Do worms protect us against autoimmune diseases? The epidemiological evidence is strongly suggestive. Ethiopian, Brazilian, Venezuelan, and Gambian adults have less asthma when infected with nematodes; Gabonese schoolchildren with schistosomiasis have fewer allergic reactions to dust mites than do those who are not so infected, and children living on farms in Germany have fewer allergies than children living in cities (Wilson & Maizels 2004). One of the most debilitating autoimmune diseases, multiple sclerosis, is virtually absent in Roma, Inuit, and Bantu, is rare in the indigenous peoples of the Americas and Asia, and is rare in the tropics generally. And in the developed world, some form of allergy now afflicts almost half of those living in industrialized societies (Holgate 1999); serious immune-mediated diseases occur in 3 to 5% of the US population (Jacobson 1997); and allergic and autoimmune diseases have increased strikingly in the last 50 years (Bach 2002, Gale 2002). Civilization has apparently flipped a switch in our immune systems. We are in the middle of a pandemic of autoimmune diseases (Fig. 1; from Bach 2002).
The Hygiene Hypothesis (Liebowitz et al. 1966, Strachan 1989) suggests that this pandemic is an unintended consequence of the cleanliness of modern civilizations caused by the elimination of parasitic worm infections. There are alternatives: both viruses and Chlamydia have their advocates. Is it specifically worm infections that protect us against autoimmune disease? Some support comes from clinical studies. Treatment with sterilized eggs of pig whipworms (Trichuris suis) administered in doses of 2500 eggs twice a week for 12 weeks led to improvement in 43% of patients with ulcerative colitis (Summers et al. 2005a); doses of 2500 eggs once every three weeks for 24 weeks led to improvement in 72% of patients with Crohn’s Disease (Summers et al. 2005b). Pig whipworms are the worm of therapeutic choice because they elicit reactions in the human immune system without establishing debilitating infections (Summers et al. 2003).
Now, a well-controlled prospective study of patients with multiple sclerosis indicates that infection with intestinal worms protects against the advancement of that disease as well. Correale and Farez (2007) identified 12 MS patients with recent worm infections, matched them with 12 MS patients who did not have worm infections, and recruited 12 healthy individuals as additional controls. They then followed all 36 individuals for 4.7 years, measuring them regularly with MRI scans for brain lesions, with behavioral tests, and with tests for presence of intestinal worms. None of the 24 originally uninfected patients acquired worms during the observation period: they remained good controls. The results were striking. MS patients with worm infections developed symptoms very, very slowly, whereas MS patients without worm infections progressed much more rapidly to serious disease (Fig. 1 from Correale and Farez (2007)).
Convinced by these results and others, the National Multiple Sclerosis Society has funded an MRI-controlled phase 2 study of helminth therapy for MS using pig whipworm eggs. One of the nastiest of the autoimmune diseases may be coming within the reach of a most surprising therapy.
Why might a parasitic worm want to manipulate the human immune system? Parasitic worms face daunting transmission problems and must survive for long periods in their vertebrate hosts to achieve reproductive success. They evolved methods of reducing the inflammatory response of their host’s immune system, in part mediated by regulatory T cells, to avoid being killed by it. Regulatory T cells are conspicuous by their absence in autoimmune patients; worm infections appear to restore them to normal levels. Once worms had evolved the ability to persist in their hosts and produce chronic infections, their hosts co-evolved to further reduce the debilitating inflammatory responses elicited by the worms, which had become predictable parts of the environment that could no longer be avoided. Both partners in the host-parasite interaction changed. Then, when modern hygiene eliminated the worms, our immune system was left with inappropriate reactions to the sudden lack of a chronic stimulus. Those inappropriate responses include, but are almost certainly not limited to, a decline in the production of regulatory T cells and associated attacks by the immune system on our own tissues, be they the myelin sheaths of nerve axons (in MS), the Islets of Langerhans in the pancreas (in insulin-dependent diabetes), or the lining of our gut (in Crohn’s disease and other types of inflammatory bowel disease).
Florence Nightingale saved thousands of lives by cleaning up the British hospitals in the Crimean War, and Ignaz Semmelweis did immense good by promoting antiseptic practice in the maternity hospitals of 19th century Vienna. Their message, that hygiene saves lives, may have had an unintended consequence when generalized outside the hospital to entire lifestyles, and may have resulted in a pandemic of autoimmune diseases. It has taken 150 years to realize that while a lot of dirt is bad for us, a little bit of the right kind might be most helpful.
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