyond Molecular Mimicry: Searching for the Missing Pathway

Australian researchers investigated this question by studying peripheral blood mononuclear cells, or PBMCs, collected from patients with acute rheumatic fever. PBMCs include several important immune-cell populations, such as lymphocytes and monocytes, that can be examined outside the body to understand how the immune system responds to stimulation.

The researchers stimulated patient immune cells with GAS-related signals and compared their responses with cells from people without acute rheumatic fever. A distinct inflammatory pattern emerged.

The findings pointed to an interaction between the inflammatory cytokine IL-1β and a population of GM-CSF-producing CD4 T cells. Together, these components formed a pathway that could help sustain inflammation after the initial infection had ended.

Discovery 1: Persistent IL-1β Production

The study found increased production of interleukin-1 beta, or IL-1β, in immune cells from patients with acute rheumatic fever.

IL-1β is a powerful inflammatory cytokine. During infection, it helps activate immune defences, recruit inflammatory cells and coordinate the response against invading organisms. This activity is normally useful and tightly regulated.

But when IL-1β production becomes excessive or prolonged, the same pathway can contribute to continuing inflammation and tissue injury. In this study, IL-1β appeared to be more than a passive marker of inflammation: it acted as an upstream signal capable of driving another important inflammatory response.

Discovery 2: Expansion of GM-CSF-Producing CD4 T Cells

A major finding was that IL-1β promoted the expansion of a population of inflammatory CD4 T cells that produced granulocyte-macrophage colony-stimulating factor, or GM-CSF.

GM-CSF was originally discovered as a growth factor that supports the production and function of certain blood and immune cells. It is also now recognised as an important amplifier of inflammation.

GM-CSF can activate monocytes and other myeloid cells, strengthen inflammatory cytokine production and sustain communication between different arms of the immune system. During infection, this response may help control microorganisms; when it persists inappropriately, however, it may contribute to tissue damage.

The study showed that patients with acute rheumatic fever had increased GM-CSF-producing CD4 T-cell responses. This offered a possible mechanism connecting infection-triggered immune activation with the continuing inflammatory injury seen in the disease.

Discovery 3: A Distinct Inflammatory T-Cell Population

The researchers identified a specific memory CD4 T-cell population defined by the surface markers:

CXCR3⁺ CCR4⁻ CCR6⁻ CD4 T cells

This population was an important source of GM-CSF. CXCR3 is associated with inflammatory T-cell migration and can help guide immune cells towards tissues producing particular chemokine signals.

The expansion of this population suggested that acute rheumatic fever involved not only higher cytokine production but also a change in the composition and behaviour of the responding T-cell compartment. The study therefore supported a model in which persistent innate immune activation and inflammatory T-cell expansion reinforced one another.

Proposed Immune Pathway

Group A Streptococcus infection
↓
Excessive or persistent IL-1β activity
↓
Expansion of GM-CSF-producing CD4 T cells
↓
Amplified inflammatory immune responses
↓
Potential contribution to heart-valve injury

This model did not replace molecular mimicry. Instead, it added another layer to the disease mechanism. Molecular mimicry may help direct the immune response towards self-tissues, while dysregulated cytokine and T-cell pathways may help determine how strongly and how long that response continues.

Repurposing an Old Drug: Hydroxychloroquine

Once an abnormal immune pathway has been identified, the next question becomes: Can it be interrupted?

The study examined whether an existing immune-modulating drug could suppress the IL-1β-driven GM-CSF response. The drug was hydroxychloroquine, commonly abbreviated as HCQ.

Hydroxychloroquine has been used for decades in autoimmune and inflammatory diseases, including systemic lupus erythematosus and rheumatoid arthritis. Researchers tested whether it could reduce the abnormal immune activation observed in cells from patients with acute rheumatic fever.

In laboratory experiments, hydroxychloroquine reduced IL-1β-driven GM-CSF expression and suppressed the expansion of inflammatory CD4 T cells.

It reduced IL-1β-associated GM-CSF responses.
It limited the expansion of inflammatory GM-CSF-producing CD4 T cells.
It altered the dysregulated immune-response pattern observed in patient cells.

