Researchers at National Jewish Health have identified an elusive
trigger of type 1 diabetes. A protein fragment formed in the
pancreas activates the immune system's T cells, leading them to
attack and destroy beta cells, which produce insulin.
The research, published in the April 5 issue of Science
Immunology, solves a long-standing mystery about the specific
molecule that triggers many cases of type 1 diabetes, and suggests
strategies to prevent and treat the condition.
"These results provide important evidence about how molecules
activate the autoimmune response in type 1 diabetes, how they are
likely created and why the immune system is fooled into launching
this misdirected attack against its own body," said Dr John
Kappler, senior author and Professor of Biomedical Research at
National Jewish Health.
Type 1 diabetes is an autoimmune condition in which the body's
immune system begins attacking its own tissues. This misdirected
attack is orchestrated by rogue T cells that mistakenly recognise
the body's own tissue as potentially harmful.
T cells sense the internal environment of the body through
receptors on their surfaces.
When these receptors fit and bind to a piece of a foreign
protein and a molecule holding it on the surface of other cells, it
becomes activated and launches an immune system T-cell response,
resulting ultimately in the elimination of the invader.
Over the years, researchers have identified a number of
pathogenic T cells in humans and mice that orchestrate the
autoimmune attack in type 1 diabetes. Many of these T cells are
triggered by the protein insulin.
There has been considerable uncertainty and controversy,
however, about exactly what part of this protein the T cells
recognise and why they might be triggered to attack the cells in
the pancreas that produce insulin.
In the Science Immunology paper, the researchers report three
crystal structures that show how human and mouse pathogenic T cells
bind to fragments of insulin and the MHCII molecule that holds them
on the cellular surface.
The crystal structures demonstrate that an insulin fragment
known as B:14-22 is the activator of these T cells. The structures
cap almost a decade of work by Drs Kappler, Dai and their
colleagues to definitively prove how the B:14-22 fragment is an
important trigger for type 1 diabetes in both species.
"These structures provide important knowledge about a major
cause of type 1 diabetes and suggest potential targets and
strategies for treating and preventing type 1 diabetes," said Dr
Shaodong Dai, co-author on the paper.
However, to make the MHCII molecules, the protein fragments and
the pathogenic T cells all fit snugly together, the researchers
altered the protein fragment; they changed several of its nine core
amino acids to improve binding to the MHCII molecules and/or
recognition by the T cells.
"When we altered the insulin fragments, they fit tightly, and in
a way that activated the pathogenic T cells," said Dr Kappler. "We
felt confident that the altered insulin fragments were the ones
that triggered the autoimmune attack, but we did not know how those
changes might occur naturally in the body. We were stumped."
A chance conversation with a colleague alerted Dr Kappler to a
natural recycling process in cells that might change the insulin
fragments into forms that trigger type 1 diabetes.
As proteins are broken apart and recycled in cells, fragments
are sometimes fused back together in new configurations by a
natural process called transpeptidation.
Beta cells in the pancreas are especially susceptible to this
fragment fusion because they constantly recycle insulin as part of
the careful regulation of glucose metabolism.
Dr Kappler and his colleagues looked at the amino acid sequence
of insulin and found many possible breaks and reconnections that
could produce amino acid sequences, similar to the ones in their
crystals, which fit snugly in the MHCII molecule and activate the
pathogenic T cells.
They tested over a dozen of these possible fusion fragments with
the pathogenic T cells in culture and found that many of them
strongly stimulated the T cells, up to 500,000 times as effectively
as the unaltered insulin fragment.
"The recycling process inside beta cells can produce many
protein fragments that can activate the pathogenic T cells from
both mice and humans to trigger type 1 diabetes," said Dr Yang
Wang, an author on the paper. "We have finally identified the
precise target for T cells that cause type 1 diabetes and
identified a process that can produce those disease triggers."
T cells mature in the thymus, where any of them that have
receptors that bind to a naturally occurring protein in the body
This helps prevent the immune system from attacking its own
body. Dr Kappler and his colleagues believe that the pathogenic T
cells in type 1 diabetes mature and escape the thymus because they
are not exposed to the fused insulin protein fragments in the
When they come across those fragments in the pancreas, they
mistake them for foreign invaders and launch an autoimmune attack
against the beta cells that produce them.