The Stages of Autoimmunity

Autoimmune disease can take years to develop, moving from silent immune misfires to full clinical symptoms. Researchers are discovering that before a diagnosis is ever made, the immune system may already be producing autoantibodies and mounting inflammatory responses against the body’s own tissues. Understanding these early “stages” of disease could facilitate prevention and earlier intervention.

To explore what happens as autoimmunity takes shape, this article features insight from Jane Buckner, MD, President of the Benaroya Research Institute at Virginia Mason Franciscan Health, and Michael Rosenblum, MD, PhD, Professor of Dermatology at the University of California, San Francisco, both of whom study the immune mechanisms that drive disease onset and regulation.

What Factors Predispose You to Autoimmunity?

Before an autoimmune disease develops, genetic and environmental factors must converge to set the stage for disease progression. “Some people are born with a genetic risk for autoimmune disease. That doesn’t mean you’re going to get an autoimmune disease, but it does mean you might be predisposed to it,” says Dr. Buckner.

These genetic factors include mutations in genes that affect immune regulation, and autoimmune diseases often involve multiple mutations simultaneously. Some examples of genetic mutations involved in autoimmunity include:

• HLA (human leukocyte antigen) region: The HLA region is a risk factor for many autoimmune diseases. This was the first genetic link to autoimmune disease found (1). HLA is involved in presenting antigens to immune cells. 
• PTPN22: PTPN22 encodes an enzyme involved in multiple signaling pathways and has been linked to numerous autoimmune diseases (2).
• FOXP3: FOXP3 is required for the development and function of regulatory T cells which help in self-tolerance (3). An autoimmune disease called immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by a FOXP3 mutation (4). 

Preclinical Autoimmunity: Autoimmunity Without Symptoms

With the specific combination of genetic predisposition and environmental exposure in place, autoimmunity can progress into what’s known as autoreactivity. At this stage the immune system responds to a self protein and generates autoantibodies against our own tissues, but there aren’t any outward symptoms. This stage is called preclinical autoimmunity or silent autoimmunity.

“Some people never progress beyond that stage,” says Buckner. Why some people develop autoimmune diseases and others do not is another area of exploration for many scientists who study autoimmunity. “We have all of these mechanisms in our body that try to regulate and control inflammation,” says Dr. Rosenblum. “Many people, including myself, believe that it’s really a defect in the ability to control inflammation that results in autoimmune diseases.”

While there have been many mechanisms proposed to explain how autoimmunity progresses, scientists have honed in on the imbalance between effector T cells, which promote inflammation, and regulatory T cells, which control inflammation, as one of the driving forces behind autoimmune disease progression. “Regulatory T cells actually wander around the body. They can be triggered to suppress inflammation,” says Buckner, who studies the role of these cells in autoimmunity. “If you don’t have them, you actually get all sorts of autoimmune diseases.”

Clinical Signs of Autoimmunity 

As autoreactivity progresses, it leads to more and more inflammation and tissue damage and you begin to see symptoms of autoimmune disease. Left unchecked, autoimmunity can be seen as a self-perpetuating feedback loop where self-antigens can’t be eliminated, tissue damage activates further immune responses, which leads to more inflammation and tissue damage, and subsequently more immune activation (5). 

Autoimmune diseases can cycle through flare-ups where symptoms worsen and remissions where symptoms wane or disappear completely for a period of time. “Flares may be driven by environmental exposures that could change that balance of your immune system in such a way to allow the autoimmunity to become more aggressive,” says Buckner. Remissions can be achieved by many mechanisms such as immunosuppressive medications.

How do you Control Autoimmunity? Can it be Reversed?

The key to keeping autoimmune disease in check is reducing inflammation by limiting effector T cell response and increasing regulatory T cell response. This can be done by boosting immune regulation and/or by targeting the specific factors driving inflammation, says Rosenblum, who studies the regulation of immune responses and autoimmune skin diseases. 

Many autoimmune diseases cannot be completely cured but treatments that modulate the immune response have been helpful in managing symptoms of disease. Rosenblum is hopeful about advancements in cell depletion therapy (6). “Cell depletion therapy is one of the only places where we’ve actually really been able to achieve cure for autoimmune diseases,” says Rosenblum.

Activities like diet and exercise can have impacts in mild forms of autoimmune disease, but for more severe forms of disease, lifestyle changes aren’t enough to tame autoimmunity. However, some autoimmune diseases, like celiac disease, IBD, or Crohn’s disease, can benefit from dietary changes.

Does Autoimmune Disease Severity Change Over Time? 

For the most part, the severity of symptoms associated with autoimmune disease remains the same throughout life. Rosenblum says that in most cases, mild forms of disease will stay mild and severe forms of disease will stay severe. “Some people actually start out relatively mild and then they develop fulminant and severe disease that is way farther on the disease spectrum in which they started,” says Rosenblum. “That’s usually rare.”

Examples of Autoimmune Disease Progression

Type 1 diabetes: Preclinical autoimmunity is characterized by the presence of diabetes-related autoantibodies (7). This stage can last years. There are no symptoms of disease, but there can be evidence that beta cells aren’t producing enough insulin. When autoimmunity manifests with clinical symptoms, treatment involves insulin injection.

Rheumatoid arthritis: Risk factors for rheumatoid arthritis include variation in the HLA allele and smoking (8). Rheumatoid arthritis autoantibodies can be detected for years before disease onset. Disease affects the joints, usually in the hands, feet, and knees, and is characterized by immune cell infiltration into the joints.

Systemic Lupus Erythematosus (SLE): Before any noticeable symptoms of SLE, the immune system is already changing and is characterized by the presence of autoantibodies, cytokines, and antigen-antibody complexes (9). Some patients progress to clinical symptoms, including fatigue, rashes, fever, and joint pain, while others do not.

Understanding the Autoimmunity Continuum to Inform Treatments

Research into how autoimmunity presents itself both on the molecular level and on the clinical level can help scientists understand more about disease progression and inform treatments. Buckner says that understanding the transition between preclinical autoimmunity to symptomatic autoimmune disease is key. “If we can pick out those people who have autoreactivity but don’t have the illness yet – that’s where we could intervene to keep them from ever getting it,” says Buckner.

About the Author

A microbiologist turned freelance science writer who works with life science companies, nonprofits, and academic institutions on anything from news stories, explainer articles, and content marketing. She shares the wonderful world of microbes on her blog The Microbial Menagerie.

Jennifer Tsang, PhD Freelance Writer for GAI

Carolyn Serraino

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