These results did not demonstrate that hydroxychloroquine is an effective treatment for acute rheumatic fever in patients. They did, however, show that the newly identified pathway could be pharmacologically modified in experimental systems.

That finding opened the possibility that existing medicines might be repurposed while researchers develop more specific immune-targeted therapies.

A Personal Note

This story is particularly personal to me because I was part of the research team that carried out this work.

Years later, I learned from a former colleague that our laboratory findings had travelled further than I realised. Clinicians in New Zealand had seen the potential of hydroxychloroquine in our work.

In 2019, two children in New Zealand with acute rheumatic fever and prolonged inflammatory responses were treated with hydroxychloroquine. Both showed favourable clinical and inflammatory responses. That early clinical experience was followed by a pilot study investigating HCQ in children with acute rheumatic fever.

The story then progressed even further. A larger randomised clinical trial was developed to investigate whether adding hydroxychloroquine to standard treatment could reduce inflammation and early heart damage in children with acute rheumatic fever.

As a laboratory researcher, this was extraordinary to learn. We had shown what hydroxychloroquine could do to inflammatory responses in cells from patients; we had not shown that it could treat a child with acute rheumatic fever. Clinicians on the other side of the Tasman saw the possibility and asked the next question.

Whether hydroxychloroquine ultimately becomes an effective treatment for acute rheumatic fever is for clinical trials to determine. But knowing that an observation from our laboratory helped inspire that journey from bench to bedside is something I will always be proud of.

Why This Discovery Still Matters

The main strategy for preventing rheumatic heart disease remains the prevention of recurrent GAS infection, particularly through long-term antibiotic prophylaxis. This approach is essential because repeated episodes of acute rheumatic fever increase the risk of progressive valve damage.

However, antibiotic prophylaxis does not directly target the inflammatory immune response once it has been activated. Identifying the IL-1β–GM-CSF pathway therefore matters because it gives researchers a more defined biological target and suggests that future strategies might combine infection prevention with therapies designed to interrupt immune-mediated tissue injury.

The subsequent investigation of hydroxychloroquine in New Zealand adds another dimension to this story. A laboratory study does not need to provide the final answer to influence medicine. Sometimes its most important contribution is to identify a biological possibility that clinicians can test.

Acute rheumatic fever also illustrates a broader biological question: Why does the immune system sometimes continue fighting after the infection that triggered it has disappeared?

Understanding how cytokines, innate immune cells and T cells interact in this setting may provide insights that extend beyond rheumatic fever.

Why Australia Became a Global Centre for RHD Research

Rheumatic heart disease disproportionately affects Aboriginal and Torres Strait Islander communities in Australia. The burden is shaped by complex and interconnected factors, including repeated exposure to GAS, overcrowded housing, barriers to healthcare access and the continuing effects of social and structural disadvantage.

For Australian researchers, rheumatic heart disease is therefore not an abstract scientific problem. It is an urgent health challenge affecting communities within Australia.

Research driven by this need has helped reveal connections between infection, inflammation and immune-mediated tissue injury. A disease with a particularly severe impact on Indigenous Australian communities has therefore contributed to answering one of immunology’s most fundamental questions:

How can an immune response that begins as protection become a source of persistent disease?

The IL-1β–GM-CSF–CD4 T-cell pathway provides a new framework for investigating that question. It also demonstrates how research focused on a neglected health problem can generate insights with relevance far beyond the disease in which they were first discovered.

That is how a local health challenge can become a global immunology discovery.

Landmark Discovery

The findings were reported in:

Kim ML et al. Circulation. 2018;138(23):2648–2661.

Key Findings

✓ A dysregulated IL-1β–GM-CSF pathway was identified in acute rheumatic fever.
✓ GM-CSF-producing CD4 T cells were expanded in patient immune responses.
✓ A distinct CXCR3⁺ CCR4⁻ CCR6⁻ CD4 T-cell population was identified as an important source of GM-CSF.
✓ Hydroxychloroquine reduced IL-1β-driven GM-CSF responses in laboratory experiments.

The study showed that acute rheumatic fever involves more than exposure to infection alone. Dysregulated immune signalling may help amplify and sustain the inflammatory response that contributes to disease.

thebiostories

How Australian Scientists Discovered a New Immune Pathway in Rheumatic Heart Disease?