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Published On August 18, 2020

CLINICAL RESEARCH

The Autoimmune Whodunnit

Autoimmune diseases are on the rise. The hunt is on to find their causes—including bacteria that may trigger the body to pick a fight with itself.

There are more than 100 known autoimmune diseases, and the incidences of many of them have been on the rise over the past decade. The ability to better diagnose these diseases may play a role in those rising numbers. But some experts argue that the increase might also be tied to environmental causes: contaminants, bacteria or other microbes that may somehow kickstart these diseases.

The causes of most autoimmune conditions are still poorly understood. The idea that some could be set off by a microscopic intruder—an infection hypothesis—is growing, given a boost by recent research. For instance, rheumatoid arthritis, lupus, uveitis (an inflammation of the eye) and other autoimmune conditions seem to show their earliest signs in the lungs, gut and other mucosal sites, where tiny invaders from outside the body can gain purchase.

Making a clear case is difficult, however, because alterations in the immune system are detectable for years, sometimes decades, before the disease is triggered. “If you look carefully, you can see that as long as 17 years prior to the clinical onset of arthritis, there are immune changes that are indicative of an evolving disease,” says Michael Holers, a rheumatologist at the University of Colorado.

In 2001, Holers and his colleagues started their Studies of the Etiology of Rheumatoid Arthritis (SERA), a project to investigate an autoimmune disease that attacks the joints over the whole course of its evolution. The researchers recruited healthy participants who had family members with RA and were therefore at higher risk of developing the condition. The researchers were able to spot changes at the very beginning of the disease by analyzing the participants’ blood.

They discovered autoimmune changes—including high levels of disease-specific autoantibodies, antibodies made against substances formed by a person’s own body, and elevated chemokines and cytokines, proteins that signal the immune system to act—present for many years prior to the clinical onset of RA. Using high resolution CT scanning, the researchers also detected that asymptomatic inflammation was happening in the lungs.

Holers says that this suggested some kind of initial change in the mucosal environment. “Chronic inflammation at multiple mucosal sites appears to be able to ultimately drive the development of antibodies in the blood and then the actual joint disease.” The team is looking “very, very hard” for the microbial culprits, “and we have some candidates that appear interesting,” Holers says.  

Building on SERA, the StopRA study is now looking to see if the process can be stopped. Led by rheumatologist Kevin Deane, also at the University of Colorado, researchers are testing whether hydroxychloroquine—a drug that has become controversial in the fight against Covid-19, but has many effective uses in autoimmune diseases—can stop the progression in patients with high levels of autoantibodies but no clinical disease yet.

Questions remain about how exactly an invader microbe can cause a body to attack its own cells. Martin Kriegel, a physician-scientist at Yale, works on lupus, an autoimmune disease that attacks the joints, skin, kidneys and other organs. In a recent study, Kriegel analyzed the blood and stool of patients with lupus and found that a molecule produced by microbes, Ro60, mimicked a molecule made by the human body that is targeted by immune cells from lupus patients. He believes this microbe might be what confuses the immune system, which begins by attacking the invader and ends up going after its own cells that carry the same protein signature.

A similar situation exists with uveitis, an autoimmune disease of the eye. The retina contains several unique antigens found nowhere else in the body. But some bacteria are known to carry similar parts of these proteins that stimulate the immune cells. The introduction of the bacteria could cause the immune system to mobilize against the bacteria first, then spill over into attacking the retina. Nida Sen, a clinician-scientist with the National Eye Institute in Bethesda, Maryland, recently showed significant differences in the gut microbiomes of patients with uveitis compared to healthy controls. “We were really encouraged with these initial findings,” she says, and now the team is more closely studying each part of that chain—the microbes present in the gut, the immune reaction and the clinical presentation of uveitis—in a larger cohort of uveitis patients to find the best place to intervene.

Sen hopes that manipulating the microbiome might help temper the disease, and better diagnostics and therapeutics might be able to head it off entirely. Kriegel has already made strides on that front with his mouse models of lupus and the microbes that carry the protein Ro60—as well as other microbes that leave the gut and instigate autoimmune responses in tissues. His team developed a vaccine to such a microbe, which caused the mouse immune system to eliminate it and prevent it from breaking through the gut barrier. In turn, the autoimmune response didn’t start, and lupus didn’t develop.

Kriegel also found that gut health played a role. Dietary interventions—such as feeding his mice a diet comparable to one rich in green bananas and raw potatoes—prevented bad bacteria from growing in the gut and breaking through the gut barrier, thereby ameliorating inflammation outside the gut. Based on human microbiome association studies at Yale, a subset of lupus patients might benefit from such a dietary intervention early on, he says. Yet another strategy that some biotech companies are developing is the use of bacteriophages, or viruses that attack specific bacteria, to eliminate the bacterial species that trigger or exacerbate autoimmunity. 

For years, the study of autoimmune disease has primarily focused on genetics. Looking at microbial changes not only offers new possibilities for treatment, such as vaccines and diet, but also an opportunity to intervene early in a disease that can grow silently for decades. “When you’re looking at preventing heart attacks, we now know that you can act early and stop the asymptomatic vascular changes that ultimately lead to disease,” Holers says. “If we can figure out what initiates autoimmune disease, what’s happening in that asymptomatic period, we hope to stop that process before the clinical disease starts,” he says.