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The human body's immune system is like a fort - a collection of mechanisms that protects against infection. It does so by identifying viruses, bacteria, parasitic worms and sometimes even tumor cells, and then killing the strangers. But the system isn't foolproof, and pathogens can evolve to find new ways to infect a host.
But in 2% of the population, the body's immune system goes haywire and fails to recognize its own parts as "self," which results in an attack on healthy cells. This can occur from before birth (as in type 1 diabetes) into old age.
There are about 80 different kinds of autoimmune disease, which can attack any organ in the body, including the brain, heart, nerves, skin, glands, joints and bones. Among the best known, besides type I diabetes, are rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis (Crohn's disease), Graves' disease, vitiligo, glomerulonephritis, chronic liver inflammation, Sjogren's syndrome, Hashimoto's thyroiditis, pernicious anemia and myasthenia gravis. While a high level of autoimmunity can harm the body, a low level, called natural autoimmunity, is apparently beneficial, as some autoimmune responses are vital to the body's functioning and the development of tolerance to self-antigens.
ALTHOUGH THE general public don't know much about autoimmune diseases, people do sit up and pay attention when someone close is diagnosed with one. While these diseases usually don't kill, they are chronic, so pharmaceutical companies "love" them because of the expensive medications that need to be purchased for life.
Scientists are developing a better understanding of the immune system and autoimmune diseases, although much remains to be discovered. Among the Israelis who have been prominent in the field is Prof. David Naor of The Hebrew University-Hadassah Medical School, whose 70th birthday and official "retirement" were marked recently with a two-day international symposium at the medical school's Magid Auditorium.
The event - attended by more than 150 doctors and researchers (including Prof. Marc Feldman of Imperial College in London, who delivered a major lecture) - concentrated on similarities and differences between cancer and autoimmune disease - a topic on which Naor has invested 40 years.
BORN IN HADERA, Naor studied at The Hebrew University, specializing in immunology. "I didn't want to be a physician; it didn't attract me," says Naor, who is tall, white-haired and fit. He worked on the side "milking" venom from vipers, which was used to produce anti-snakebite serum in horses and camels. It was Pini Amitai, the veteran Jerusalem reptile expert, who taught Naor how to "milk" snakes. His interest in autoimmune diseases and cancer, he says, didn't result from anyone close to him having such a disease. Naor's 1967 degree thesis was published in Nature. He did post-doctoral studies at the University of California at Berkeley and at the University of California in San Francisco. Since 1972, he has been a HU faculty member, teaching and researching immunology.
"Seventy is just the beginning," Naor says in a Jerusalem Post interview during the symposium. "I'm not retiring; I'm only starting, working on all kinds of projects. We have our own company, Maimonidex, in Tel Aviv that makes antibodies against rheumatoid arthritis. And I continue to teach."
NAOR EXPLAINS that the reaction of the body to cancer is an autoimmune reaction. "Tumors are like any other tissue, but unfortunately, the immune system's reaction to cancer is weaker than to bacteria or other pathogens, and often can't be seen. As I see it, cancer cells know how to deal with the immune system, as they divide faster and release toxic materials that act against the immune system, which doesn't know how to counterattack. Our challenge is to understand why the immune reaction to cancer is so weak. Knowing the answer will be a great advance."
During the symposium, Israeli and foreign lecturers presented research and theories on how to induce the immune system to destroy malignant cells without harming healthy tissue. Naor said he hoped the gathering would help further this important line of research.
In both cancer and autoimmune diseases, healthy cells are destroyed - in the former due to cells that grow and spread in an uncontrolled fashion, and in the latter due to the body's immune system mistakenly destroying vital tissue.
"This is a paradoxical situation," states Naor, "since if only it were possible to induce an autoimmune reaction against cancer cells, we could eliminate cancer."
Indeed, it has been known for years that the immune system is not indifferent to some malignant tumors, and tries to eliminate them in the same way it fights off bacteria. But this phenomenon shows up only rarely, and the immune system is usually not successful in fighting off cancerous cells.
