Prion proteins are unlikely to prompt an immune response, experts in the disease said today. The finding clears the way for a prion vaccine, said Adriano Aguzzi, professor of neuropathology at the University of Zurich.

"Prion diseases are a worldwide problem, particularly since the outbreak of mad cow disease in Europe," said Fred Cohen, professor of pharmacology at the University of California at San Francisco. "It's not just the cows that are mad - people really want to know how to tackle these diseases."

Bovine spongiform encephalopathy (BSE), or mad cow disease, is just one of a class of neurodegenerative prion diseases that also includes Creutzfeld-Jakob disease in humans, and scrapie in sheep.

Prion diseases have at their root the abnormal form of a small glycoprotein called prion protein, or PrP. PrP is expressed in healthy cells (PrP-cellular, or PrP-c) with no ill effects, and is covalently indistinguishable from the deleterious form (PrP-scrapie, or PrP-sc).

The two forms of PrP have different structures, or conformations, however: PrP-sc is rich in beta sheets, while PrP-c is rich in alpha helices. PrP-sc is also resistant to proteases that would normally destroy PrP-c.

One therapeutic strategy to prion disease is a vaccine against PrP-sc. But because PrP-sc has the same amino acid sequence as PrP-c, researchers have feared that a vaccine to PrP-sc could trigger an autoimmune response against PrP-c, the normal version of the protein.

But vaccines are a safe therapy against prion disease, said Aguzzi, and autoimmune responses to PrP-c antibodies will kick in only when the body is swamped with PrP-c, Aguzzi said.

To determine whether there is a threshold protein level that holds autoimmunity at bay, Aguzzi looked at mice that overexpressed the PrP gene and therefore had excessive systemic PrP-C.

When challenged with antibodies to PrP-c, the transgenic mice had a "tremendous autoimmune response," he said. Control mice, which express normal levels of PrP-c, did not show an immune response.

The finding confirms the idea of a protein threshold, Aguzzi said. "Normal, wild-type expression levels of PrP-c protein should not induce an immune response," he said, and a vaccine against PrP-c should therefore not induce autoimmunity.

Prion diseases arise through infection or mutation, either inherited or sporadic. Infection with PrP-sc seems to switch brain cells from producing normal PrP-C to make PrP-sc instead. In contrast, mutations in the gene expressing PrP gives rise to proteins that switch from benign PrP-c to deadly PrP-sc.

Protein misfolding is a problem not only in prion diseases but in a range of degenerative diseases of the central nervous system, including Alzheimer's disease, Huntington's disease, amyotropic lateral sclerosis (ALS).

Research into prion diseases may also provide insights to other neurodegenerative disorders, said Cohen. "By developing an understanding of prion diseases," he added, "we will all be better off."