One of the biggest mysteries about type 1 diabetes (T1D) is that no one understands exactly why – or how – it starts. But a team led by Peter Linsley, PhD, and Karen Cerosaletti, PhD, recently uncovered a clue that could help solve this mystery and maybe even open the door to new therapies that stop the disease.
The research team’s discovery revolves around a subset of T cells, which attack healthy cells in people with T1D and other autoimmune diseases.
T cells have receptors (called TCRs), that stick off their surfaces. Those receptors are made of two chains of molecules called amino acids, the alpha chain and the beta chain. Researchers have spent countless hours examining the beta chains — but we know much less about TCR alpha chains.
Studying beta chains in T1D had given researchers the impression that TCRs were extremely different from one person to another, and didn’t seem related to disease. But Dr. Linsley’s team discovered something surprising and different: A subset of cells with alpha chains that were the same between several individuals who were recently diagnosed with T1D. And that’s what led to their new finding.
“We looked where no one else had looked and found that alpha chains had properties suggesting they could be a target for treating T1D,” Dr. Linsley says.
Look where no one has looked, find what no one has found
After discovering these shared alpha chains in people with recently-diagnosed T1D, the research team wanted to take a closer look. That’s when they noticed an unusual concentration of cells called cross-reactive T cells. Most T cells react to just one thing, like a single virus. But cross-reactive T cells can react to multiple things — like insulin-producing cells in the pancreas. When T cells attack those cells, it leads to T1D.
Dr. Linsley and his colleagues saw a build-up of potentially cross-reactive cells sharing alpha chains in people who were recently diagnosed with T1D. Those cells seemed to go away in patients who had the disease for a long time.
Having lots of these cells right when T1D starts could mean they play a role in causing the disease. And because they were present across many participants with recently diagnosed T1D, they could potentially be a target for therapies.
Studying twins and others to learn more
Dr. Linsley’s team has many more questions to answer to fully understand the implications of their discovery. Next, they’ll work with other collaborators to learn more, including Andrea Steck, MD, from the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus. They’ll study samples from twins where one twin has T1D and the other doesn’t. Twins share a large percentage of genes, so studying pairs of twins can help scientists understand whether genetics or other factors are involved in disease.
“If we see these shared alpha chains in the twin that has T1D but not in the one that doesn’t, that’s strong evidence that it's important in disease and could potentially be a good target for treatment,” Dr. Linsley says.
March 17, 2022
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