Naor says he doesn't think there will be a single solution for all autoimmune diseases. "Each involves a different antigen, so I think there has to be a separate treatment for each, just as cancer is a collection of diseases with different treatments, depending on the affected organ."
PROF. YEHUDA SHOENFELD, a leading clinical immunologist (one of 150 in Israel), and an expert in rheumatology and allergy at Sheba Medical Center in Tel Hashomer, praises Naor for his "great contributions in the development of antibodies for the treatment of autoimmune diseases and cancer."
Shoenfeld, who spoke at the opening of the symposium, noted that several factors trigger autoimmune disease.
"There is a genetic component, but it's not 100%; if a parent has an autoimmune disease, it increases the risk of it being contracted by the child, but this is far from inevitable," says Shoenfeld. Another factor, he says, is a viral, bacterial, parasitic, fungal or other type of infection that causes an immune reaction. Since the pathogen has a protein structure similar to that of healthy body cells, the immune system may attack healthy tissue as well. Any infection can bring it about, but only about 2% of the population gets autoimmune diseases, so there must be a combination of factors, including damage to the normal immune reaction.
"We all have several lines of defense. If one breaks down and other factors are present, autoimmune disease can appear at any time, although it happens more frequently as people age." Certain drugs may also trigger the autoimmune reaction by affecting the regulating mechanism. There are various environmental factors such as the sun (which can trigger lupus attacks), paints (scleroderma) and even living near an airport. Women are much more susceptible than men to autoimmune diseases, the Sheba immunologist notes, because their sex hormones affect their immune systems.
IN HIS LECTURE, which he titled "Smelling Autoimmunity," Shoenfeld focussed on systemic lupus erythematosus, which affects a large number of organs and tissues. It may also affect the central nervous system (CNS) and a person's mental state. CNS involvement in lupus is very common, and linked with more than 20 antibodies, he says. Among the symptoms of lupus is depression. "If a psychiatric manifestation is caused by an autoimmune disease, could it be that other psychiatric conditions whose cause we don't yet know are also due to autoimmune diseases?"
Shoenfeld and colleagues injected one of these lupus antibodies, called anti-P-Ribosomal (anti-P-R), into the brain vescicles of mice. They quickly developed "depressive behavior," which in mice is observed when they are put into containers of water containing a maze and expected to swim to safety. Those that became depressed just floated rather than swimming to find safety. This was the first evidence that injecting a specific antibody into the brain can cause depression, relates Shoenfeld, whose findings were published last March. "Then we injected [the anti-depressant] fluoxetine [Prozac] into the depressed mice, and they swam."
The human-purified anti-P-R antibodies were shown to bind to CNS structures (the limbic system) in the brain, where the smell apparatus functions. When they bind with this part in the brain, it can create depression and harm the sense of smell.
"We found that in many psychiatric conditions, patients lose their sense of smell, opening up the possibility that aromatherapy with certain odors can relieve the condition. We tried exposing depressed rats to lemon and citrus fragrances. This helped more than antidepressants, and the mice started to swim. Aromatherapy has already been tested in elderly Japanese. Perhaps we will be able to repair depression with good smells," Shoenfeld suggested. "A sniffing test may even predict who will develop Alzheimer's. We have neglected smell in the treatment of central nervous system disorders."
Autoimmune diseases are difficult, but there is hope. Steroids may be taken to suppress the immune system, but these can be harmful if taken for too long because they affect a variety of organs and expose patients to infections. A variety of major new drugs such as Remicade have been developed that are alleviating several inflammatory diseases, allowing patients to live normal or near-normal lives.
"There is a revolution with biological drugs for autoimmune diseases, and the discoveries are also occurring in Israel," says Shoenfeld. "As they may afflict not only the elderly but also young people - as with multiple sclerosis and rheumatoid arthritis - treating them has a major economic as well as personal impact. Successful new medications can help go back to work."