April 20, 2007

Speaker outlines process that sparks diabetes

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Washington University’s Emil Unanue, M.D., right, talks with Thomas Aune, Ph.D., at last week’s Discovery Lecture. (photo by Anne Rayner)

Speaker outlines process that sparks diabetes

Emil Unanue, M.D., widely recognized as one of the leading figures in contemporary immunology, has applied his considerable expertise to deciphering the bits of proteins that may trigger autoimmune diabetes.

He shared his group's findings last week at the Ernest W. Goodpasture Lecture in Investigative Pathology, part of the Vanderbilt Discovery Lecture series.

“It's been a lot of fun applying the basic biology of antigen presentation to this spontaneous autoimmune disease,” said Unanue, professor of Pathology at Washington University School of Medicine in St. Louis.

“Antigen presentation” refers to the immune system process that displays small pieces of pathogens on the cell surface of “antigen presenting cells,” in combination with a special group of molecules known as the major histocompatibility complex (MHC). This process, which was first described by Unanue and colleagues, is the basis for how the immune system recognizes and responds to pathogens.

Unanue and colleagues have used biochemical and cellular studies focused on a model protein — chicken lysozyme — to determine the “precise chemical rules for the interactions of different segments of the protein with a given MHC,” he said.

The group decided about 10 years ago to study autoimmune diabetes.

“For lysozyme we knew all of the segments of the protein,” Unanue said. “For autoimmune diabetes, we were facing a complete unknown: what beta cell proteins and peptides are being presented to trigger this disease?”

Type 1 diabetes is caused by an autoimmune process — mediated by T cells — that destroys the insulin-producing beta cells of the pancreas. Unanue and colleagues are after the beta cell antigens that are displayed on antigen presenting cells and recognized by “diabetogenic T cells.”

They have studied the non-obese diabetic (NOD) mouse — a mouse strain that spontaneously develops diabetes which mimics the human disease both genetically and in its cellular reaction. The NOD mice have an MHC protein similar to the human MHC protein that is associated with the development of type 1 diabetes.

Unanue and colleagues have definitively determined the features of peptides that bind to the diabetic-propensity MHC molecule, he said, and they are currently characterizing the “real” autoimmune antigens from beta cells.

The list is long.

“There are a lot of beta cell proteins and peptides being presented,” Unanue said. “It's very interesting, the plethora of proteins that we can identify as immunogenic and the complete breakdown of self-tolerance in this kind of autoimmune disease.”

Unanue sees identifying the specific beta cell peptides as the way forward for peptide therapies — strategies that aim to use peptides to prevent autoimmune disease by activating regulatory elements of the immune response.

“I think having data where we know exactly the sequence that is involved can lead to a more rational approach for peptide therapy, which I think is the way to go,” he said.

Prior to Unanue's lecture, Robert Collins, M.D., John L. Shapiro Professor of Pathology, offered remembrances of Ernest Goodpasture, M.D., who served as chair of Pathology at Vanderbilt from 1924 to 1955.

It was Goodpasture, Collins said, who was key to establishing the legitimacy of the Vanderbilt School of Medicine after its reorganization in 1925. Goodpasture was best known for a chick embryo technique for culturing viruses that led to the development of vaccines for yellow fever, influenza, smallpox and typhus.

The Goodpasture Lectureship was established by Goodpasture's friends and colleagues, and the Department of Pathology.

For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.