Objective
When the immune system starts making proteins called autoantibodies, unfortunately, these autoantibodies recognize normal islet-beta cells. This interaction often involves a team effort between two types of immune cells: B cells and T cells. T cells kick things off by recognizing certain proteins, which then activate B cells to start producing autoantibodies. There's a protein called lymphocyte activation gene-3 (LAG-3) that plays a role in this process. When T cells get activated, they release a form of LAG-3 called soluble LAG-3 (sLAG-3), which can be found in the blood and tells us that the T cells are activated and the immune system is responsive. High levels of sLAG-3 have been linked to better outcomes in certain diseases, like cancer. Scientists want to find out if sLAG-3 levels could help predict when someone is about to develop autoimmunity, like in type 1 diabetes (T1D), even before autoantibodies show up. They also want to see if they can use sLAG-3 levels along with other tests to track the progression of T1D in people with a family history of the disease. Finally, they're investigating how LAG-3 impacts the way T cells recognize and respond to specific proteins involved in T1D.
Background Rationale
Type 1 diabetes (T1D) is a condition where the immune system mistakenly attacks and destroys the insulin-producing cells in the pancreas. This leads to a lack of insulin, causing blood sugar levels to rise. However, we still don't fully understand why this happens. Despite knowing that the number of people developing T1D is increasing each year, fewer of them have the specific genetic risk factors we typically associate with the disease. This is concerning because it suggests that something other than genetics might be triggering T1D. Scientists think that factors like viral infections, stress, and oxidative stress could be involved. Certain genetic markers, like the DR3/4-DQ8 HLA allele, increase the risk of developing T1D. Because T1D often runs in families, doctors can use tests to check for specific autoantibodies and genetic markers in close relatives of T1D patients. These tests can detect autoantibodies against certain proteins, which can appear many years before symptoms of T1D show up. Researchers are looking into ways to prevent T1D before it even starts, but so far, it's been challenging to find a successful method. Teplizumab, a recent medication, has received FDA approval to postpone the onset of T1D, but it is still difficult to prevent the disease from developing in the first place.
Description of Project
Type 1 diabetes (T1D) happens when the body's immune system attacks and destroys insulin-producing cells in the pancreas. Before symptoms appear, special blood tests can find certain antibodies that show a high risk of developing T1D. Teplizumab is a brand-new medication that the FDA has approved to help delay T1D symptoms. But stopping the disease from happening is still tough. The antibodies we test for now mean that the immune system is already attacking the pancreas. It would be better to start treatment before these antibodies show up, but we need better ways to know who's at risk. So, scientists are looking for new signs in the blood thhttps://jdrf.smartsimple.us/Apps/app_editopportunity.jsp?appid=103068&nextlevel=1&opportunityid=2543927#cfdiv_1361567at could tell us who might get T1D before the symptoms start.
Anticipated Outcome
We need to study the relationship between sLAG-3 and other markers in the body, like CD4+ T cells that respond to specific proteins. This will help us understand how the immune system responds when the body releases its own proteins during autoimmune or inflammatory conditions. This process can lead to the immune system targeting more proteins, which is called epitope spreading. By understanding these processes, we can choose which proteins to focus on when developing treatments to help the immune system tolerate its own proteins in type 1 diabetes. This will help us better understand the disease and develop new treatments.
Our results will guide the way toward earlier detection, in some instances, prior to any antibody production, opening the door for therapy intervention that is safe and effective very early in the process, before a significant loss of beta cells and insulin secretion are present.
Relevance to T1D
The work described is in line with the goals of JDRF, which is to find ways to determine who will progress to T1D in families from those afflicted with T1D prior to the onset of disease. This work provides a starting point as well as a way to assess the efficacy of treatment. This early detection puts us way out in front of the disease progression, i.e. prior to any autoantibody production but focuses on the true effectors T cells that precede autoantibody detection. This way, we can ensure that we are initiating therapy before fulminant autoimmunity has taken place.