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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).

From: Bach, JF. 2002. N. Engl. J. Med. 347: 911-931
From: Bach, JF. 2002. N. Engl. J. Med. 347: 911-931

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)).

From: Correale J, and Farez, M. (2007) Ann. Neurol. 61 (2): 97–108
From: Correale J, and Farez, M. (2007) Ann. Neurol. 61 (2): 97–108

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.

Literature cited

Bach, JF. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. New England Journal of Medicine 347: 911-931. PMID 12239261

Correale J, Farez M. 2007. Association between parasite infection and immune responses in multiple sclerosis. Annals of Neurology 61 (2): 97–108. PMID 17230481

Falcone FH, Pritchard DI. 2005. Parasite role reversal: worms on trial. Trends Parasitol. 21 (4): 157–60. PMID 15780835

Fleming J, Fabry Z. 2007. The Hygiene Hypothesis and Multiple Sclerosis. Annals of Neurology 61: 85-89. PMID 17315205

Gale EA. 2002. The rise of childhood type I diabetes in the 20th century. Diabetes 51: 3353-3361. PMID: 12453886 (Journal Full-text)

Holgate ST. 1999. The epidemic of allergy and asthma. Nature 402 (suppl 1) : B2-B4. PMID 10586888

Jacobson DL, Gange SJ, Rose NR, Graham NM. 1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clinical Immunology and Immunopathology 84: 223-243. PMID: 9281381

Leonardi-Bee J, Pritchard D, Britton J. 2006. Asthma and current intestinal parasite infection: systematic review and meta-analysis. American Journal of Respiratory and Critical Care Medicine 174: 512–523. PMID 16778161(Journal Full-text)

Liebowitz U, Antonovsky A, Medialie JM, et al. 1966. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. Journal of Neurology, Neurosurgery and Psychiatry 29: 60-68. PMID: 5910580 (PMC Full-text)

Strachan D.P. 1989. Hay fever, hygiene, and household size. BMJ 299 (6710): 1259-1260. PMID: 2513902 (PMC Full-text)

Summers RW, Elliott DE, Qadir K, Urban JF, Thompson R, Weinstock JV. 2003. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Amerian Journal of Gastroenterology 98 (9): 2034–41. PMID 14499784

Summers RW, Elliott DE, Urban JF, Thompson RA, Weinstock JV. 2005a. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 128 (4): 825–32. PMID 15825065

Summers RW, Elliott DE, Urban JF, Thompson R, Weinstock JV. 2005b. Trichuris suis therapy in Crohn’s disease. Gut 54 (1): 87–90. PMID 15591509 (PMC Full-text)

Wilson, M.S. and Maisels, R.M. (2004). Regulation of allergy and autoimmunity in helminth infection. Clinical Reviews of Allergy and Immunology 26: 35-50. PMID 14755074

One Response to “Pig worms and multiple sclerosis: the unintended consequences of hygiene”

  1. Graham Rook says:

    MICROBES, EVOLUTION and CHRONIC INFLAMMATORY DISORDERS

    Stephen Stearns highlights the fascinating epidemiology that links our changing microbial environment to the increase in multiple sclerosis (MS) in developing countries, and the “experiment of nature”, in which disease progression was seen to stop in a subgroup of MS patients in Argentina who developed untreated helminth infections (Correale and Farez 2007). These individuals developed circulating regulatory T cells that suppressed lymphocyte responses to a peptide derived from human myelin. Thus the mammal-helminth interaction has evolved the ability to do two things: first, it drives immunoregulation that suppresses the inevitably unsuccessful, pointless and harmful response to the established helminth itself: secondly, the helminth acts as a “regulatory cell adjuvant”. That is to say, in the presence of helminths the immune system is persuaded to simultaneously increase the regulatory response to other antigens not derived from the helminth. In the Argentinian study the helminths drove regulatory cells that recognised myelin. (Incidentally, Correale et al do not attribute the effect to any particular helminth. Whipworm has been used in studies of inflammatory bowel disease in man, but there are also plans to use hookworm for clinical trials in MS and in allergic disorders (Mortimer et al. 2006). The relative efficacy of different helminths is unknown).

    One of the suggested mechanisms involves modulation of the function of dendritic cells (Rook 2007). These cells determine whether aggressive or regulatory lymphocytes are activated in response to antigens. Components of the helminths are recognised by the dendritic cells as being derived from organisms that are harmless or that must be tolerated, so a regulatory response is initiated. However such modified dendritic cells also process other antigens from the gut, airways and self, and so indirectly drive regulatory responses to the target antigens of the various chronic inflammatory disorders (inflammatory bowel disease, allergies and autoimmunity) that are increasing in developed countries. From a Darwinian point of view the hypothesis is that the presence of certain organisms, that we have called “Old Friends”, is now a physiological necessity for priming the appropriate level of immunoregulation. So are these effects all due to helminths? And are they all due to modulation of dendritic cell function? The answer to both questions is no, as discussed in the next paragraph.

