Scientists from The Scripps Research Institute have provided an answer to the 40-year-old mystery of how certain genetic mutations lead to Type 1 diabetes. This new molecular understanding could lead to novel therapies for Type 1 diabetes and other autoimmune diseases.
The study was published in an advanced, online issue of the Journal of Clinical Investigation on April 19, 2010, and will appear in the May print edition of the journal.
"People have been looking for the mechanism linking HLA and autoimmunity for 40 years," said Scripps Research Professor Luc Teyton, who led the study with Scripps Research Professor Ian Wilson. "This study provides a big leap forward in understanding and suggests a critical new target to intervene in type 1 diabetes."
Teyton notes that his lab has been trying to solve the mystery of autoimmune mechanisms and related conditions like celiac disease for some 25 years.
A Life-Threatening Condition
This new study focuses on Type 1, or insulin-dependent diabetes, a rapidly progressive disease of the young that leads to high blood sugar, coma, and death if not treated with replacement insulin.
Type 1 diabetes occurs when the body's immune system attacks insulin-producing â cells in the pancreas. Without insulin, the glucose in the bloodstream increases dramatically; early symptoms are unusual thirst, increased output of urine, fatigue, and unusual hunger accompanied by weight loss.
Currently, the only therapy available is to compensate for the destruction of the body's insulin-producing cells by injecting insulin on an ongoing basis.
While genes predispose people to many different types of diseases in many different ways, specific genetic variations are an especially strong predictor of the development of type 1 diabetes. Three genetic variations in particular (HLA-DQ2, HLA-DQ8, and HLA-DR0405)—all located in the region of the genome called HLA for "human leukocyte antigen"—are known to dramatically increase risk of coming down with the condition.
These three genes encode molecules that present peptides (protein fragments) to the body's T cells. T cells then determine whether the peptide being presented is dangerous and needs to be eliminated from the body—as in the case of foreign invaders such as bacteria or viruses—or whether the peptide is "self," part of the host and something the immune system needs to leave alone. However, in the context of type 1 diabetes, T cells aggressively attack the body's own cells.
The scientists wanted to know on a molecular level how mutations in the immune surveillance machinery could lead to type 1 diabetes.
"We were interested in trying to understand why certain MHC molecules (which are molecules in mice analogous to HLA molecules in humans) are linked to autoimmune disease, particularly type 1 diabetes," said Research Associate Adam Corper of the Wilson lab, who was first author of the paper with Kenji Yoshida of the Teyton lab. "In particular, we wanted to know why a single residue at position 57 on the â chain of HLA molecules seems to be linked to the disease."
In the new research, the team used a series of structural and biophysical studies to answer that question.
Previously, Teyton and Wilson labs had determined the structure of a "diabetogenic" MHC molecule and found that mutations to position 57 caused only subtle changes. It did not, as some had speculated, cause the molecule to become unstable and non-functional.
Now, in the new study the researchers found that diabetes-causing mutations changed the charge at one end of the MHC peptide-binding groove. In individuals not predisposed to type 1diabetes, MHC molecules usually have a negatively charged residue at position 57. In contrast, disease-causing MHC molecules have a neutral residue at position 57 and consequently the surrounding region is more positively charged.
The result of this molecular change was that the mutated MHC molecules selected a unique subset of T cells that bound to it strongly, with "higher affinity." These T cells may overreact and potentially misidentify "self" peptides as dangerous rather than harmless.
"We found that the MHC region around position 57 can be seen by the T cell receptor," said Teyton. "That's the big novelty of the paper—for the first time, we show that it is not only essential for peptide binding, but also critical for the selection of T cells. Finally, we have an idea of why those particular MHC molecules are associated with disease."
Corper added, "What we have here is potentially a way of breaking 'tolerance'—the mechanism where the immune system doesn't respond to self. Obviously, if that breaks down you get autoimmune disease."
The team is now investigating potential antibody or small molecule therapies that could target and correct mutated MHC.
In addition to Teyton, Wilson, Corper, and Yoshida (currently assistant professor at Meijo University, Japan), the authors of the paper, "The diabetogenic murine MHC class II molecule I-Ag7 is endowed with a switch which modulates TCR affinity," include Rana Herro of Scripps Research and Bana Jabri of the University of Chicago.
The study was supported by the National Institutes of Health.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.
Keith McKeown | EurekAlert!
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
20.04.2018 | Physics and Astronomy
20.04.2018 | Interdisciplinary Research
20.04.2018 | Physics and Astronomy