Autoimmune diseases represent an attack on the self. Immune cells that usually recognize threats from outside the body begin to mistakenly identify the body’s own cells as invaders. This leads to the production of autoantibodies that target the body’s cells and mark them for the immune system to destroy. 

However, the presence of autoantibodies alone doesn’t mean someone has an autoimmune disease — yet. “Autoantibodies are present many times years, sometimes even decades, before patients develop a disease,” said Judith James, a rheumatologist at the Oklahoma Medical Research Foundation who studies systemic lupus erythematosus (SLE) and other autoimmune diseases. At the same time, she added, “some people have them for life and never get sick.”

James and other scientists are searching for early biomarkers that will identify people at risk of autoimmune disease before it starts, with the ultimate goal to intervene and prevent development of disease altogether. Yet, because these individuals aren’t sick yet and some may never develop autoimmune disease, preventative treatments must be non-toxic with only minimal side effects.

Researchers studying type 1 diabetes have gotten the closest to finding such a preventative treatment. In 2022, the Food and Drug Administration (FDA) approved teplizumab to delay the onset of type 1 diabetes in children (1). However, teplizumab doesn’t work to prevent the progression to autoimmune disease entirely. Still, scientists investigating early biomarkers of autoimmunity are hopeful that the success from teplizumab will be used as a model for other autoimmune diseases too. “That took them 25 years of studies to finally get that drug approved, but it's changing the game now,” said Kevin Deane, a rheumatologist studying rheumatoid arthritis (RA) at the University of Colorado School of Medicine. “That's super exciting, and it's nice that they're doing it, leading the way. I think that's going to change how we think [about studying and preventing autoimmune disease].”

The field is making progress, but the immune system and all the possible ways it can lead to autoimmune disease are incredibly complex. “[The immune system has] got to fight off infections. It's got to heal wounds. It's got to clear cancers. And do all that perfectly well, and then shut down,” said Deane. “Understanding that's going to be the key to stopping the diseases from developing, but it's also going to help us [learn] how to have better immune health in general.”

Delaying diabetes

In type 1 diabetes, T cells erroneously destroy the beta cells in the pancreas that produce insulin. Teplizumab is a monoclonal antibody that is believed to delay the onset of type 1 diabetes by binding to and exhausting the CD8+ T cells that target and kill beta cells. With these cells in an exhausted state, beta cell function is preserved for a longer time. 

The work behind teplizumab started 30 years ago in mouse models, said Kevan Herold, an immunologist at Yale School of Medicine. Herold contributed to early work that ultimately led his colleague, Jeffrey Bluestone, now at Sonoma Biotherapeutics, to engineer teplizumab. Herold then led a Phase 2 clinical trial that infused teplizumab into patients for 14 days, and the researchers showed that the drug delayed the onset of type 1 diabetes by two years on average (2). But Herold said that for some people, the drug holds off the onset for much longer — in some cases more than 10 years. “In the prevention space, I think it's fair to say that any time without diabetes is very, very important,” said Herold.

After teplizumab’s FDA approval, many physicians and researchers around the U.S. began increasing efforts to screen children at risk who may benefit from the treatment. However, screening is complicated by the fact that most people with type 1 diabetes do not have a relative with the condition (3). “There is now a lot of momentum focused to say, well, how do we find people at risk, or how do we find people with those characteristics that we could offer treatment to delay disease onset?” said Aaron Michels, an endocrinologist and researcher who studies type 1 diabetes at the University of Colorado. Much of Michels’ recent work has focused on studying DNA sequences of diabetes-specific T cells as a way to determine how long it will be before someone develops type 1 diabetes.

Michels also brings life experience to his research. He is a patient with type 1 diabetes himself, a physician who treats diabetes patients, and a father of a child with type 1 diabetes. He is hopeful that type 1 diabetes will be not just delayed but completely prevented and cured in his lifetime. “The parent perspective in me would say, man, my daughter was five — that was really, really tough and challenging. Three years would be a lot. But what if we could push it out of childhood … and then eventually, how do we keep it from ever developing?” he said. “What we're really going [to] need to do [to] delay longer or completely prevent, is probably use a combination of therapies with well-known and synergistic mechanisms of action.”

