For over thirty years HD has eluded the focused efforts of researchers. At one time the autoimmune thesis was hotly debated.
One leading researcher suspected a retrovirus had inserted into the genome. Since then huntingtin and the excessive CAG repeats have been found. It is tempting to think of excessive the CAGs as the functional equivalent of the virus that was searched for and not found.
Today the money is on the effect of aggregated huntingtin in cells. It is hotly debated if cell deposits are related to the progression of HD. --Jerry 23-May-2001
From: Mapping Fate by Alice Wexler
| The contradictory results led to a heightened level of acrimony at foundation workshops and other HD meetings, centering not only around the autoimmunity hypothesis but increasingly around the skin fibroblast, cell membrane, and other studies, whose promising early results had begun to unravel. |
A quite different avenue of research approached Huntington's as an autoimmune disease. Within a year or two after the Columbus symposium, Dad had hired David Barkley to act as a part-time science director for the foundation, with a half-time appointment at UCLA. Barkley worked with John Menkes on his studies of fibroblasts, but his heart was in the autoimmune thesis. Barkley theorized that Huntington's is caused by a retro virus—a type of RNA virus—that was accidentally inserted into the genome and thereafter passed down within families in a dominant fashion. The abnormal product of the retrovirus could provoke a response from the immune system. This was a novel idea since, at the time, retroviruses had barely been identified and were not known to exist in humans. Barkley cheerfully acknowledged the arguments against this idea, namely the lack of inflammation caused by lymphocyte infiltration in the diseased brain tissue, a sign often taken as the definitive marker of autoimmune disease. But he was convinced that the disproportionate number of those with the juvenile form of Huntington's who inherit the disease from their fathers pointed strongly toward immune system involvement.
The key question was to find out whether people with Huntington's mount an immune response to whatever it is that causes the disease. If they do, the immune response itself might be detectable even before clinical symptoms appeared and therefore would be useful for presymptomatic testing. More important, antibodies could be used to target the agent responsible for killing off cells in the brain.
Barkley decided to test his hypothesis with a complicated set of experiments. The early results looked encouraging. They seemed to indicate that people with Huntington's do indeed have in their brains an antigen (a substance that provokes the production of antibodies), possibly the lethal HD product, that individuals without the disease do not have. The cellular immune system of the affected individuals might be activated by this antigen, provoking the body to attack its own tissues and thereby causing the death of neurons in the brain.
Unfortunately, the unknown antigen did not appear to be exclusive to Huntington's disease. It also showed up in the brains of people who had died of multiple sclerosis. Moreover, the differences were not consistent, and Barkley's unconventional experimental technique was too cumbersome to be used for diagnostic purposes. Researchers also questioned whether the differences were caused by drug treatments rather than by disease.
By 1978, participants at the workshops were sharply divided on the issue. While some investigators continued to support further efforts to clarify the results, others were impatient with the attention focused on the autoimmune theory. The contradictory results led to a heightened level of acrimony at foundation workshops and other HD meetings, centering not only around the autoimmunity hypothesis but increasingly around the skin fibroblast, cell membrane, and other studies, whose promising early results had begun to unravel. The great numbers of variables in all these studies—differences in culture media, different ways of computing statistical significance,and especially genetic differences between people that were unrelated to Huntington's disease—made replication of the results difficult. At best the reported differences between HD and normal cells contained too much overlap to be useful. Surveying the mass of conflicting evidence accumulated about Huntington's over the years, Andre Barbeau wrote in January 1978, "It is high time for a coordinated, integrated effort to unravel this mess and to pinpoint which one of these defects has a chance to be primary."