‘Mirror image’ findings could result in better therapies for autoimmune diseases

By DIANNE SHAW
UNC Lineberger Comprehensive Cancer Center

CHAPEL HILL -- Researchers at the University of North Carolina at Chapel Hill’s School of Medicine have made a novel discovery that could open new research avenues and create more precise, less toxic therapies for autoimmune diseases.

Their study appears Sunday (Dec. 7) as an advance online publication in the January issue of the journal Nature Medicine. The research team includes Dr. Ronald Falk, Thurston professor of medicine and chief of the School of Medicine’s division of nephrology and hypertension; Dr. Gloria Preston, associate professor; and Dr. Will Pendergraft, a postdoctoral fellow.

Autoimmune diseases – which include lupus, rheumatoid arthritis, myasthenia gravis, Grave’s disease and small vessel vasculitis – are caused when antibodies produced by an individual’s immune system are mistakenly directed to attack the body’s own tissues.

The breakthrough came when the UNC researchers discovered that patients with autoimmune disease harbor antibodies reactive to a normal "self" protein (the autoantigen of this disease), as well as to its mirror image protein. In other words, parallel to the existence of the normal "self" proteins are other proteins complementary to "self" proteins.

Falk likened the research team’s observations and eventual findings to the work of M.C. Escher, a graphic artist whose work incorporates optical illusions and unconventional patterns that may elude the viewer’s eye at first glance.

"In an Escher drawing, the eye focuses on one image, but there is a parallel image that interconnects with the dominant image. UNC proposes that in autoimmunity, the parallel image has been

overlooked in the past, and may be, in fact, the culprit and trigger for autoimmunity," he said.

That discovery led the researchers to propose that the initiating event in autoimmunity is the production of an antibody against a protein complementary to a normal "self" protein. This event triggers a chain reaction of cellular events leading to the eventual evolution of antibodies that react against "self."

The key to understanding this sequence of events is in clarifying the interactions of proteins with their corresponding counterparts, said Preston. The novelty here, she added, is the discovery of mirror image immunologic components as primary in triggering an autoimmune response.

Why an individual’s immune system makes these errors has long been a mystery, and the UNC findings may explain how and why these errors occur – and offer a new theory for the development of autoimmunity, Falk said.

However, the source of the complementary, or mirror image, proteins still is not clear. They may be carried by microbes. Some evidence suggests that patients produce them themselves by an irregular transcription process. Transcription is the process of constructing a messenger RNA using a DNA molecule as a template with a resulting transfer of genetic information to the messenger RNA.

A cell’s normal mRNA is called sense mRNA because it has the correct base sequence. However, UNC researchers found antisense mRNA molecules in some patients with autoimmune disease.

Antisense mRNA is made from the same genomic region as sense RNA but from the opposite DNA strand, which when transcribed has a very different base sequence. These mRNAs are then used as templates for the synthesis of proteins, and because of their common genomic origin, these two proteins are considered complementary to each other.

Funding for the research came from a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health.

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Note: Contact Falk (extension 224), Preston (extension 231) and Pendergraft (extension 232) at (919) 966-2561

Contact: Dianne Shaw, (919) 966-7834