Trialing treatments

With the success of teplizumab for type 1 diabetes, researchers studying other autoimmune diseases are excited to potentially follow a similar path. For rheumatoid arthritis (RA), an autoimmune disease that affects the joints, it hasn’t worked out so quickly just yet. Deane recently completed a Phase 2 trial called StopRA in which researchers tested the drug hydroxychloroquine to prevent RA. But they found that the drug wasn’t successful, so they stopped the study last summer (4). Deane said that most drugs in clinical trials have failed to prevent RA except for abatacept, a fusion protein drug that binds to antigen-presenting cells and decreases the activity of T cells, which has shown promise so far in Phase 2 trials (5,6). “We are looking for the next intervention that we think might even work better than the ones we've got,” said Deane. 

[The immune system has] got to fight off infections. It's got to heal wounds. It's got to clear cancers. And do all that perfectly well, and then shut down. 
– Kevin Deane, University of Colorado School of Medicine

Part of the challenge in being able to prevent RA stems from the difficulty in understanding who is at risk. “People who come into the clinic with rheumatoid arthritis, they all look super different. You could see a kid with full-blown rheumatoid arthritis who's 15 years old. You could see an 85-year-old woman. You could see everything in between. And just understanding that diversity, I think that's been a surprise and a challenge,” said Deane.

To identify patients who may be at risk of developing SLE, James and her team are developing prediction models that incorporate immune system characteristics, such as antibody compositions or cytokine levels from blood samples, and clinical features from screening questionnaires. “Our hope is that we can use directed therapy for a short period of time to be able to kind of help people reset,” she said. Based on James’s work finding that viral reactivation of the Epstein-Barr virus is associated with and likely contributes to the development of SLE, she also hopes that upcoming Epstein-Barr virus vaccines may be able to help train the immune system to respond to the virus in a way that does not lead to SLE (7,8).

Battling the brain

Autoimmune diseases can also take root in the brain, attacking neurons and other brain cells. The Epstein-Barr virus has also been found to be a major player in this case. In 2022, researchers at Harvard University studied 10 million young adults in the U.S. military and showed that the risk of developing multiple sclerosis (MS) increased by 32 times after infection with the virus (9). 

Researchers hypothesized that the virus may lead to autoimmune disease because viral protein sequences mimic normal human proteins, like the brain’s myelin proteins in the case of MS. “What it means is that the immune system tried to destroy the virus but the virus looks like self-proteins, so it destroys self-proteins,” said Francisco Quintana, a neuroimmunologist at Brigham and Women's Hospital and Harvard Medical School. “Why that does not happen in most of us [infected with Epstein-Barr virus] is not clear.”

In 2014, researchers in Quintana’s laboratory found that children who developed multiple sclerosis had immune systems that recognized and attacked more self-proteins in the brain (10). “In people that did not eventually develop multiple sclerosis, there was some initial recognition of brain proteins by the immune system, but then the immune system forgot about it or learned to control itself,” said Quintana. To attempt to stop the immune system from recognizing and attacking central nervous system (CNS) proteins, Quintana and his group developed nanoparticles that induce immune tolerance and reduce inflammation (11). His team has also recently engineered strong probiotics to modulate the immune system’s response to CNS proteins (12). “It turns out that the T cells that reach the brain actually are educated in our guts, and they go from the gut to the CNS,” he said.

Quintana’s team recently published new data showing that autoimmune disease arises in the brain because of a memory-like mechanism that exists in astrocyte cells (13). “What we found is that actually the tissue remembers,” said Quintana. “Non-immune cells in the tissue … are exposed to inflammatory factors. And then as we just showed, they undergo epigenetic changes by which they kind of remember that tissue was inflamed.” As a result, if those same cells are exposed to another inflammatory trigger years down the line, it will lead to a full-blown inflammatory response. 

