Twin study asks if immune systems are shaped by our genes or our lives

Identical twins Nicole and Amanda Campbell may look and sound alike, but that's where the similarities end.

"Amanda and I have very different personalities," Nicole says.

"We process information differently. We see the world differently."

And there's another difference between the Campbell twins, now in their 40s, which scientists want to learn more about: their immune responses.

Nicole and Amanda are in remission from separate chronic, immune-mediated inflammatory diseases.

Nicole was diagnosed with Crohn's disease, a long-term condition that causes swelling and irritation in the digestive tract, when she was about 11.

And Amanda was 24 when she was diagnosed with multiple sclerosis (MS), an autoimmune disease that disrupts the flow of information between the brain and the rest of the body.

Both conditions have a genetic link.

Scientists have long been fascinated by what drives the body's immune response.

Is it primarily the genes we are born with, or the environment we live in?

A new Australian-led twin study aims to learn more about why two genetically similar people, like Amanda and Nicole, may respond differently to infections, diseases and treatments.

Understanding the immune system

Immune systems are complex networks that protect the body against infection.

White blood cells, or memory cells, recognise when a known germ reinfects the body and remember how to fight it off.

Vaccines work by mimicking a virus or bacteria, teaching the body to make antibodies against the real thing.

But different people's immune systems can respond differently to vaccines or infections.

Some of this is due to genetics, but some is due to environmental exposures, like diet, lifestyle, past infections and stress.

Jason Tye-Din, director of the Snow Centre for Immune Health, which is running the study, says researchers plan to use blood samples from 100 healthy sets of twins to monitor how their immune system cells respond under certain laboratory conditions.

Professor Tye-Din says this will help them understand how the immune system works on "a very fundamental level", including more about how immune cells divide, survive and die off.

"This shapes very much how we as people respond to vaccines or infections or why we might be at risk of developing certain diseases or how we respond differently to different treatments," he says.

Using twins for this research, Professor Tye-Din says, allows scientists to control for the genetic influence, so they can narrow in on environmental factors.

MS, twins and genetics

This isn't the first study to put twins under the microscope.

One of the first known classical twin studies was in 1922, led by German ophthalmologist Walter Jablonski, who examined the eyes of 52 pairs of identical and non-identical twins to understand more about the genetics of a common visual impairment called refractive error.

Florian Ingelfinger, immunologist at the German Cancer Consortium's Freiburg site, says twin studies give scientists the "unique opportunity" to separate genetic from environmental influences.

"That distinction really matters: environmental risks may point towards prevention, while genetic risks can reveal new therapeutic targets," he says.

Dr Ingelfinger led a separate study, published in Nature in 2022, examining 61 pairs of identical twins — one with MS and one without — looking at immune differences between each pair on a cellular level.

His team wanted to learn more about why one twin remained healthy while the other's immune system attacked its own central nervous system.

Dr Ingelfinger says they found some specific differences.

"The strongest difference was in a cell type we did not expect at all: a very early, naive-like T helper cell," he says.

T helper cells alert other cells to fight infection.

In twins with MS, these cells showed "altered communication", potentially making them more sensitive to inflammation.

Dr Ingelfinger says the findings suggest that while genetics may create a "susceptibility" to MS, "something else during life is needed to turn that susceptibility into disease".

"This is highly relevant because every one of us has a very unique immune system," he says.

"Everything we do, including sports, nutrition, smoking, alcohol and previous infections, can shape how our immune system behaves.

"At the same time, our genes also have a massive influence."

Healthy twins key to findings

Unlike Dr Ingelfinger's study, Australian researchers are recruiting sets of healthy twins.

This was an important variable in a study led by Petter Brodin, professor of paediatric immunology at Stockholm's Karolinska Institute and published in Cell in 2015.

"Healthy twins strip away disease as a confounder," he says.

"If we'd studied sick people, we couldn't tell whether differences were cause or consequence of illness."

Professor Brodin's study looked at 105 healthy twins and measured how each person's immune cells responded to germs and their antibody levels against vaccinations.

They found the "single biggest driver" of someone's immune response was past infection history, specifically prior infection with cytomegalovirus, a common virus most people encounter at some point without symptoms.

Professor Brodin says this finding has significant implications for long-held assumptions about nature versus nurture.

"[The immune system] is built to be shaped by what you're actually exposed to over a lifetime, not primarily by what you inherited," he says.

"That makes biological sense: the immune system's entire job is to respond to a changing external world of pathogens, so it would be a poor design if it were rigidly hardwired by genetics before any of those exposures occurred."

Professor Brodin's study, which included twins aged 8 to 82, found the age of each twin pair was also significant and suggested heritability wasn't "fixed" but "eroded with time".

Back in Australia, Professor Tye-Din hopes his study, still in a very early phase with registration still open, will help scientists learn more about how the immune system works.