New research suggests that a hybrid cell may be behind type 1 diabetes.
Many experts believe that type 1 diabetes is a type of condition that occurs when the immune system attacks the body's own tissue.
However, although evidence from numerous studies strongly suggests that type 1 diabetes has autoimmune origins, the underlying biological mechanisms have not been clear.
The new study is the work of scientists at Johns Hopkins University School of Medicine in Baltimore, MD, and collaborators from other institutions, including the IBM Thomas J. Watson Research Center in Yorktown Heights, NY.
In a Cell paper, the authors describe how they found an "unexpected" hybrid of B and T immune cells that appears "to be involved in mediating autoimmunity."
They discuss how the discovery breaks the "paradigm" that cells of the adaptive immune system can only be T or B cells.
The finding also challenges doubts that some scientists have cast on the idea that a "rogue hybrid" or "X cell" drives the autoimmune response behind type 1 diabetes.
"The cell we have identified," says study co-author Abdel-Rahim A. Hamad, an associate professor of pathology at the Johns Hopkins University School of Medicine, "is a hybrid between the two primary workhorses of the adaptive immune system, B lymphocytes and T lymphocytes."
He explains that not only did they find the so-called X cell, but that they also found "strong evidence for it being a major driver of the autoimmune response believed to cause type 1 diabetes."
However, he cautions that their findings are not enough to prove that the hybrid cell directly causes type 1 diabetes. Further studies should now pursue this aim.
Type 1 diabetes and autoimmunity
Diabetes occurs when there is too much sugar, or glucose, in a person's blood. In people with type 1 diabetes, this develops when the pancreas does not make enough insulin, which is the hormone that helps cells absorb and use glucose for energy.
Having too much sugar in the blood is dangerous and causes long-term damage to organs. People with type 1 diabetes have to take insulin every day.
According to the Centers for Disease Control and Prevention (CDC), around 5% of the 30.3 million people with diabetes in the United States have type 1.
Doctors used to call type 1 diabetes "juvenile diabetes" because, although it can develop at any age, it more commonly arises during childhood.
Experts believe that type 1 diabetes is an autoimmune condition wherein the immune system attacks and destroys the insulin-producing beta cells in the pancreas. However, they are not clear about the cell processes involved.
The autoimmune response relies on two types of white blood cell: B lymphocytes and T lymphocytes. Together, the two cells identify and attack entities that present a threat, such as invading bacteria, viruses, and other agents.
Each cell has its own type of cell receptor, which is a type of protein that only allows specific signals into the cell when it matches with a unique binding partner. Thus, B cells have B cell receptors (BCRs) and T cells have T cell receptors (TCRs).
Hybrid has both T and B cell receptors
The hybrid cell that Hamad and his colleagues found is a rare "dual expressor (DE)" cell that expresses working BCRs and TCRs.
The immune response usually begins when a surveillance cell called an antigen-presenting cell (APC) spots an invader and captures its signature.
The APC then travels to a reservoir, such as a lymph node, that harbors immature B and T cells and presents them with the signature, or antigen, of the invader.
Immature T cells with TCRs that match the antigen respond to the APC summons by converting into either killer or helper T cells. Killer T cells react by attacking the invader directly.
Helper T cells, however, respond by triggering immature B cells. If the B cells have the matching antigen, they make antibodies that attack and destroy the invader. If they do not, they make an imprint of the antigen so that they can mount an attack in the future.
Immune system sees insulin as the target
In autoimmune responses, however, the antigen does not identify a foreign invader, but healthy cells in the body's own tissues. The result is a powerful attack that can wreak serious damage. In type 1 diabetes, this results in the destruction of pancreatic beta cells.
In their study paper, the authors explain that scientists do not fully understand the antigens that "drive activation of autoreactive T cells," despite the fact that researchers have examined them "extensively."
In the case of type 1 diabetes, scientists believe that the immune system sees insulin as the antigen.
Hamad says that scientists generally agree that T cells see insulin as the antigen "when the hormone is bound to a site on the APC known as HLA-DQ8."
"However," he adds, "our experiments indicate that it is a weak binding and not likely to trigger the strong immune reaction that leads to type 1 diabetes."
He and his colleagues found that the DE cell that they discovered produces a unique protein called x-Id peptide. By means of various cell experiments, they showed that when x-Id peptide takes the place of insulin, the binding is much tighter and gives rise to an immune reaction that is 10,000 stronger.
Potential for screening and immunotherapy
Using computer simulations, the researchers at IBM Thomas J. Watson Research Center were able to pinpoint the molecular mechanism of the x-Id peptide binding. They were also able to predict how strong the T cell response would be.
The team also found that people with type 1 diabetes are more likely to have DE lymphocytes and x-Id peptide in their blood than people without diabetes.
"This finding," Hamad argues, "combined with our conclusion that the x-Id peptide primes T cells to direct the attack on insulin-producing cells, strongly supports a connection between DE cells and type 1 diabetes."
He suggests that, with more research, the findings could lead to the development of screening methods that can identify people with a higher risk of type 1 diabetes.
Another possibility is that the findings could lead to immunotherapies that either destroy DE cells or alter them so that they cannot trigger an autoimmune reaction.
"What is unique about the entity we found is that it can act as both a B cell and a T cell. This probably accentuates the autoimmune response because one lymphocyte is simultaneously performing the functions that normally require the concerted actions of two."
Abdel-Rahim A. Hamad