Type 1 diabetes is classified as an autoimmune disease in which the immune system mounts an attack against the body’s insulin-secreting cells. According to Dr. Stephan Kissler, Investigator in the Section on Immunobiology at Joslin Diabetes Center, and Assistant Professor of Medicine at Harvard Medical School, our understanding of the genetic basis of this autoimmune reaction, is severely lacking.
Dozens of genetic mutations have been implicated in type 1 diabetes, and research is ongoing to uncover each gene’s role in disease onset and progression. Kissler’s lab has focused on one of these genes – known as RGS1 – and his team have recently elucidated its role in promoting the autoimmune response present in type 1 diabetics.
Researchers know that T cells are responsible for invading the pancreas and damaging insulin-producing beta cells, and that B cells produce antibodies that are targeted towards the pancreatic cells. Kissler and his colleagues recently discovered that in a mouse model of type 1 diabetes, RGS1 has an effect on T follicular helper cells that are necessary for B cell development and antibody production.
“In a nutshell, what we found is that this gene has an effect on the frequency of these T follicular helper cells, which are important for the B cells and seem to be important for the disease,” said Kissler. Previous clinical studies have identified that patients with the disease have higher levels of T follicular helper cells circulating in the blood.
When Kissler and his team engineered mice to produce lower levels of RGS1 protein, they found that the progression of the disease was not impeded. According to the researchers, this result suggests that RGS1 may not be the best therapeutic target for diabetes.
“Inhibiting RGS1 didn’t prevent autoimmune diabetes from happening, which is slightly disappointing but not surprising because any one of these genes in humans has a very small effect on risk,” said Kissler. Despite the disappointing result, Kissler’s group could still uncover a valuable target in one of the other genes they study, which are thought to be involved in type 1 diabetes and other autoimmune disorders.
In addition to its potential role in immune response, RGS1 is also thought to be involved in cell migration. Kissler points out that mutations of the gene have also been associated with other autoimmune disorders including multiple sclerosis.
Despite the finding that inhibiting RGS1 did not have an effect on the movement of T cells into the pancreas, the researcher did find that the gene manipulation was able to alter the way the cells move within the spleen and the lymph nodes. As these organs are important in facilitating the interaction between T follicular helper cells and B cells to encourage antibody production, this was a particularly crucial finding.
“The RGS1 gene is important to allow activated T cells to move into the regions with all the B cells, where they help the B cells get activated and produce antibodies,” said Kissler. “These are the T follicular helper cells. If you don’t have any of these cells, the antibody production doesn’t work anymore.”
“Overall, the T follicular helper cells are important for B cells, you have more of those T cells in people with type 1 diabetes, they seem to be very important for the disease, and we have a new explanation of why RGS1 has been implicated,” he said. The researchers plan to continue to test other genes to determine their effect on the progression of type 1 diabetes.