Proteomics

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 Nature Biotechnology, 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 autoimmune disorders. 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 immune system, 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. Autoimmune diseases 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 pancreatic cells. 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 immune cells."

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 protein 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.

Source: Medical News Today © MediLexicon International Ltd 2004-2011 (03/06/11)

Australian researchers will aim to discover the proteins that cause multiple sclerosis (MS), thanks to a new nationwide research effort.

The national research project is the first of its kind in Australia and one of the first of its kind in the world.

"This collaborative research project has the potential to find crucial answers about a debilitating disease that affects millions of people worldwide," says the Hon. Mark Butler MP, Parliamentary Secretary for Health.

More than 2.5 million people worldwide have MS, with the disease costing the Australian community alone an estimated $2 billion each year. Despite considerable research efforts so far, there are few effective treatments for MS.

The new research project will receive funding of $1 million over four years, starting this year, under the Australian Research Council's Linkage Projects funding scheme and from MS Research Australia (MSRA), the research arm of MS Australia.

The research is a major national collaboration between the University of Adelaide, Monash University, University of Queensland and the Sir Charles Gairdner Hospital, with the University of Adelaide as lead institution.

"With MS, there are a number of major stages that occur in the disease, including activation and remission," says the lead investigator, Professor Shaun McColl (School of Molecular & Biomedical Science, University of Adelaide).

"At each of these major stages, certain genes are activated. Those genes express proteins, and we believe these could have the effect of switching the disease on and off. If we can discover the key proteins and their roles in the development of MS, we could go a long way towards finding potential treatments or cures for the condition," he says.

The area of research involved in discovering such proteins is known as proteomics.

"There is no doubt that identification of a set of proteins that are specifically linked to different stages and pathological processes in MS will provide insight into the disease," says Professor Claude Bernard (Multiple Sclerosis Research Lab, Monash University). "It will also help evaluate the prognosis of patients with MS, guide their treatment and provide novel therapeutic approaches," he says.

Mr Jeremy Wright, Executive Director of MS Research Australia, says: "This is a natural step for MSRA to help researchers make important new discoveries that will translate into real outcomes for people with MS. Together with the ARC, we are investing $1 million into this promising new area for MS research."

Source: Medical News Today © 2009 MediLexicon International Ltd (27/08/09)