“The important thing is that this is a concept — I don't think it’s specific just to the CNS — that applies to every tissue. We have [unpublished] data showing that that applies to every inflamed tissue,” said Quintana. “By the time we are aware that the immune system is out of control, it’s not just the immune system. It’s already imprinted [as] memories of inflammation in the inflamed tissue.” Quintana said that to have efficacious therapies, researchers must address this memory aspect as well.

Looking skin-deep

Before symptoms of autoimmune diseases become apparent, there’s often silent damage going on for months or years. By the time the patient is aware of symptoms, it’s often too late to reverse the disease.

Fortunately, that’s not the case for vitiligo, an autoimmune skin condition. The pigment damage that happens when the immune system attacks skin cells can be reversed in many parts of the body — except for areas without hair follicles, like the hands. “The reason why it's reversible is that melanocyte stem cells live in the hair follicles within the hair, and they have to because once your hair falls out, you generate a new hair, which happens every few months. … Those cells can also crawl out of the hair back into the skin to re-pigment vitiligo,” said John Harris, a dermatologist and vitiligo researcher at the UMass Chan Medical School. 

However, it’s a very long treatment process that can take years, and common treatments like janus kinase (JAK) inhibitors can have extreme side effects such as sudden death. Harris is working with computational biologist Manuel Garber, also at UMass Chan Medical School, to find cellular and genetic biomarkers of the disease with the aim of discovering targeted treatments that could prevent vitiligo from ever starting. When they compared the skin of vitiligo patients to healthy controls, they found inflammatory differences even in the unaffected skin of vitiligo patients. “We hypothesized based on that, that the markers that we find in the normal-looking skin of a vitiligo patient might be the same markers that will occur in the skin of a healthy patient just before they develop vitiligo,” said Harris. Their team is now recruiting 1,000 people with family members who have vitiligo to find out if that’s the case. 

Harris also studies vitiligo as a model of disease progression that he hopes could help advance treatments for other autoimmune diseases too. That’s because vitiligo progression can be easily observed on the skin. Harris recalled that the Banting Medal winner George Eisenbarth called type 1 diabetes, “vitiligo of the pancreas” because there are thought to be little spots on the pancreas where inflammation happens (14). “If you have one spot of vitiligo, I can see it and diagnose vitiligo. If you have one spot of diabetes, you have it [but don’t know] until much, much, much later,” said Harris.

As scientists continue to pursue the goal of preventative treatments for autoimmune diseases, one challenge looms large. “A lot of autoimmune diseases are so rare that — would you have to recruit 10,000 people or 50,000 people and watch them in order to get enough [people] who get to disease?” asked Harris.

It's fair to say that any time without diabetes is very, very important. 
– Kevan Herold, Yale School of Medicine

For diseases like RA, Deane emphasized the need for many more people to participate in research before they get sick. “People have got to be interested in this to help us move ahead,” he said. “People who feel good don't necessarily want to participate in studies, but without that, we can't advance.”

At the same time, the researchers remain optimistic that they will find biomarkers of at-risk patients and eventually develop treatments that will stop and even reverse autoimmune disease. “I definitely think, yes, we will get [there],” said James. “[When] I started working on lupus, I really wanted to find a cure. And I think once the damage has been done, once the pathways are all dysregulated, it's really hard to unring that bell. But for me, the best option would be for us to be able to find effective prevention strategies.”

Harris agreed. “That's why we're doing this very difficult study. It takes a lot of our time and effort and a lot of people and a lot of coordination, and it's because we believe that this is going to be what changes the course of how we treat or prevent autoimmune disease and the applicability to other diseases,” he said.

September 30, 2024: An earlier version of the story incorrectly mentioned that George Eisenbarth won the Nobel prize. The story has been updated to specify that he won the Banting Medal.

References

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