Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps Research scientists reveal how genetic mutations may cause type 1 diabetes

20.04.2010
The findings point to a new drug target for type 1 diabetes and other autoimmune diseases

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."

Breaking Tolerance

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!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>