Regulatory Immune Cell Diversity Tempers Autoimmunity in Rheumatoid Arthritis
Untangling the root cause of rheumatoid arthritis has been a difficult task for immunologists, as decades of research has pointed to multiple culprits in our immune system, with contradictory lines of evidence. Now, researchers at The Wistar Institute announce that it takes a diverse array of regulatory T cells (a specialized subset of white blood cells) to prevent the immune system from generating the tissue-specific inflammation that is a hallmark of the disease. Regulatory T cell diversity, the researchers say, provides a cumulative protective effect against rheumatoid arthritis. When that diversity is not present, it allows the immune system to attack joints.
The Wistar scientists presented their findings, developed in a mouse model of rheumatoid arthritis, in the May 1 issue of the Journal of Immunology. Defining the immune mechanisms involved in rheumatoid arthritis could point to new therapies for the disease.
“Our results show, surprisingly, that suppressing the immune response against a single target will not shut down the inflammatory response that causes rheumatoid arthritis,” said Andrew J. Caton, Ph.D., senior author and professor in The Wistar Institute Cancer Center’s Tumor Microenvironment and Metastasis program. “Instead, an array of inflammation-stimulating antigens may be involved in causing the disease, since our study shows that an array of regulatory T cells is required to temper the immune system’s attack on joints.”
Rheumatoid arthritis (RA) is an autoimmune disorder that occurs as the immune system attacks the synovium, the membrane that lines all the joints of the body. It is a common disorder that causes uncontrolled inflammation - resulting in pain and swelling - around the joints. It is thought that approximately one percent of the adult population, worldwide, suffers from rheumatoid arthritis. RA has shown to be exacerbated by drinking and smoking, and the disease can lead to an overall increased risk of death.
While the exact cause of RA is unknown, the Caton laboratory and others have shown that a variety of white blood cells called regulatory T cells (or Tregs) are a necessary component to either restrain (or encourage) the immune system’s inflammatory response. Tregs are activated as molecules on their surface membranes called T cell receptors interact with “friendly” or “self” molecules - a way for the immune system to recognize friend from foe. Mismanagement of these Tregs, which normally serve to restrain the immune system from over-reacting to healthy tissue, could then lead to runaway inflammation.
In this study, the researchers sought to examine how T cell receptors affect the ability of Tregs to suppress arthritis in a mouse that had been bred to express a “self” molecule that drives arthritis. They showed that an array of Tregs given to the mice effectively stops arthritis. Unexpectedly, however, Tregs that are specific for the surrogate “self” molecule do not prevent arthritis.
“We find that the Treg responsible for recognition of the disease-initiating self antigen are sufficient for stopping arthritis, but a diverse repertoire of Tregs are very effective,” Caton said. “All of these Tregs, together, influence other components of the immune system which serves to slow down the inflammatory process that causes RA.”
YESTERDAY
- Treatments for the pain, swelling, dysfunction and disability resulting from the inflammation and joint deformity of RA were limited to aspirin, colloidal gold and steroids.
- Although they relieved symptoms, steroids did not retard disease progression and had serious side effects including hypertension, diabetes, osteoporosis and cataracts. Similarly, aspirin and gold had limited effectiveness and significant side effects.
- Drugs such as methotrexate and cyclosporine were also used, but they were insufficient in some patients, ineffective in other patients, and had intolerable side effects.
- Patients with RA had a 10-20 year shortened lifespan due to infection, premature atherosclerosis, cancer and other causes.
- During this period, treatment evolved to include non-steroidal anti-inflammatory medicines that reduce swelling and pain, but do not influence the deforming progression of the disease.
According to Caton, their findings also point to a possible answer of why the immune system targets the membranes that line joints. Tregs influence other types of T cells to produce a substance known as IL-17, and these cells often travel through the body’s lymphatic system where they then drain out into the joints.
“The big unanswered question of RA is ‘why are joints targeted?’” Caton said. “Of all the tissues in the body, of all the places our immune system could attack, this question remains.”
“One idea is that the immune system isn’t deliberately attacking joints in patients with rheumatoid arthritis,” Caton said, “but the joint inflammation is a side effect of the natural tendency of these cells to accumulate in these areas of the body.”
TODAY
- Diagnosis of RA, to distinguish it from other inflammatory diseases, has improved with the identification of highly-specific antibodies (proteins made by the immune system that are normally used to fight invading pathogens, such as bacteria and viruses) and autoantibodies, which mistakenly detect the body’s own tissues as foreign.
- Research in animal models of arthritis and on tissue from patients undergoing joint replacement, provided remarkable insight into the disease process. Additionally, better characterization of the inflammatory process led to the identification of several molecules to be targeted for novel drug development.
- Many biologics - drugs in the form of biological molecules, such as antibodies- have become available. Because of the specific targeting, the biologics have helped many RA patients for whom other treatments were inadequate, with fewer side effects. Biologics have also been shown to be safe and effective for many pediatric arthritis patients.
- Several of the biologics in wide use for RA block the activity of molecules involved in inflammation and immune-system regulation, such as tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6).
Funding for this project was provided by the National Institutes of Health’s National Institute for Allergy and Infectious Disease and National Cancer Institute, and a grant from Sibley Memorial Hospital.
The lead author of this study is Soyoung Oh, Ph.D., a postdoctoral fellow in the Caton laboratory, and co-authors include Caton laboratory members Malinda Aitken, Donald M. Simons, Ph.D, Alissa Basehoar, Victoria Garcia, and Elizabeth Kropf.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures.
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