Environmental factors--what role in autoimmune diseases?

http://www.aarda.org/infocus_article.php?ID=33

From InFocus Newsletter, September 2006 

•  Fundamentally, all autoimmune diseases are a consequence of impaired immune function that results from interactions of genetic and environmental factors. Despite important progress, much remains to be learned about these factors and their interactions. Advances in this area are providing a foundation for more effective therapies and prevention strategies.

• Approximately one-third of the risk of developing an autoimmune disease can be attributed to heritable factors; the remainder is thought to be associated with non-inherited events.
• Some of these events arise from the randomness that characterizes human exposures; and others, from the diversity of the immune system itself--a diversity that enables the immune system to recognize a broad range of bacteria and viruses.

• These environmental factors account for the occurrence of autoimmune disease in only one member of a pair of genetically identical animals or identical twins.

• Certain environmental agents play a clear role in instigating autoimmune processes. For example, drugs such as procainamide and hydrolyzine can induce a lupus-like syndrome in genetically-susceptible individuals that remits when the drug is discontinued. Other drug-induced autoimmune diseases have been described, including some of the hemolytic anemias, thrombocytopenias, and the leukopenias.
   
• The possible role of exposure to various metals in autoimmune disease has been explored, primarily through laboratory and animal studies.

• Generally, metals inhibit immune cell proliferation and activation, with notable exceptions. Mercury, gold, and silver, for example, can induce lymphocyte proliferation and subsequent autoimmunity.

• Genetically-susceptible mice develop a lupus-like condition when dosed with mercury, silver, or gold. It is likely, however, that the autoimmune disorders that result from exposure to various metals occur through distinct mechanisms.
   
• Abnormal immune responses may also be due to a deficiency of a specific substance. For example, selenium deficiency has been linked with autoimmune thyroiditis and cardiomyopathy in humans; some people with these disorders improve when given selenium supplements. As with studies of the role of metals, the mechanism of action remains unclear. 

• Other environmental exposures have been studied, but associating such exposures with specific disorders is difficult.
• Some epidemiologic information suggests an association between dietary iodine and iodine-thyroiditis, and between silica and both scleroderma and lupus in certain industrial settings.
• Additional research has explored possible relationships between autoimmune disease and exposures to organic compounds, principally the halogenated hydrocarbon trichloroethylene (TCE) and polychlorinated biphenyls (PCBs). TCE metabolites have been associated with systemic lupus erythematosus, systemic sclerosis, and other autoimmune disorders. The evidence for PCB effects is sparse.
• Similarly, a few epidemiologic studies have examined occupational exposures to dioxins; however, firm epidemiologic evidence of a cause and effect association has yet to be shown. Similarly, investigations of exposure to pesticides and estrogenic compounds are areas of considerable research interest, but they require additional exploration.
   
• Ultraviolet radiation from sun exposure can exacerbate disease in patients with systemic lupus erythematosus.
• Other epidemiologic studies suggest that ultraviolet exposure may be protective in multiple sclerosis and rheumatoid arthritis; however, conflicting animal studies indicate that ultraviolet exposure may increase autoimmune disease risk in genetically-predisposed individuals.
   
• Infectious agents are the most often cited environmental factors implicated as triggers of autoimmune diseases. A classic example is the central role of the Group A beta-hemolytic streptococcus in the development of rheumatic heart disease. Acute Guillain-Barr? syndrome has been associated with a number of bacterial and viral infections, and reactive arthritis has been linked to a variety of intestinal infections.

• Indirect evidence has implicated a number of infections in type 1 diabetes and multiple sclerosis, and it has focused renewed attention on the possible role of Epstein-Barr virus (EBV) in lupus and rheumatoid arthritis.
   
• Despite these leads, the exact mechanisms by which infection induces a particular autoimmune disease are unknown. In the case of streptococcus, it is believed than an antigen of the microorganism resembles an antigen present in the heart and that a cross-reactive immune response to the infecting microorganism causes immune-mediated damage to the heart. The phenomenon is referred to as molecular mimicry. In other instances, microorganisms or local inflammation may alter antigens of the host so that the immune system sees them as foreign. Infections may also increase immune cell expression of co-stimulatory molecules and thus promote autoimmune responses.
  
  --Source: Progress in Autoimmune Diseases Research, NIH Autoimmune Diseases Coordinating Committee "Report to Congress," March 2005
  
  

Pig-to-Monkey Transplant Treats Diabetes

http://www.technologyreview.com/biomedicine/22636/?nlid=2019
Embryonic tissue could let xenotransplants evade the host's immune system.

• Using embryonic tissue for interspecies organ transplants offers a way to evade the host's immune system, say scientists who used the method to treat type 1 diabetes in primates. By transplanting embryonic pancreatic tissue from pigs to monkeys, Israeli researchers report that they were able to reverse the primates' insulin deficiency.
• The key, the researchers say, is the embryonic tissue's ability to grow into a new pancreas that uses blood vessels from the host animal. The host blood vessels are not subject to the dangerous immune reaction that has always dogged xenotransplants of mature pancreatic material.
• The research team, led by Yair Reisner of the Weizmann Institute, claims that the results, published in the latest issue of the journal PNAS, could offer an attractive replacement therapy for type 1 diabetes, an autoimmune disease in which the destruction of the pancreas means that sufferers rely on injections of the hormone insulin to control their blood-sugar levels.
• In an earlier study, the researchers found evidence that semiformed pancreatic tissue taken from pig embryos at 42 days of gestation appeared to offer the best combination of characteristics for xenotransplantation.
• According to Reisner, if they're harvested too early, there may not be enough partially differentiated pancreatic cells. But if taken too late, the tissues' ability to grow into a new organ is diminished, perhaps because they contain too few stem cells, while their ability to cause immune rejection increases.
• In the latest study, the researchers transplanted 42-day-old pig pancreatic tissue into monkeys with induced type 1 diabetes. The first pair of animals involved in the study died soon after transplantation from an infection caused by too much immunosuppressive therapy.
• The second pair of animals received milder immunotherapy and survived for a year. Furthermore, within five months of treatment, the animals had grown new pancreases and were no longer reliant on insulin injections.
  