    A little more history leads to a further broadening of these concepts. The earliest hint of the “hygiene hypothesis” of which I am aware comes from a book written by Charles Harrison Blackley in 1873 (Blackley 1873). He observed that hay fever was increasing in rich educated city dwellers but was rarely seen in farmers; (it became rather snobbish and prestigious to have hay fever!). This effect has been re-discovered in rigorous modern studies. Notably, contact with cow sheds in early life protects strongly from allergies (Riedler et al. 2001). What organisms and mechanisms have been implicated? Several groups are trying to identify the beneficial components of the cow shed environment. Meanwhile animal models and preliminary clinical studies show that in addition to helminths there are other “Old Friends”, such as saprophytic mycobacteria (ubiquitous in mud and untreated water) and lactobacilli involved in fermentation (or in rotting vegetable matter before the advent of the refrigerator). All of these can operate via the dendritic cell pathway described above (Discussed in Rook 2007).

    However other organisms and mechanisms have also been implicated. Infection with hepatitis A virus (HAV), which was almost universal until about 1970, but is now sporadic or rare, appears to modulate the balance of regulatory cells to effector cells via a different mechanism. It turns out that the receptor for HAV on the cell surface, known as TIM-1, is involved in the regulation of T lymphocyte differentiation, and the “normal” balance of certain subsets of effector cells to their corresponding regulatory cells may be exceeded in modern individuals who no longer get this infection (McIntire et al. 2003).

    Finally, it has been known for many years that the gut flora are involved in driving immunoregulation (Kohashi et al. 1985; Sudo et al. 1997). Now oral administration of a single polysaccharide from the intestinal symbiont Bacteroides fragilis has been shown to partially restore regulation of inflammation in mice devoid of gut microbiota (Mazmanian et al. 2008).

    In conclusion, we should not consider autoimmunity and helminths in isolation. There are several groups of organisms that modulate immunoregulation, and experimentally, when they have been tested, they all seem to operate in models of all the types of chronic inflammatory disorder that are increasing in the modern world. There seems to be a basic principle emerging; mammalian evolutionary history has led to a situation where the establishment of appropriate levels of immunoregulation is driven by the presence of organisms that are harmless or must be tolerated, and so act as signals for regulatory rather than aggressive responses. Many of these organisms are depleted from the modern environment. The term “hygiene hypothesis” is turning out to be a bad one. Domestic hygiene is not really the issue. The “Old Friends” are depleted by major changes of lifestyle, many of which pre-date modern hygiene, so “Old Friends” hypothesis might be a better term.

    References

    Blackley, C. H. (1873). Experimental Researches on the Causes and Nature of Catarrhus Aestivus (Hay-fever and Hay-asthma). London, Baillière Tindall and Cox.

    Correale, J. and M. Farez (2007). “Association between parasite infection and immune responses in multiple sclerosis.” Ann. Neurol. 61(2): 97-108. PMID: 17230481

    Kohashi, O., Y. Kohashi, T. Takahashi, A. Ozawa and N. Shigematsu (1985). “Reverse effect of gram-positive bacteria vs. gram-negative bacteria on adjuvant-induced arthritis in germfree rats.” Microbiol. Immunol. 29: 487-497. PMID: 2931580

    Mazmanian, S. K., J. L. Round and D. L. Kasper (2008). “A microbial symbiosis factor prevents intestinal inflammatory disease.” Nature 453(7195): 620-5. PMID: 18509436

    McIntire, J. J., S. E. Umetsu, C. Macaubas, E. G. Hoyte, C. Cinnioglu, L. L. Cavalli-Sforza, G. S. Barsh, J. F. Hallmayer, P. A. Underhill, N. J. Risch, G. J. Freeman, R. H. DeKruyff and D. T. Umetsu (2003). “Immunology: hepatitis A virus link to atopic disease.” Nature 425(6958): 576. PMID: 14534576

    Mortimer, K., A. Brown, J. Feary, C. Jagger, S. Lewis, M. Antoniak, D. Pritchard and J. Britton (2006). “Dose-ranging study for trials of therapeutic infection with Necator americanus in humans.” Am. J. Trop. Med. Hyg. 75(5): 914-20. PMID: 17123987

    Riedler, J., C. Braun-Fahrlander, W. Eder, M. Schreuer, M. Waser, S. Maisch, D. Carr, R. Schierl, D. Nowak and E. von Mutius (2001). “Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey.” Lancet 358(9288): 1129-1133. PMID: 11597666

    Rook, G. A. (2007). “The hygiene hypothesis and the increasing prevalence of chronic inflammatory disorders.” Trans. R. Soc. Trop. Med. Hyg. 101(11): 1072-4. PMID: 17619029

    Sudo, N., S. Sawamura, K. Tanaka, Y. Aiba, C. Kubo and Y. Koga (1997). “The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction.” J. Immunol. 159: 1739-1754. PMID: 9257835

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