This study will examine the earliest stages of autoimmunity, when the body's immune system first mistakes the body's own tissues as foreign and attacks them. The results may provide new insight into how immune cells malfunction in autoimmunity, using autoimmune thyroid disease as the "naturally occurring" experimental model.
Naturally occurring studies examine what happens as an event occurs. In this case, the event concerns patients with autoimmune multiple sclerosis (MS) who were participating in a clinical trial (supported by other funders) of a therapy that depletes immune cells. The investigators considered immunosuppressive therapy to be a potentially effective means to reduce the immune cells' mistaken attack against the fatty sheath, called myelin, that insulates brain and spinal cord cells and facilitates transmission of signals from one cell to another. The experimental therapy showed some positive effects in reducing immune attacks against myelin, especially when given early in the course of the disease. This prompted the investigators to test the immunosuppressive treatment in newly diagnosed MS patients.
After a year of treatment, however, the investigators found that one-third of the clinical trial patients developed a new autoimmune disease of the thyroid called Graves disease. Medication easily controls this autoimmune hyperthyroid condition, and newly diagnosed MS patients continue to elect to enroll in clinical trial of immunosuppressive treatment for MS, with full knowledge that they may develop treatable Graves disease.
With Dana support, the Cambridge researchers now will study consenting MS patients who have been participating in the MS clinical trial for less than a year. The study will include 50 patients receiving the experimental MS treatment, and 10 patients not receiving this experimental treatment. The investigators will study the patients' immune system actions and follow the patients. Based on the researchers' prior findings, an estimated one-third of the patients will subsequently develop Graves disease in a year. The investigators will determine, in those patients who develop Graves disease, whether there were any differences in the functioning of their immune systems compared to those who do not develop Grave's disease.
The researchers suspect that in autoimmune MS there is a genetically determined acceleration in the turnover of immune T cells. Similarly, in MS immunosuppressive therapy, there is a depletion of T cells followed by an accelerated turnover and generation of new T cells. There are several types of T cells. One type, called a "memory" T cell learns to identify an invader, remember it, and attack it when it is encountered. Another type of T cell is a "regulatory" T cell. These keep the memory T cells in check. The researchers hypothesize that far more memory T cells compared to regulatory T cells are produced during the frequent turnovers of T cells. A percentage of these "memory" T cells, however, incorrectly learn or fail to correctly remember the identity of an invader. As more memory T cells are produced, this increases the probability that a great number of the memory T cells will have this problem, and misidentify the body's own cells as invaders and attack them.
The investigators hypothesize that this is why a substantial number of MS patients undergoing immunosuppressive therapy develop autoimmune thyroid disease. Many of the memory T cells mistake thyroid tissue as foreign. In untreated MS patients, the same genetically-driven overproduction of memory T cells may occur, with some of the memory T cells mistakenly attacking myelin.
This excessive imbalance between memory and regulatory T cells, the researchers hypothesize, occurs in people who have a defect in the genes that promote T cell expansion. This genetic defect, they postulate, puts those who have it at greater risk of developing one of the many types of autoimmune diseases that exist. By studying the immune system before and during the onset of autoimmune thyroid disease, the investigators will try to determine if these hypotheses are correct.