This is my attempt to explain the many diverse facts about HD. This comes from an engineer not from a biologist. Some ideas presented here are not main stream biology. I thank the biologists and medical professionals that have given me their time to my dogged arguments.
If there is objection or comment to these ideas, I will publish them here. The following will most likely change from time to time. --Jerry 02Feb01; updated 23-Sep-01
Huntington's disease (HD) is dominant disorder caused by an expansion of the poly Q tract of the huntingtin gene. The gene is widely expressed but only a narrow sub-set of cells are affected. Just how the HD gene causes HD is unknown.
Insight may be gained by comparing HD to better understood diseases that have related effects.
The diagram shows aspects of two diseases. A form of cancer is described in red. Huntington's disease with diabetes is described in blue.
Starting at he left, the red lines show that cancer genes cause this cancer. The cancer activates the immune system which in turn kills cancer cells. Brain cells are also killed.
The blue lines show that the huntingtin gene also activates the immune system. In this diagram the neurological defects of Huntington's disease are caused by an activated immune system. The effects of the activated immune system on incidental cancer is also shown as is the tendency for carriers of mutant huntingtin to develop diabetes. The diagram also depicts the early Alzheimer's pathology prevalent in HD patients.
Lung cancer and other cancers are sometimes associated with brain cell death. Brain cell death in cancer patients is called paraneoplastic cerebellar degeneration (PCD). PCD is caused by the collateral destruction of brain cells by the immune system attacking a tumor. Nat Med 1998 Nov;4(11):1321-4, Albert ML et al. HD carriers are protected from many forms of cancer. "The lower incidence of cancer among patients with Huntington's disease seems to be related to intrinsic biologic factors." Cancer 1999 Oct 1;86(7):1342-6, Sorensen SA et al. Tumor protein p53 is perhaps the single most important human tumor suppressor. Mol Genet Metab 2000 Jun;70(2):85-98, Grimberg A. At some CAG expansion, mutant huntingtin may mimic p53. P53 is regulated by mutant huntingtin. (ref)
One explanation for PCD is that factors such as P53, interleukin (IL)-1 or tumor necrosis factor-alpha (TNFalpha) are upregulated by the immune system and this causes brain cell death.
The immune system could recognize the expanded CAG tract in a immune reactive way as it does a CpG bacterial tract. A CpG bacterial motif will cause antibodies against tumors. Cancer Res. 1999 Nov 1;59(21):5429-32, Carpentier AF, et al. It is tempting to think that the CAG tract is recognized by the immune system. "Aside from its function as the 'blueprint of life' that encodes genetic information, DNA can have direct immune activities. The immune system has evolved a defense mechanism that is able to distinguish microbial DNA from our own because of differences in the frequency and methylation of CpG dinucleotides in particular base contexts." Pharmacol Ther 1999 Nov;84(2):113-20 Krieg AM, et al. There may be alternative interaction at the DNA-RNA level that causes the CAG tract to activate the immune system. Cells in the immune system may be protected from apoptosis by mutant huntingtin. Tumor necrosis factor could be upregulated. The fact is that HD carriers have immunity from cancer. It is suggested that immune system activation from a tumor or HD can act in a parallel way to kill brain cells. Just how this happens remains to be found.
Both PCD and HD result from the destruction of very specific cell populations. PCD patients have a wide spectrum of defects from patient to patient. Some symptoms are congruent with those of HD. The symptoms of HD are not consistent from patient to patient. The specificity in PCD is explained by immune system targeting (1)from a variety of cancers and the history of the immune system. It is tempting to think that HD can be explained in the same immune related way.
HD patients have a heightened immune system. "The data indicate an activation of various immune system compartments in Huntington's disease and that systemic immunological alterations might be important in the course of the disease." Clin Chem Lab Med 1998 Oct;36(10):747-50 Leblhuber F., et al.
It is proposed that the heightened immune system is a direct effect of the mutant huntingtin gene. In particular it is suggested that the hair pin structures formed by mutant huntingtin directly affect the methylation of CpG islands to mimic bacteria.
"Results from the analysis of family data indicate that HD affected relatives of an HD proband with diabetes are 7 times as likely to have diabetes over the proband's non-HD relatives." Clin Genet 1985 Jan;27(1):62-7 Farrer LA.
Diabetes is an auto-immune disease that, in HD gene carriers, seems to be caused by a heightened immune system that is likely a primary effect mutant huntingtin. Other auto-immune diseases may also be more common in HD carriers. "Auto-immune disease occurs when the immune system attacks self-molecules as a result of a breakdown of immunologic tolerance to autoreactive immune cells. Many auto-immune disorders have been strongly associated with genetic, infectious, and/or environmental predisposing factors. Comprising multiple disorders and symptoms ranging from organ-specific to systemic, auto-immune diseases include insulin-dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, thyroiditis, and multiple sclerosis." Environ Health Perspect 1999 Oct;107(Suppl 5):661-665 Smith DA, et al.
Scientists have long believed that immune system cells in the brain, called microglia, are somehow incensed to attack the neurons in Alzheimer's patients. There is a curious fact about HD patients and AD. HD patients have a high incidence of Alzheimer pathology. AD appears early but progresses more slowly in HD patients. "The reasons for the early onset but mild progress of Alzheimer-like lesions in HD and their contribution to cognitive decline await further elucidation." J Neural Transm. 1998;105(8-9):787-99. Jellinger KA.
There is much anecdotal evidence that carriers of the mutant gene have immunity from common childhood illness, colds and the flu. Here is a typical comment, "Maybe it's just me but my husband and several gene positive friends of mine NEVER seem to get sick... I'm talking colds, flu, virus etc!! Now I realize some may stay home more than us caregivers however the flu, viruses and colds have run rampant thru our home and Joe NEVER gets it!! I've heard the same from others. Any thoughts or comments on this? I'd be interested in what some physicians may think of this.... (other than me being crazy that is) Is there any significants to this?? " Harvard Neurology Web Forum 2/30/99
Grafts to treat HD have been disappointing. Animal grafts have failed. "Although striatal grafts exerted a statistically significant influence on several indices of this impairment, all behavioral effects were small and did not exert any clinically relevant effect on the profound neurological deficiency of the transgenic mice." Exp Neurol 1998 Nov;154(1):31-40 ,Dunnett SB, et al. The viability of tissue implants may be mediated by components of the immune system. Any reported benefits of cell implants to treat HD may due to the effects of immune suppression drugs such as cyclosporin.
The above evidence, taken in its entirety is argument that the mutant huntingtin gene directly affects the immune system. HD carriers have immunity from common infections and cancers. HD may have a similar mechanism to PCD in which an immune response to a non related element targets and destroys, brain cells. Treatments that are effective for autoimmune diseases may be effective for HD. Anti inflammatory medications or supplements may treat HD.
To understand HD, with the goal of developing effective treatment, four facts must be accounted for.