Deciphering the cryptic codes of autoimmune disease

Autoimmune diseases are a collection of unpredictable illnesses that exact a terrible toll on millions of people globally. Some are quite common, others are exceedingly rare, many are misunderstood, and they all have one thing in common: the immune system mistakes the body’s own tissues as something foreign and attacks.

As a result, immune cells are sent in to deal with tissues marked for destruction. Itchy skin, inflammation, fatigue, swelling and pain ensues. Depending on the disease, it may strike multiple organs or target joints, nerves, kidneys, the brain, eyes or digestive system.

Although much about autoimmune diseases remains a mystery, a lot can happen in a decade. It wasn’t until 2012 that researchers first compiled a list of the whole spectrum of autoimmune diseases, featuring 81 disorders that together affect 4.5% of the world’s population – and many more women than men.

Then, in 2020, a landmark study underscored what clinical observations had suggested: autoimmune diseases are on the rise worldwide. Researchers found that antinuclear antibodies, a common indicator of autoimmunity, have been increasing in the US since the late 1980s – and had nearly tripled in teenagers in that time.

The reasons why remain unclear. Genes play a part in autoimmune disease, but it’s not the whole story, says immunologist Matthew Cook, from the Australian National University. The steady increase in autoimmune diseases seen over a few short decades outstrips the pace of gradual genetic change that happens over generations and “implies there must be some change in the environment”, says Cook.

There are many possible culprits. Low levels of vitamin D and common viral infections have been linked to multiple sclerosis, a disabling disease which damages nerve cells. Fast foods and sugary diets have been blamed for disturbing people’s gut microbiome, which might amplify inflammation. Air pollution can trigger arthritis flares. Smoking is another risk factor.

Knowing that these lifestyle factors influence autoimmune disease means prevention may be possible, but many of these factors – diet, air pollution – are only getting worse, says epidemiologist Ingrid van der Mei, of the Menzies Institute of Medical Research. “To turn around those societal trends is incredibly hard,” she says. “So then it comes down to finding better treatments.”

With no cure in sight and the number of people living with autoimmune disease expected to grow, researchers are also trying to pinpoint the root cause of autoimmune disease – or even if there is one – and understand what makes one person more susceptible than the next.

Ordinarily, the immune system purges itself of any rogue elements that mistakenly assault the body’s own tissues. But these ‘self-tolerance’ mechanisms break down in autoimmune disease, says Cook. Environmental factors most likely trigger autoimmune disease in people with an underlying genetic predisposition, he adds.

“Even within an individual family, there can be people who carry the genetic variants who are pretty healthy and others who have devastating autoimmune diseases. So this tells us there are probably other environmental modifiers as well.”

Cheaper, faster sequencing technologies have enabled researchers to comb people’s entire genome for errors that disrupt the immune response. Dissecting how the immune system goes haywire in rare cases of autoimmune disease with a single faulty gene has yielded many insights over the past decade, says Cook.

“The next question is to see how broadly those mechanisms that we’ve unveiled through investigating rare instances of autoimmunity apply in the more common versions of autoimmunity,” he says, because most autoimmune diseases are not explained by one faulty gene alone.

Only by understanding which parts of the immune system malfunction in specific autoimmune diseases can more effective therapies with fewer side effects be developed.

The current mainstays of treatment for autoimmune diseases are broad-acting drugs that dampen the immune system so it stops attacking something it shouldn’t. But often these treatments only treat symptoms or target the tail-end of the inflammatory process, not the root cause of disease.

“A lot of treatments for autoimmune disease at the moment suppress all the immune cells when we really want to just target the cells that are causing the disease,” explains Joanne Reed, a researcher at the Westmead Institute for Medical Research who’s examining autoimmune disease.

Reed is homing in on individual immune cells, to see what differs between healthy cells and defective immune agents. In 2020, her team’s work identified the precise immune cells that turned ‘rogue’ in four patients with Sjögren’s syndrome and were responsible for causing their symptoms.

These cells also carried genetic mutations that Reed says mark the early stages of autoimmune disease. If detected in other patients, it could open the door to early intervention and targeted treatments. “We’re continuing that line of investigation, trying to identify these rogue cells in other related autoimmune diseases, such as lupus and coeliac disease,” says Reed.

This strategy of targeting the specific cells that cause disease is slowly starting to pay off in rheumatoid arthritis (RA), which affects roughly 1 in 100 people.

Since 2015, University of Queensland rheumatologist Ranjeny Thomas has led a series of trials testing an immunotherapy designed to re-educate the ‘chief conductors’ of the immune response in RA – dendritic cells – so they regulate, not activate, other immune cells.

“These first-in-human exploratory trials aim to disrupt the future management of autoimmune diseases, from managing symptoms to preventing progress from autoimmunity to disease,” says Thomas.

Elsewhere on the treatment front, researchers have made inroads in identifying a common set of genes that are activated in autoimmune diseases that attack completely different tissues, including type 1 diabetes, RA, MS and lupus. This suggests drugs already in use to treat one autoimmune disease could be repurposed to treat another.  

While it’s good to have options, patients diagnosed with the same autoimmune disease can respond very differently to the same treatment. The challenge is figuring out which drug is going to work for which person – without going through the rigmarole of trialling one therapy after the next.

Take lupus, for example, which has seen little progress compared to more common autoimmune diseases. Faced with few treatment options – the second drug for lupus was only approved in the US in 2021 – and a disease that manifests in myriad ways, researchers are now trying group patients based on their genetic makeup. 

“By understanding more about the main differences between patients, we can identify different groups of patients – and perhaps find out particular treatments work really well in some patients,” explains computational biologist William Figgett, of the Garvan Institute of Medical Research.

Called precision medicine, this approach is the next frontier for autoimmune disease research, says Cook, who heads up the Centre for Personalised Immunology at ANU.

At the centre, researchers use genome editing techniques to engineer mouse models with precisely the same genetic defect as a patient, so they can figure out which immune pathways are disrupted and test possible treatments. If one exists and it’s effective, other people who have the same genetic marker might benefit as well.

“We’ve got proof-of-principle for this approach now from rare instances of autoimmunity,” says Cook. “The next challenge is to build on this progress, to be able to use precision therapies much more broadly across the spectrum of autoimmune disease.”

Other researchers are still chasing preventative strategies to reduce the overall burden of autoimmune diseases, and working on new therapies designed to limit or reverse tissue damage which can appear years before any symptoms.

Pharmaceutical giant Moderna has an mRNA vaccine in the works that’s designed to protect against common viral infections that can trigger MS. A large randomised controlled trial also found that over five years, vitamin D supplements reduced the risk of autoimmune disease in older people.

But given the complexity of autoimmune disease, there is slim chance of one easy fix.

“What’s really driven these new findings in autoimmune disease in the last decade has been major improvements in technology,” says Reed. But there are no quick fixes. “These are really complex diseases. There are multiple genes, multiple environmental factors that all tie into it.”