Autoimmune disorders, in which the immune system goes awry and begins to attack some element of the body, are now well-known as the basis for such diseases as multiple sclerosis and systemic lupus erythematosus.
But it is less well known that an autoimmune disorder can also develop as a consequence of other diseases, nearly defeating efforts at diagnosis. The trail can be equally surprising in the other direction: A rare autoimmune disorder can lead researchers to insight on some major diseases.
In both types of cases, the brain offers examples of particular interest, because it is generally considered to be protected from the immune system by nature of its unique capillary system, known as the blood-brain barrier.
An example of the first type of case is the "paraneoplastic syndromes." These are instances in which patients with cancer suddenly begin to show signs of neurological disease such as difficulty speaking or loss of coordination—due not to the spread of the cancer, but to an autoimmune attack on the brain.
Jerome Posner, of Memorial Sloan-Kettering Cancer Center, thinks these syndromes occur when cancer cells begin making proteins that normally are produced only by neurons. The "abnormal"proteins, he suspects, are seen by the immune system as an antigen, triggering immune attack on healthy neurons as well as on the cancer cells.
To complicate the clinical picture, Posner says, Often the neurological disease appears first and the detection of the cancer is delayed by a year or more." The neurological disease is difficult to diagnose because it appears to have arisen from nowhere; meanwhile, ironically, autoimmune attack is keeping the cancer at bay.
Posner hopes that the great sensitivity of the immune system can eventually be harnessed to an even greater discrimination in recognizing antigens, priming antibodies to take aim against slow-growing disease such as cancer at an earlier stage. Such antibodies might also be directed to deliver anti-cancer drugs only to genuine cancer cells, thereby minimizing the side effects of treatment.
In the second type of case, a particularly striking example of an autoimmune impact on the brain is a rare disorder called stiff-man syndrome. In this disease the immune system begins to impair the neurons that inhibit muscle activity; the result is a progressive and painful rigidity of the muscles, often leaving the patient bedridden.
Although stiff-man syndrome affects only a few hundred people throughout the world, its study may help in the struggle to control a disorder that affects many more: insulin-dependent diabetes. As determined by cell biologists Pietro De Camilli and Michele Solimena of the Yale School of Medicine, in many cases the autoimmune attacks are triggered by a specific product of these neurons known as "glutamic acid decarboxylase" (GAD). Once Solimena and De Camille observed that many people with stiff-man syndrome also have insulin-dependent diabetes, they wondered whether GAD autoimmunity was involved there as well. It was already known that the cells of the pancreas, which produce insulin, also produce GAD. In collaboration with Steinunn Backkeskov at the University of California-San Francisco, the Yale researchers have established that diabetic patients develop autoimmunity to GAD. The diabetic patient's lack of insulin, which arises from autoimmune destruction of insulin-producing cells in the pancreas, may therefore result from autoimmunity to GAD.
An entirely different disease is implicated by a small group of women with stiff-man syndrome who also suffer from breast cancer. In these cases, the trigger for the autoimmune attack is apparently not GAD but another neuronal protein called amphiphysin—which has now been found in some breast tumors. This may represent a new parancoplastic syndrome like those leading to a loss of coordination. As researchers continue to explore such face-offs between the immune and the central nervous system, studies of some little-known diseases promise to shed light far beyond their original focus.