Researchers identify molecular link between autoimmune disease and lymphoma risk

Patients with autoimmune diseases such as lupus and rheumatoid arthritis have an increased risk of developing lymphoma, a form of blood cancer that affects the lymphatic system. Researchers have now identified a mechanism that may help explain this connection.

The immune system is designed to protect us against viruses and bacteria. In autoimmune diseases however, the immune system instead attacks the body’s own cells. Conditions such as systemic lupus erythematosus (lupus) and rheumatoid arthritis are well-known examples. It is estimated that just under 250,000 people in Norway live with some form of autoimmune disease, with approximately 8% to 10% of the population worldwide.

Researchers have long known that people with autoimmune diseases are more likely to develop lymphoma.”

Ramakrishna Prabhu Gopalakrishnan, researcher, University of Oslo (UiO) and Oslo University Hospital (OUS)

“But it has been unclear what actually links these diseases at the molecular level,” he adds.

In a new study, published in Nature Communications, Gopalakrishnan and colleagues describe a possible mechanism that could help explain why ongoing autoimmune reactions can increase the risk of lymphoma.

A finely tuned collaboration

Two types of white blood cells, B cells and T cells, are crucial components of the immune system and work together to combat infections. B cells produce antibodies that recognise and bind to foreign substances such as viruses and bacteria. T cells help coordinate the immune response and can either support or dampen the activity of other immune cells.

Under normal conditions, this collaboration between B and T cells is tightly regulated.

When the immune system never switches off

In this study, the researchers found that when the interaction between B cells and T cells becomes too strong and poorly regulated, the cells begin to activate one another continuously.

“At first, this leads to autoimmune disease. Over time, this prolonged and abnormal activation can also contribute to the development of lymphoma,” says Professor Bjarne Bogen at UiO and OUS.

The discovery could have implications for how lymphoma is treated in the future.

“The study is an important step towards understanding how our immune system, which normally protects us, can in some cases also contribute to cancer,” he says.

Two signals that drive the disease forward

To understand the significance of the findings, it is useful to look more closely at what the researchers discovered. Using a mouse model, they investigated how the collaboration between B and T cells becomes chronic.

The researchers identified two crucial signals, or “messages” that immune cells send to one another and that together drive the chronic activation.

The first signal occurs when B cells mistakenly recognise the body’s own molecules as if they were foreign and dangerous. This misrecognition partially activates the B cells.

For full activation, the B cell requires a second signal.

This second signal occurs when T cells recognise a specific part of the B cell’s own antibody structure. This recognition amplifies the activation that has already started in the B cells.

“When these signals act together, a persistent and self-reinforcing cycle can develop, in which B and T cells can keep each other active,” explains Gopalakrishnan.

When control mechanisms fail

Normally, this mutual activation is controlled by regulatory T cells, a subset of T cells that ensure the immune response does not become excessive or harmful.

However, this control mechanism sometimes fails.

When that happens, the body loses control over the mutual activation between B and T cells. This leads to an abnormal and uncontrolled interaction and chronic overstimulation.

Such prolonged activation of immune cells can cause autoimmunity and thus contribute to the development of autoimmune diseases.

From defence mechanism to cancer risk

At the same time, chronic overstimulation also increases the risk of genetic errors. When cells are constantly active and dividing, the likelihood of harmful genetic changes increases. Over time, this can cause both B cells and T cells to become cancerous.

“The same immune reaction that starts as an autoimmune disease can, over time, lay the groundwork for cancer development,” Gopalakrishnan points out.

“Our findings suggest that long-lasting and abnormal collaboration between specific immune cells may be a key driving force behind the development of lymphoma,” he adds.

Important implications for future treatment

Several epidemiological studies have previously shown that patients with autoimmune diseases have an increased risk of developing non-Hodgkin B-cell lymphoma, a common type of lymphoma.

This new study now provides a biological explanation for that association.

By clarifying how lymphoma can develop at the molecular and cellular level, the researchers hope their findings will eventually contribute to better prevention and treatment strategies.

“In principle, this knowledge could make it possible to disrupt the harmful immune activation that occurs early in disease development,” says Bogen.

“If we can intervene at the right time, it may be possible to reduce cancer risk in patients with autoimmune diseases, to develop more targeted treatments for lymphoma, and perhaps even to halt disease progression before cancer arises.”