• This indicates that the replacement organs had sufficient islets--tiny, insulin-producing structures consisting of around 1,500 beta cells, which have their own intricate vascular systems.
• Radioimmunoassay tests confirmed that the insulin produced by the monkey was porcine, while the network of vessels running through the new organ was made of host cells. "This is important because it meant the monkey's immune system did not attack the vessels," says Reisner.
• This type of immune reaction has been a bugbear for researchers, he says, because primates, including humans, produce a class of antibodies that attack the sugar molecules that coat pig blood-vessel tissue.
• Significant immunosuppressive therapy is still needed to reduce other types of host immune reaction against the pig pancreatic cells. But Reisner claims that this is at the level typically seen in transplant medicine--even though the researchers report that both animals died from infections and drug toxicity a year after their transplants. He adds that there is scope for further reducing the amount of therapy required. "We're fine-tuning things to reduce the levels of toxicity," he says. "The important thing is that we set out to show that a pancreas could be grown this way, and that it could correct the uncontrolled glucose levels caused by diabetes, which is what we've done."
• Reisner believes that the technique could eventually help humans with the same condition. Human-to-human pancreatic transplants have been shown to be effective, but a lack of donors severely limits the number of such treatments available.
• Other approaches to reversing type 1 diabetes are also emerging. Of particular interest are methods that seek to reprogram a patient's immune system to stop it from attacking the pancreas. Recently, it was reported that destroying pancreas-killing immune cells and replacing them with a patient's own stem cells can help her gain control over blood-sugar levels.

• A more extreme approach is to completely wipe out a diabetic's immune system and rebuild it using his bone-marrow stem cells--a strategy that has raised some safety concerns.

• "This is an interesting approach that seeks to avoid transplants," says Reisner. "It could work if used early on in the disease, while the patient still has some pancreatic tissue. But later on, when all the beta cells are destroyed, an alternative approach like ours might have to be used."

Narcolepsy: A Case of the Body Attacking Itself?

http://sciencenow.sciencemag.org/cgi/content/full/2009/504/2?etoc

By Gisela Telis ScienceNOW Daily News 4 May 2009

• The millions of people who suffer from narcolepsy might have their immune system to blame. Researchers have tied the disabling sleep disorder to two immune system genes, suggesting that it's an autoimmune disease. The discovery may eventually lead to improved narcolepsy treatments.

• Narcolepsy affects 1 in every 2000 people, making it about as common as multiple sclerosis. The disorder encompasses an odd constellation of symptoms, including overwhelming daytime drowsiness, uncontrollable sleep attacks, and cataplexy, a sudden loss of muscle tone after an intense emotional outburst, like a good laugh. Sufferers rely on a mix of stimulants and sleep-suppressing drugs to control the disorder, but no cure exists.

• Emmanuel Mignot, a sleep researcher with the Stanford University School of Medicine in Palo Alto, California, has been studying narcolepsy for more than 20 years. In the late 1990s, his team discovered that narcoleptics lack hypocretin, a hormone produced by a few brain cells that helps keep people and animals awake. In narcoleptic patients, the mechanism that makes the hormone is intact, but the cells are missing, suggesting that something destroys them.

• Narcoleptics are also likely to have a specific variant of the human leukocyte antigen. HLA instigates the body's immune response by presenting fragments from pathogens to the immune cells, which in turn fight the pathogens off. Most autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are associated with specific HLAs. Although later studies found no further evidence of an immune link, the coincidence made Mignot and many other sleep researchers suspect that an autoimmune attack was ravaging narcoleptics' hypocretin-producing cells.

• To test the idea, Mignot teamed with Stanford geneticist Joachim Hallmayer and a network of colleagues spanning three continents. The researchers analyzed DNA from nearly 4000 participants, all of whom shared the same narcolepsy-linked HLA but only about half of whom had narcolepsy. They found that the narcoleptics in the study shared a version of another gene that tells T cells--the immune cells that destroy intruders--how to react to the pathogens that HLA molecules bring them. The result indicates that T cells and HLA, which together regulate much of the body's immune response, gang up in a unique way to destroy narcoleptics' hypocretin cells, the team report online this week in Nature Genetics.

• The study doesn't explain why T cells target the hypocretin cells specifically, says Mignot. It also sheds no light on what triggers the attack in the first place, a mystery for most autoimmune diseases. "We don't know why bodies go haywire and start attacking themselves," he says. But Mignot hopes future studies will reveal the culprit. In the meantime, knowing the autoimmune trigger could lead to new and more effective treatments for narcolepsy, he says.

• "We've known for years that narcolepsy is probably an autoimmune disease, but every attempt to prove it has turned up nothing," says Michael Silber, a neuroscientist with the Mayo Clinic in Rochester, Minnesota. "This study doesn't conclusively prove narcolepsy is autoimmune, but it's a major step in that direction."