Researchers at the University of Pennsylvania analyzed nearly a million immune cells from organ donors, identified a unique subpopulation of CD4 cells in the lymph nodes of the pancreas and changes in B cells in the spleen, and offer a direction for developing a simple blood test that would detect the immune failure that leads to type 1 diabetes even before the insulin-producing cells are permanently lost.
PHILADELPHIA – Type 1 diabetes (T1D) affects nearly two million Americans, and by the time most people are diagnosed, most of the insulin-producing cells in the pancreas have already been destroyed. Now, identifying a group of “attacking” immune cells hidden in the lymph nodes of the pancreas that appear earlier in the course of the disease may provide the first real opportunity for early detection and even prevention of type 1 diabetes, according to new research from the Perelman School of Medicine at the University of Pennsylvania, published in Science Immunology.
“For the first time, the study was able to catch the attacking cells ‘red-hot’ while the disease is still developing; we are not just seeing the destruction after the immune system has already destroyed the insulin-producing cells in the pancreas,” said Prof. Golnaz Vahedi, a genetics researcher and co-author of the paper.
Two proteins that function as "superswitches" in the pancreas
The researchers analyzed nearly a million immune cells – a single cell at a time – taken from the pancreatic lymph nodes and spleens of 43 organ donors: some with active type 1 diabetes, some at early risk for the disease, and some healthy.
This analysis identified a unique subpopulation of cells CD4 T – a type of immune system “helper cell” – in the lymph nodes of the pancreas in people with active type 1 diabetes. These cells powerfully “turn on” two proteins, NFKB1 and-BACH2, which function as superswitches: they turn groups of genes on and off in a way that increases the immune attack on insulin-producing cells (beta cells).
“The study showed that the same cell pattern also appears in people in the pre-diabetic stage of type 1 diabetes, who are not yet showing clinical symptoms,” said Vahidi. “This suggests that the immune failure begins early, at a stage when there are still pools of healthy beta cells that can potentially be salvaged.”
Clues in the blood – via the spleen
In the spleen, the researchers also identified molecular changes unique to type 1 diabetes in B cells – another type of white blood cell. Importantly, these signals can also be detected in simple blood samples.
This suggests the possibility of developing a blood test in the future that would identify the risk of type 1 diabetes. Years ago Symptoms such as high blood sugar appear.
“The changes in the spleen that can be detected in the blood mean we can monitor children at risk – for example, family members of type 1 diabetics – without the need for invasive procedures,” explains Vahidi. “If we can block the pathways that feed these ‘rogue’ CD4 cells, we may be able to delay or even prevent type 1 diabetes altogether.”
The gift of donors' lives as raw material for science
The research team worked with samples of pancreas and lymph node tissue donated by deceased organ donors and their families.
“It was the work of the Gift of Life Donor Program, Penn transplant surgeons, collection teams, laboratory personnel – and most importantly the donors themselves – that made this research possible,” emphasizes Vahidi.
To date, the researchers have analyzed pancreatic tissue and lymph nodes from more than two hundred organ donors, producing a large-scale database that is available to the entire scientific community through PANC-DB, a public database shared with Vanderbilt University, the University of Florida, and Stanford.
“Each dataset represents countless late nights and a single donor gift,” says Prof. Robert Faryabi, a pathologist and disease researcher and co-editor of the study. “This is collaborative science at its finest – surgeons, scientists, families and donors together making the impossible possible.”
Using artificial intelligence to "map" type 1 diabetes
The study is part of a program Human Pancreas Analysis Program (HPAP), led by Prof. Ali Naji and Prof. Klaus Kaestner. The program was established in 2016 with funding from the US National Institutes of Health (NIH), with the aim of systematically studying the pancreas and understanding exactly what goes wrong in it before and during the development of type 1 and type 2 diabetes. The program's funding was recently extended for another four years.
Now, Vahidi, along with her colleagues, aims to develop artificial intelligence models that can not only detect type 1 diabetes earlier, but also Mapping the disease at the molecular level.
“Our goal is to teach AI systems the molecular language of type 1 diabetes – to train them on the disease cells in the lymph nodes of the pancreas, so that they can detect their subtle traces in the blood, even when they are like a needle in a haystack,” said Vahidi.
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