Although there are over 100 autoimmune disorders, researchers don’t know exactly why the body’s immune system signals cells to target the body's own healthy organs and tissues. Some common autoimmune diseases include Type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
Autoimmune diseases have a significant impact in terms of overall prevalence and mortality — at least 3% of the United States population has an autoimmune disease, and autoimmune diseases are among the leading causes of death among young and middle-aged women. Collectively, these diseases affect more than 24 million people in the United States. An additional 8 million people have autoantibodies, indicating a person’s chance of developing autoimmune disease.
Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newlydiagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100 000 person-years. Prevalence rates range from less than five per 100 000 (e.g., chronic active hepatitis, uveitis) to more than 500 per 100,000 (Grave disease, rheumatoid arthritis, thyroiditis).
Current treatments for autoimmune disease can only address the symptoms. According to Professor Chris Goodnow, executive director of the Garvan Institute and director of the UNSW Sydney Cellular Genomics Futures Institute, studying rogue immune cells is challenging because they are so rare in a blood sample (less than one in every 400 cells).
However, researchers have developed a technique that allows them to look directly at the cells that cause autoimmune disease. They used cellular genomics to develop a method to zoom in on these disease-causing immune cells in the blood samples of four patients with cryoglobulinemic vasculitis — a severe inflammation of the blood vessels.
First, the researchers separated individual cells and then separated their genetic material, which allowed them to isolate immune cells that produce rheumatoid factors, the antibody proteins that target healthy tissues in the body associated with the most common autoimmune diseases, including rheumatoid arthritis. Once isolated, the researchers then analyzed the DNA and messenger RNA of each of these “rogue” cells, scanning more than a million positions in the genome to identify DNA variants that may be at the root of disease.
They discovered genetic changes in the cells at the root of an autoimmune disease for the first time, tracing an “evolutionary tree” of how normal immune cells develop into disease-causing cells. They also found that some of the first gene mutations that occurred in these rogue cells were known to drive lymphomas. They uncovered “lymphoma driver mutations,” including a variant of the CARD11 gene, which allowed the rogue immune cells to evade immune tolerance checkpoints and multiply unchecked.
The researchers also found that cells with the lymphoma driver mutations accumulated further mutations that caused the rheumatoid factors they produced to aggregate at lower temperatures.
This explains the patients' cryoglobulinemic vasculitis, a severe condition that develops in some people with Sjogren’s syndrome, systemic lupus, rheumatoid arthritis, or hepatitis C virus infection. In these individuals, rheumatoid factors in the blood aggregate at colder temperatures closer to the skin and in the kidneys, nerves, and other organs, which damages blood vessels and often proves very difficult to treat.
Autoimmune diseases are affecting more people for reasons unknown. By uncovering specific mutations that mark early stages of autoimmune disease and diagnosing patients at these stages, it may be possible to combine the knowledge of these mutations with new targeted treatments for lymphoma to intervene in disease progression or to track how well a patient is responding to treatments.
The researchers are now planning follow-up studies to investigate mutations of autoimmune cells in a range of other diseases, including lupus, celiac disease and Type 1 diabetes.
