A strain of herpesvirus may use a kind of molecular mirror to sabotage cells in the eye, resulting in a common autoimmune disease that can lead to blindness. The finding, reported in tomorrow's issue of Science, gives insight into potential treatments for people with ocular herpes, the principal infectious cause of blindness in developed countries.
The first clue to the importance of this molecular mimicry in herpes stromal keratitis (HSK), an autoimmune disease of the eye caused by infection with herpes virus 1 (HSV-1), came about 3 years ago. While studying why some mice resist HSK, a team led by immunologist Harvey Cantor of Harvard Medical School in Boston found that possession of a particular variant of one type of antibody renders T cells incapable of attacking tissue in the cornea, the transparent covering of the iris and pupil. This suggested that the T cells, presumably triggered by HSV-1, were attacking a similar protein on the cornea. But T cells in mice with the variant antibody had learned to recognize the protein as "self" and so couldn't respond. The link to viral mimicry came when Cantor's group found that the same variant sequence is indeed present on corneal cells and also in a herpesvirus protein called UL6.
To prove that the UL6 protein sequence does in fact trigger the autoimmune attack of HSK, Cantor and his team have now infected mice with either normal HSV-1 or a strain that they had genetically altered to lack the UL6 protein. The result was striking: T cells from mice given virus containing native UL6 protein caused disease, while T cells of animals given the altered virus did not. Furthermore, more than 75% of mice infected with virus bearing the normal protein developed severe corneal autoimmune disease, whereas fewer than 20% of mice infected with mutant virus did, and their symptoms were barely detectable.
The finding is the "final piece of evidence that during an infection, a virus can bring about autoimmune disease [by molecular mimicry]," says viral immunologist Michael Oldstone of The Scripps Research Institute in La Jolla, California, who first proposed the hypothesis in 1982. But molecular mimicry is unlikely to be the whole story, says Abner Notkins, a viral immunologist at the National Institute of Dental Research in Bethesda, Maryland. He notes that in many autoimmune diseases, the immune system targets many proteins, not just the initial one mimicked by a virus.
But if the immune system is indeed attacking the corneal protein identified by the Cantor group, the discovery could "in principle allow us to disrupt or arrest this component" of the attack, says M. Reza Dana, an ophthalmologist and ocular immunologist at Harvard Medical School, perhaps by inactivating the specific set of immune cells responsible for it.