A promising new approach to autoimmune diseases

June 2, 2011

Researchers from Harvard Medical School and MIT have developed a new approach for identifying the "self" proteins targeted in autoimmune diseases such as multiple sclerosis, diabetes and rheumatoid arthritis.

In a paper published in , H. Benjamin Larman and colleagues showed that errant immune responses which mistakenly target the body's own proteins rather than foreign invaders can now be examined in molecular detail. Further research could lead to new insights into the exact causes of these debilitating . The results come from the laboratory of Stephen Elledge, the Gregor Mendel Professor of Genetics and Medicine at HMS and senior author of the study.

The , the body's main line of defense against disease, has a critical responsibility to distinguish self-derived proteins from those of invaders like viruses and bacteria. arise when a person's immune system fails to make that critical distinction and mistakenly attacks a normal tissue, such as nerve, joint, or insulin-producing . These disorders are usually progressive and in some cases even lead to life-threating disease. Understanding where the immune system went wrong has been a major goal for generations of biomedical researchers.

"Knowledge of the self-antigens involved in autoimmune processes is important not only for understanding disease etiology, but also for developing diagnostic tests," the authors write. "In addition, physicians may someday use antigen-specific therapies to destroy or disable auto-reactive ."

But looking through the haystack of cellular complexity for those single-needle self-antigens targeted by the immune system has proved daunting, to say the least. Ideally, scientists would be to develop some kind of biological magnet that could pull these fine needles out of the mass.

In this report, the researchers describe an approach which does just that.

Elledge and colleagues improved upon a well-established technique called phage display in which bacterial viruses, called bacteriophage, display DNA-encoded protein fragments on their surfaces. As Nicole Solimini, co-corresponding author on the paper, explained, the researchers "built a reproduction of all the proteins in the human body (collectively, the human proteome) by synthesizing the corresponding DNA fragments for expression on the surface of bacteriophage."

This new proteome library provides a physical link between the protein being studied and the gene that makes it, allowing researchers to look for and identify interactions between any human proteins, such as that between an autoantibody in a patient's blood and a self-protein that prompts an autoimmune response. In fact, this technology can be used to look for any type of interaction between human proteins, providing a powerful new tool to biomedical investigators in any discipline.

Applying their technology to autoimmune disease, the team developed a technique called phage immunoprecipitation sequencing ("PhIP-Seq"). Using cerebrospinal fluid from three patients suffering from an autoimmune disorder called paraneoplastic neurological disease, the researchers could identify known and previously unreported self-proteins targeted by patients' immune systems—that is, interactions between an autoantibody in the cerebrospinal fluid and the self-protein that drives the autoimmune response.

According to Larman, "a small sample of blood from a diabetic patient, synovial fluid from an arthritic joint, or cerebrospinal fluid from a patient with multiple sclerosis would be mixed together with the proteomic library. The self-reactive antibodies in the patient's sample will seek out and then bind to the targeted proteins in our library. We can then separate out the antibody-bound fragments and determine their identity by high-throughput, next-generation DNA sequencing."

Based on six years of laboratory work at HMS, the project is directly linked to the ongoing success of the Human Genome Project, which had already made available almost all of the genes the body needs in order to build, operate and repair itself. As the end products of individual genes, the body's many individual proteins are central players in all aspects of health and disease.

Explore further: Immune responses spread from one protein to another in type 1 diabetes

Related Stories

New proteins detected on silicone breast implants

December 19, 2006

Scientists in Austria are reporting detection of previously unrecognized proteins that accumulate on the surface of silicone breast implants after implants are in the body. Georg Wick and colleagues say that the proteins ...

Dendritic cells ensure immune tolerance

March 16, 2009

Dendritic cells are essential to the body's immune defenses. Now, Ludwig-Maximilians-Universitaet Muenchen (Germany) researchers show that they also have to protect the body from itself: They help to identify any immune cells ...

Type 1 diabetes linked to immune response to wheat

August 20, 2009

Scientists at the Ottawa Hospital Research Institute and the University of Ottawa have discovered what may be an important clue to the cause of type 1 diabetes. Dr. Fraser Scott and his team tested 42 people with type 1 diabetes ...

Discovery prompts new theory on cause of autoimmune diseases

May 3, 2010

The recent discovery of a protein fragment capable of causing diabetes in mice has spurred researchers at National Jewish Health and the University of Colorado Denver to propose a new hypothesis about the cause of diabetes ...

New drug target for immune diseases discovered

August 3, 2010

Researchers from Mount Sinai School of Medicine have found a new mechanism that explains how certain immune cells are activated to create protective antibodies against infections or pathological antibodies such as those present ...

Recommended for you

Basic research fuels advanced discovery

August 26, 2016

Clinical trials and translational medicine have certainly given people hope and rapid pathways to cures for some of mankind's most troublesome diseases, but now is not the time to overlook the power of basic research, says ...

New method creates endless supply of kidney precursor cells

August 25, 2016

Salk Institute scientists have discovered the holy grail of endless youthfulness—at least when it comes to one type of human kidney precursor cell. Previous attempts to maintain cultures of the so-called nephron progenitor ...

New avenue for understanding cause of common diseases

August 25, 2016

A ground-breaking Auckland study could lead to discoveries about many common diseases such as diabetes, cancer and dementia. The new finding could also illuminate the broader role of the enigmatic mitochondria in human development.

Strict diet combats rare progeria aging disorders

August 25, 2016

Mice with a severe aging disease live three times longer if they eat thirty percent less. Moreover, they age much healthier than mice that eat as much as they want. These are findings of a joint study being published today ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.